Organic Chemistry

Organic Chemistry
有机化学双语教学
授课教案
王 梅
大连理工大学
Organic
OrganicChemistry
Chemistry
Chapter 1 Chemical Bonds
Textbook: Joseph M. Hornback, University of Denver
About lectures: Bilingual
„
Reference books:
1. Organic Chemistry – Written by R.T. Morrison
and R.N. Boyd
2. Organic Chemistry – Written by L. G. Wade, JR.
3. Organic Chemistry – Written by T. W. G. Solomons
and C. B. Fryhle
4. Organic Chemistry – Written by John McMurry
5. 有机化学 - 高占先主编（“十一五”国家级规划教材）
高等教育出版社
6. 基础有机化学－ 邢其毅等人，人民教育出版社
„
1.1~1.2 Introduction
„
1.3 The structure theory of organic chemistry
„
„
Organic chemistry is the study of organic compounds.
Organic compounds are the compounds of carbon.
In organic compounds: C-C C-H C-N C-X (halogen, 卤素)
C-O C-S C-P C-B C-Si
O
made by a German chemist,
NH4OCN
H2N-C-NH2 Friedrich Woehler, in 1828
△
„
„
ammonium cyanate
urea
（尿素）
(氰酸铵)
ammonium (cation) -- 铵, NH4+, e.g. NH4OH, NH4Cl
ammonia -- 氨, NH3
~hydroxide, ~chloride
amine -- 胺, RNH2, R2NH, R3N
„
Saturated and unsaturated bonds
Chemical bond – binding force between two atoms
Valence (化合价) – the capability of an atom to combine
C O
C
with atoms
O
C
N
S
C
single bond
tetravalent divalent
trivalent
C C
C N
X (F,Cl,Br,I)
H
C N
C C
univalent
Prefix used in organic chemistry:
mono- or uni-; di- or bi- or bis-; tri-; tetra-; penta-; hexa-; hepta-;
octa-; nona-; deca-; undeca-; dodeca-; trideca-; … icosa-
double bond
saturated bond
triple bond
unsaturated bond
Empirical formula, molecular formula and structural formula
■
EF: CnH2n+2 CnH2n CnH2n-2 CnH2nO
CnH2n+2O
MF: C4H10… C5H10… C4H6… C3H6O… C2H6O
SF: C4H10:
C
C C C
C-C-C-C
C
C=C-C-C
O
C C C
C C C C
C
O
C O C
O
C C C H
C C OH
¾
C
C
C
C C C C
C
C
C2H6O:
C
C-C-C=C
C
C-C=C-C
C C C C
¾
C-C=C-C-C
C=C-C-C-C
C3H6O:
¾
¾
C5H10:
C4H6:
1.6 The representations of structural formulas
C
C
a. Dot formula – Lewis structure
b. Dash formula
c. Condensed formula
d. Bond-line formula
e.g. C3H8O (2-propanol):
H
H H H
.. H
.. H
..
H:C:
H C C C H
.. C:H
..
.. C:
H :O
.. : H
H OH H
H
dot formula
dash formula
CH3CHCH3
OH
OH
CH3CH(OH)CH3
condensed
formula
bond-line
formula
1
1.4, 1.5, 1.10 and 1.12 Chemical bonds and dipole moments
C3H6 (cyclopropane):
CH2 CH2
(偶极矩)
CH2
á
C6H12 (2-methyl-2-pentene):
(CH3)2C=CHCH2CH3
á
e. Three-dimensional formula (CH2FCH2F)
A—B
Ionic bond—the bond formed between two atoms with
different electronegativity (电负性) (△EN =∣ENA –
ENB∣≥1.7)
Covalent bond—the bond formed between two atoms
with the same or similar electronegativity (△EN<1.7)
e.g.
hold on
H4
H3
2H
C
C
1H
C
C
F
1H
F
H4
F
F
covalent bond:
H3
1H
H3 hold on
F
2H
ionic bond:
e. positive e. negative
C
C
F
H4
2H
H
H C H (Methane)
⊕ ..
Na . Cl
.. :
...
0.9
3.1
μ= 0
Br
H
Covalent bonds:
1) Non-polar covalent bond--the bond formed between two atoms
with the same or almost the same electronegativity (0≤△EN<0.6)
C—C
C—H
H—H
2) Polar covalent bond--the bond formed between two atoms with
similar electronegativity (0.6 ≤ △EN < 1.7)
C—O
Polar covalent bond:
partial e. positive
H—Cl
e.g.
total µ
Br
μ= 0
vector
sum
δO
+
+
δ
δH ╰╯
105 H
+
δH
δN
δ- δ + δO=C=O
total µ vector
sum
H
+
Hδ
partial e. negative
δδ
H . Cl
.. :
+ ..
H
μ = (e)(d)
Cl
Dipole Moment
e – the amount of charge separation
(μ, vector, unit: D-debye)
d – the distance of the charge separation 1 D = 3.336 × 10−30 C⋅m
(coulomb meter)
e.g.
CH3
CH3 N CH3
:O:
..
(trimethylamine oxide)
8
FCN= 5 - 2 = +1
FCO= 6 -( 2 + 6 ) = -1
2
FCM = + 1 - 1 = 0
1.7 and 1.8 Formal charges
The Formal Charge of each atom in a molecule is equal to :
group number of atom –
( number of shared es + number of unshared es)
2
ClO4- (perchlorate ion)
..
:O:
..
..
:O
FCO = 6 - 2 - 6 = -1
.. Cl O
.. :
2
:O
.. :
FCCl = 7 - 8 = +3
2
FCM = 4×(-1) + 3 = -1
2
1.9, 3.7~3.9 and 4.9 Resonance effect (共振效应)
CO32-
(carbonate ion)
Lewis structure:
C
..
:O
..
..
O:
:O
.. :
.. C
:O
..
..
:O :
A
C
O
.. :
:O
..
B
theory:
1) Resonance structures differ with each other only in positions
of electrons which are in conjugated p orbitals, without
changing the relative position of the atomic nuclei.
2) The real molecular or ionic structures are better represented
by a hybrid of all possible resonance structures.
e.g.
2
δO 3
1
C13
2
Oδ - 2
- δO
3
3
..
O
.. :
..
:O:
C
:O
.. :
™ Resonance
..
:O
..
O
.. :
C
hybrid structure
Resonance structures (π−electron delocalization)
3) Resonance effect results in the stabilization of a molecule or an
ion.
O
O
+
e.g. C6H5O- (phenoxy)
2) Each resonance structure must have the same number of
electrons and the same total charge, the same unpaired
electrons.
O
O
.
CH2 CH CH CH2
O
5 important rules for writing resonance structures:
1) In drawing resonance structures, the nuclei of atoms may not be
moved, only electrons in conjugated p orbitals may be moved.
3) The relative stability of resonance structures can be judged by
the following factors: the octet rule, the number and location of
formal charges, and the interactions between charges in the
structure.
+
Conjugated p orbitals: adjacent, parallel p orbitals
4) The actual structure resembles the most stable resonance structure.
5) The resonance stabilization energy increases as the number of
important resonance structures increases.
+
+
+
CH2 CH CH2 CH2
CH2 CH CH CH3
CH2 CH CH CH3
2
+
+
+
1
3
CH2 CH CH CH2
.
.
CH2 CH CH CH2
..
+
+
CH2 N N :
CH2 N N:
diazomethane
2
1
重氮甲烷
.. ..
CH2 N N :
CH2 N N:
3
4
Chapter 2 Organic Compounds - A First Look
2.1~2.3 Brief introduction of hydrocarbons
„
Hydrocarbons – alkanes, alkenes, alkynes and arenes
1. alkane (C-C and/or C-H single bond, saturated
compound):
{
chain alkanes (CnH2n+2) C2H6,C3H8
cycloalkanes(CnH2n)
, ,C5H10,C6H12
e.g. C2H6:
(ethane)
H
H
C
H
H
C
H
H
3
internal olefins (CH3CH=CHCH3)
2. alkene (olefin, C=C double bond, unsaturated compound):
{
linear olefins terminal olefins (CH2=CHCH2CH3)
(alkenes)
chain alkenes
branched olefins (internal and terminal)
(alkenes)
C
C
C−C=C−C C=C−C−C
chain alkenes (CnH2n) C2H4,C3H6...
cycloalkenes(CnH2n-2) C5H8
, C6H10
H
H
C2H4:
(ethene)
H
H
H
Cl
Cl
H
C C
H
C C
Cl
C C
3. alkyne (C≡C bond, unsaturated compound):
H
Cl
Cl
Cl
H
cis-1,2-dichloro trans-1,2-dichloro
ethene
ethene
H
Cl
C C
H
H
H
no cis/trans isomers
4. arene—aromatic hydrocarbons, e.g. benzene (苯),
naphthalene (萘), anthracene (蒽), phenanthrene (菲) …
„
chain alkynes(CnH2n-2) C2H2,C3H4,..
C C
Bond length and bond energy of hydrocarbons
„ Bond length: the distance between the nuclei of two
bonded atoms.
„ Bond dissociation energy (D): the amount of energy
required for homolysis of a covalent bond.
„ Bond energy ( D): the average value of bond
dissociation energy in a molecule.
internal alkynes (H3CC≡CCH3)
terminal alkynes (CH3CH2C≡CH)
For binuclear molecules: H2, Cl2 D = D
For multinuclear molecules:
D (CH4) = (D1+D2+D3+D4)/4
bond length: sp3
sp2
sp
C−C > C=C > C C
2sAO(25%) 2sAO(33%) 2sAO(50%)
C-H bond energy ( D):
CH3CH3 < CH2=CH2 < HC CH
C(sp3)-H < C(sp2)-H < C(sp)-H
2.5 Degree of unsaturation (The index of hydrogen
deficiency)
degree of unsaturation (DU, the total number of multiple
bonds and rings)
DU =
C6H8:
(2N C +2) - (N H )
2
the total number of H in
the molecule
the number of H for the saturated compound
DU =
2× 6+2-8
=3
2
C6H8
cat. H2
3H2
C6H14
2H2
C6H12
C=C−C=C−C=C
If DU = the consumed molar amount of H2, no ring exists in
the molecule.
If DU > the consumed molar amount of H2, there are n rings in
the molecule.
n = DU – the actually consumed molar amount of H2
4
2.6, 2.7, 4.7 Physical properties and molecular structures
Some other examples:
◆
CH2=CHCH2Cl DU =
2× 3+2-(5+1)
=1
2
HC C-O-CH3 DU =
2× 3+2-4
2
HC C-N-CH3 DU =
H
=2
2× 3+2-5+1
=2
2
Forces that act among molecules and ions
i. ion-ion force
ii. dipole-dipole force
µ
H
H
H +
δ δ− H δ+ δ− H δ+ δ−
H C
C Cl ...... C Cl
Cl ......
H
H
H
iii. London force (色散力，instantaneous dipole, induced dipole)
Factors which determine the magnitude of London force are as
follows:
a. polarizability – e.g. radius of atom: F < Cl < Br < I
b. the surface of a molecule
◆
iv. Hydrogen bonds (N, O, S, F, Cl, Br)
e.g.
δ−
δ+ F +
δ
F
H
H δ− H
δ−
H
F
F
Main factors that influence b.p. of organic compounds
i. The weight of molecules
CH4
C2H6
C3H8
b.p.
-162℃
-88℃
-42℃
ii. The polarity of molecules
Cl
R
R
O
H
H
H
O
R
O
H
R
µ
C==C
Cl
C==C
H
H
larger dipole moment
b.p. 60.5 ℃
O
b.p.
H
Cl
Cl
µ =0
H
47.7 ℃
CH2FCH2F < CH3CHF2
iii. The surface of molecules
CH3
b.p. CH3CH2CH2CH2CH3 >CH3 C CH3
CH3
iv. H-bonds
C2H6O:
CH3CH2OH
H-bond
78℃
CH3OCH3
no H-bond
-25℃
H
b.p.
C
O
H C
Oδ
H
δ+
>
O
OH
forming intermolecular forming intramolecular H-bond,
no intermolecular H-bond.
H-bond
C5H10O
<
O b.p.
88℃
OH
140℃
5
Main factors that influence m.p. of organic compounds
◆ all above-mentioned factors
◆ symmetry of molecules
◆ rigidity of molecules
e.g.
◆
C
C
C C OH C C C C OH C C C OH
C
>
symmetry
>
m.p. 25℃
-90℃
-108 ℃
surface 3
1
2
b.p. 82.5
117.7
108.0
A functional group is the part of a molecule where most
of its reactions take place.
e.g.
-OH -NH2 -CHO -COOH
hydroxy amino formyl carboxy
◆
(氨基) (甲酰基)
(羧基)
Some important prefixes and words used in organic
chemistry
C
C
neo-( 新 ) C C C neopentane C C C neopentyl
C
C
sec-( 仲) C-C-C-C
sec-butyl
CH3—Me; C2H5—Et; C3H7—Pr; C4H9—Bu;
n-Bu
C-C-C-C-
i-Bu
C
C-C-C-
CH2 CH2 CH3CH2CH3
rigidity
>
m.p. -126.6
-189.9℃
℃
◆
Solubilities
Like dissolves like.
hydrophobic hydrophilic
lipophobic
lipophilic
n—normal (正）
2.8 Functional groups
(羟基)
CH2
t-Bu sec-Bu
C
C-C- C-C-C-C
C
CH3CH2CH2CH2CH3
CH3CH2CH2CH2CH2
n-pentane
n-pentyl
i—iso- (异）
C
C C C C
C
C C C C
isopentane
isopentyl
t—tert- (叔）
C
C C
C
tert-butyl
primary carbon(1) CH3CH3 .
伯碳
secondary carbon(2 ) C-C-C
C
仲碳
tertiary carbon(3 )C-C-C
叔碳
C
quaternary carbon(4 C
) -C-C
季碳
C
6
Alkanes: methane, ethane, propane, butane, pentane,
hexane, heptane, octane, nonane, decane,
undecane, dodecane, …nonadecane, icosane
phenyl groups
alkyl groups – methyl…decyl…(omit “-ane”, add “-yl”)
◆
烷基
alkenyl groups R2C=C
R1
(omit “-e”, add “yl”)
烯基
(CH2=CH- vinyl; CH3CH=CH- 1-propenyl 丙烯基)
( -CH2CH=CH2 3-propenyl allyl 烯丙基)
alkynyl groups – RC C
炔基
(omit “-e”, add “yl”)
(HC C , acetylenyl; CH3C C , 1-propynyl)
suffix (as a functional group in trivial names, only
for small molecules C1~C4)
F fluoride
Cl chloride
Br bromide
I iodide
CH3CH2Br
bromoethane
ethylbromide
CH3CHCH3
I
2-iodopropane
isopropyliodide
Brief introduction of functional groups
systematic name (IUPAC)
trivial name
1) Haloalkanes (alkyl halides)—RX (卤代烷)
prefix (as a substituent in systematic names)
F fluoroCl
Cl chloroCH3(CH2)5CHCH3
Br bromo2-chlorooctane
I iodo-
2) Alcohols—ROH
as a substituent
OH hydroxyOH
primary
alcohol
OCH3
C-C-C-C
sec-butyl methyl ether
2-methoxybutane
▲
as a functional group
suffix: -ol
OH
CH3CH2CHCOOH
2-hydroxybutanoic acid
C-C-OH
3) Ethers – ROR
-OR alkoxyOCH3
C-C-C-COOH
2-methoxybutanoic acid
CH2 苄基
benzyl groups
CH3CH2CHCH3
2-butanol
C
C-C-OH
C
OH
C-C-C
secondary
alcohol
tertiary
alcohol
4) Amines RNH2, RR’NH, RR’R”N
ether
NH2
C-C-O-C-C
primary amine
(di)ethyl ether
secondary amine Me2NH
C-C-O-C
C
C
(2-ethoxypropane)
ethyl isopropyl ether
The italic prefix sec, tert and di, tri…should not be
considered, but the prefix iso, neo should be considered.
tertiary amine
_ NH amino_
2
C
C-C-C-C-C-N-C
C-C-C-C
Et3N
2-butylamine
dimethylamine
triethylamine
Suffix:
_ amine
dimethylaminopentane
N,N-dimethylpentylamine
7
5) Aldehydes—RCHO
6) Ketones
RCOR’
Suffix:
O
C
R C
formyl
H （甲酰基）
al
H
carbaldehyde
H
butanal
cyclohexanecarbaldehyde
7) Carboxylic acids— RCOOH
Suffix:
-(o)ic acid
COOH carboxy-
RCOOH
-carboxylic acid
Suffix:
amide
O
RC
NH2
O
carboxamide
O
O
R C OH HO R C
2
O
OH △ R C
R C
O
O
C C
O
N,N-dimethylbutanamide cyclopropane
carboxamide
Suffix:
RCOOR'
carboxylate
ethyl butanoate
O
C-C C
isopropyl cyclopentanecarboxylate
O
11) Acyl halides R C X (酰卤)
Suffix:
(o)ic anhydride
C-C-C C
O
C
C O C
C
O
C-C-C-C OC C
O
10) Carboxylic anhydrides— RC-O-CR' (酸酐)
O
O
C NH2
cyclohexanecarboxylic acid
carbamoyl
Suffix:
苯乙酮
O
C-C-C C NMe2
O
C-C-C C NH2
butanamide
O
O
O
C-C-C-C-C
CCH 3
H
methyl phenyl ketone 3-oxopentanal
COOR' alkoxycarbonyl
O
8) Amides— RC NH2
C C
suffix: -one
or the word “ketone”
(o)ate
C-C-C-COOH
butanoic acid
O
C-C-C-C-C
3-pentanone
(diethyl ketone)
oxo-
C=O
9) Ester –RCOOR’
COOH
O
C NH2
RCOR
CHO
O
C-C-C C
carbonyl
C=O
O
O
O
O
ethanoic anhydride butanoic propanoic anhydride
butyric propionic anhydride
acetic anhydride
O
RC F -oyl fluoride
O
-oyl chloride
RC
Cl
O
-oyl bromide
RC
Br
O
RC I
-oyl iodide
O
C
F
benzoyl fluoride
O
C-C-C-C
Cl
butanoyl chloride
8
Additional paragraph 1. Brief introduction of classification
of organic reactions, intermediates and reagents
■ Classification of organic reactions
◆ concerted reactions
X Y
A B
"X Y "
ionic reactions
X Y polar
+
X : +Y
+
solvents intermediate
Y
X
A
A B
transition state
◆ radical reactions
X
◆
B
X Y polar
+
X + Y:
solvents intermediate
heterolytic cleavage---heterolysis (异裂）
hν or
Y or peroxides X . + Y.
intermediate
homolytical cleavage---homolysis（均裂）
„
„
Classification of organic intermediates
The most important intermediates in organic reactions
are carbocations, carbanions and carbon free radicals.
.. sp3
C
+ σ
σ C 120
+
empty p
σ
carbocation—sp2
C.
C:
C+
σ C
120
p
carbon free
radical sp2
carbanion—sp3
Chapter 3 Orbitals and Valence Bond Theory
The shapes of AOs
„
+
_
s--sphere (positive phase sign)
px, py, pz--two lobes (one
with a positive phase sign,
and another with a negative
phase sign)
+
The energy of atomic orbitals
1s < 2s < 2px,py,pz < 3s < 3px,py,pz
(degenerate orbitals, 简并轨道)
N-bromosuccinimide---NBS
溴代丁二酰亚胺
σ
σ
~109
3.2 Atomic orbitals (AO)
„
Classification of organic reagents
◆ radical reagents:
O
e.g. peroxides (R-O-O-R), RC OOH , H2O2
azo (偶氮) compounds R N=N R'
◆
O
NBr
O
ionic reagents:
i. electrophilic reagents: cation (H+,Y+), electron deficient Lewis
acids (AlCl3, BH3, BF3…)
ii. nucleophilic reagents:
anion
..
.. (OH , OR , Y ), electron rich
Lewis bases ( NH3 , H2O : , RSH,
¨ :PR3…)
¨
„How
to fill electrons into AOs
3 principles:
i. The Aufbau principle (能量最低原理): Orbitals with
lowest energy are filled first.
ii. The Pauli exclusion principle (鲍利不相容原理)
A maximum of 2es can be placed into each
( )
orbital and the spins of the two es must be
paired.
iii. Hund’s rule (洪特规则): For degenerate orbitals, one e
should be filled to each orbital with their spins unpaired,
until each orbital has one e, then the left es can be filled
to each degenerate orbital in a way of spin paired with
the first e.
9
3.3 Molecular orbitals
e.g.
C (6e)
O (8e)
S (16e)
2p
2p
3p
2s
2s
3s
1s
1s
2p
The formation of molecular orbitals (MO)
bonding MO: 2AOs of the same phase sign overlap
with each other.
◆
+
ψ M = φA+ φ B
+
ψ *M = φ A
The type of MOs in organic compounds
σSS
+
sA
+
+
σSp
+
+ σ*pp
σpp
+
pB
important points----hybrid orbitals (杂化轨道)
the type and the shape of hybrid orbitals: sp3, sp2, sp
i. sp3---tetrahedron, 109°, single bond, 4 hybrid orbitals, each
+
πpp
+
πpp
π*pp
+
pA + pB
πpp
+
pA
pB
In CH4:
H
C H
H
H
C atom is tetravalent.
Four C-H bonds are equal.
The shape of methane is tetrahedron.
9
0
1
„
++
pB
+
π*pp
pB
3.4~3.6, 1.11, 4.8 valence bond theory and shapes
of molecules
„
++
* p
σp
A B
pB
+
pB
pA
+
ii. π bonds (double or triple bonds, shoulder to
shoulder overlap)
*
+ σSp*
Sp
+
_
σSp
+
sA
++
σpp
σSS
+
+
sB
+
σSp
+
σ*Sp sA
sB
σpp
σ*SS
++
+
_
σSS
pA
++
pA
+
i. σ bonds (single bonds, head to head overlap):
φB
σ*pp
◆
+
σpApB
pB
pA
1s
+
sA
+
antibonding MO: 2AOs of opposite phase sign overlap
with each other.
2s
σ*SS
+
hybrid orbital comprises 1/4 SO and 3/4 PO.
CH2Cl2 has no stereoisomer.
e.g. CH4 (methane)
C(6e) 2p
valence
shell(4e) 2s
promotion
ground state
sp3
hybridization
excited state
hybrid orbital
Cl
H
C
Cl
H
H
H
C
Cl
Cl Cl
Cl
C
H
H
energy: Es < Esp3 < Ep
10
H2O or R2O
O (8e, 6e in its valence shell)
other examples: NH3 or NR3
N(7e, 5es in its valence shell)
2p
2s
N
H
107
H
sp3
2s
Non-bonding e pair (lone pair es)
has larger repulsive force than
bonding electrons.
..
µ
2p
sp3
hybridization
..
H
107 H
H
H
µ
O
105 H
107
ii. sp2—triangular plane, 120°, 3 hybrid orbitals, 3 σ bonds,
O ..
O
µ
R
R
O
e.g. CH C CH (acetone)
3
3
each hybrid orbitals comprises 1/3 SO and 2/3 PO.
e.g. BF3
B (5e, 3e in its valence shell)
promotion
C 2p
2p
p (unhybridized)
sp2
promotion
2s
sp2
PZ
2s
sp2
3sp2
O
F
B
F
F
B
120
F
sp2
2p
F
F
PZ
2s
sp2
unhybridized PO
iii. sp--linear, 180°, 2 hybrid orbitals, 2 σ bonds, each hybrid
y
C
σ bond
+
σ bond
C
+
orbital comprises 1/2SO and 1/2PO.
+
σ bond
C +
+ sp2
..
+ O ..
x
sp2
e.g. BeCl2
2p
Be (4e, 2e in its valence shell)
promotion
pCl
_
pCl
Be
sp
+
H3C 119.6
+
..
C O:
+
H3C
x
+
C
π bond
_
C
unhybridized
sp
2s
PZ π PZ
+
+
C σO
p
sp
180
Cl
Be
Cl
σ bond
11
e.g.
C
CH acetylene
HC
sp
promotion
2p
p
sp
2s
sp2
sp
H+ + C +
sp sp
πY
σ
σ
+ C + +H
sp sp
H
+
+ _
_
+
+ _
_
σ
+ +PY
C
+ PY
+
C H
PZ
PZ
sp3
x
πZ
5 points worthy of note:
Normally, only the hybridization of AOs for one or two
central atoms is considered.
ii. All hybrid orbitals will form σ bonds or be occupied by
2 paired es, an unhybridized PO with one e will form a π
i.
v. AOs with one e may attend or may not attend the
hybridization, it depends on whether there is a
double or a triple bond formed by the atom.
bond.
AO’s without es will not attend the hybridization.
general, AOs with lone pair es will attend the
hybridization, but if the lone pair es are needed for
forming an aromatic ring or for gaining resonance
stabilization, they will not attend the hybridization.
..
.. p
..
H
2
3
N H N-sp
N-sp
N
N
H
R
R
R
iii.
iv.In
Chapter 4 Proton Transfer—A Simple
Reaction
◆
◆
conjugate acids and conjugate bases
O
H
A + H3O
[H2O] a constant
„
Ka =
[ A ] [ H3 O + ]
[ HA ]
pKa = -logKa
The equilibrium of an acid-base reaction always favors
the formation of the weaker acids and weaker bases.
H+
+
+ H2O
OH
acetic acid base
CH3C
+
HA + H2O
4.1~4.4 Bronsted-Lowry acid-base theory
The essence of Bronsted acid-base reactions is proton transfer. A
Bronsted acid is a proton donor, and a base is a proton acceptor.
Ka and pKa
O
+
+ H3O
O
acetate anion hydronium ion
conjugate base conjugate acid
CH3C
C6H5CO2H + OH
C6H5CO2 + H2O
H+
HC CH + NH2
acid
base
HC C + NH3
weaker
weaker
12
4.10 Tables of acids and bases (p 131)
◆
the order of acidity of the following important
compounds:
acidity: RH < RCH=CH2 < NH3 < RC CH
+
< ROH < H2O < RCO2H < H3O
4.5~4.9 Factors that determine the acidity of an organic acid
1) The atom to which the H is bonded
in a row of the periodic table: (electronegativity)
acidity: the 2nd row (sp 3)C-H < N-H < O-H < F-H
in a column of the periodic table: (radius)
basicity: R > RCH=CH > NH2 > RC C
> RO > OH > RCO2 > H2O
acidity: HF < HCl < HBr < HI
H 2O < H 2S
CH 3OH < CH 3SH
2) Inductive effect
e.g.
X-CH2COOH X = H IE = 0
X-CH2COOH X: e-withdrawing
X-CH2COOH X: e-donating(e-releasing)
e
X: electron donating groups
e
X: electron withdrawing groups:
+
-O > -COO (y ) > C(CH3)3
> CH(CH3)2 > CH2CH3 > CH3
+
NH 4, NR 4 (y+ ) > NO 2 > CN > COOH > COOR
>
>
C=O > F > Cl > Br > I > OCH
3~
OH > C CR
> CH=CH 2
e.g.
Cl3CCOOH > Cl 2CHCOOH > ClCH 2COOH > CH3COOH
3) Hydrogen bond
CH3CH2CHCOOH >CH3CHCH2COOH >
Cl
Cl
CH2CH2CH2COOH > CH3CH2CH2COOH
Cl
FCH2COOH > ClCH2COOH > BrCH2COOH > ICH2COOH
electronegativity: F > Cl > Br > I
OH
>
acidity:
C
O
H
O O
CH
H
OH
OH
Cl
CH2CH3
13
4) Hybridization
..
:O:
..
:O:
(sp3)C-H < (sp2)C-H < (sp)C-H
s25%,p75% s33%,p67% s50%,p50%
electronegativity: (sp3)C<(sp2)C<(sp)C
5) Resonance effect
e.g.
Ka=1.3 × 10
..
: OH
O
OH
-10
..
: OH
.. +
OH
+ H3O⊕
+ H2O
-18
Ka= 10
.. +
OH
..
:O
phenoxide ion
OH
OH
..
O:
..
:O
OH
O
+ H3O⊕
+ H2O
.. +
OH
general order of acidity:
RCOOH > PhOH > H 2O > ROH
separated opposite charge
Two important concepts for comparing the acidity of
compounds:
◆
e.g.
phenols
i. A substituent on the meta-position of a benzene
ring has only IE, no RE.
electronic effect
electronic effect
pKa(H2O/25℃)
OH
e-withdrawing IE
8.39
e-withdrawing IE
e-withdrawing RE
7.15
e-withdrawing IE
9.02
e-withdrawing IE
9.38
NO2
OH
e-withdrawing IE
IE e-releasing IE
e-withdrawing RE
RE e-releasing RE
NO2
OH
Cl
ii. If the negative charge on the conjugate base of an
acid can be delocalized by RE or IE, the acidity of
the acid will increase.
OH
e-releasing RE
Cl
4.11 Acid-base reactions
e.g.
phenols
electronic effect
pKa(H2O/25℃)
e-withdrawing IE
9.65
OH
OCH3
OH
9.94
OH
10.21
OCH3
氢
H(1H)
氘
D(2H)
deuterium
氚
T(3H)
H2 O
D2O
tritium
CH3CH2D
CH3CH2 Li⊕ + D2O
e-withdrawing IE
e-releasing RE
isotopes:
⊕
CH3CH2D + Li OD
acid
base
14
Additional paragraph 4.12 Lewis acid-base theory
CH3C≡CD
(electron theory of acid-base)
CH3C C Na⊕+ H2O
CH3C CH + NaOH
-
base
acid
CH3C C Na⊕+ NH3
CH3C CH + NaNH2
CH3C CD + NaOD
CH3C CNa + D2O
Chapter 5 Functional Groups and
Nomenclature I
t5.1~5.4
n+
Lewis acids: AlCl3, BF3, ZnCl2, FeCl3, SnCl4 , Y ...
..
..
..
..
Lewis bases: NH3, H2O: , R2O: , RNH2, C=C, C C,
..
n
RR'C=O: , Y ...
⊕
H3N
H3N: + AlCl3
H
RO:
.. + BF3
CH2
+ Ag⊕
CH2
H⊕
RO
.. BF3
+
+
δCH
δ
2
Ag
+
δ CH2
2) Nomenclature of branched-chain alkanes
i. Choose the longest continuous chain with the greatest
number of substituents as the parent body.
Nomenclature of alkanes
1) Nomenclature of unbranched-chain alkanes
Suffix: -ane methane ~ decane ~ nonadecane
Alkyl groups: Suffix: -yl
C-C-C-C-C-C-C
C C C
C C
C
C-C-C-C-C-C
C
C
3-methylheptane
2,3,5-trimethyl-4propylheptane
CH3-, C-C-, C-C-C-, C-C-C, C-C-C-C-,
methyl ethyl propyl isopropyl
C-C-C-C,
sec-butyl
C
C-C-C-,
isobutyl
2-methylpropyl
C
C-C
C
butyl
tert-butyl
C C C
C-C-C-C-C-C-C
C-C-C-C-C-C
C C C
2,3,5-trimethylhexane
3-ethyl-5-methylheptane
AlCl3
ii. Give the lowest position numbers for substituents.
C C
C-C-C-C-C
C
C C
C-C-C-C-C
C
2,3,3-trimethylpentane
2,2,4-trimethylpentane
5.5 Nomenclature of cycloalkanes
1) monocyclic compounds
cyclo + the name of alkane
iii. Give the first listed substituent a lower position number;
the sum of the position numbers for all sbustituents should
be as low as possible.
C-C-C-C-C-C
Cl Cl Cl
cyclopropane
2,3,5-trichlorohexane
not 2,4,5-trichlorohexane
cyclopentane cyclohexane
monosubstituted:
Cl
2,7,8-trimethyldecane
C-C-(CH2)4-C-C-C-C
not 3,4,9-trimethyldecane
C
CC
chlorocyclohexane
CH3
methylcyclopentane
15
Multi-substituted: Give the functional group the lowest
position number. The sum of position numbers for all
substituents should be as low as possible.
2) Bicyclic compounds（双环）
bicyclo[x.y.z] + the name of alkane
the number of carbon bridge, from large to small number.
1
CH
CH2
CH2 CH2
H2C
CH CH2
H2C
Cl
Cl
OH
CH 3
1-chloro-3-methylcyclohexane 3-chlorocyclopentanol
1-甲基-3-氯环己烷
9
1
5
3
1
7
8
5
4
2
2
3
4
7 6
7
3
8
3-cyclohexylcyclopentanol
8
6
6
2
bicyclo[3.2.1]octane 8-methylbicyclo- 5,6-dimethylbicyclo
[2.2.2]-2-octene
[3.2.1]octane
OH
cyclopentylcyclohexane
7
6
5
4
8
4
9 1
5
3
2
8-methylbicyclo[4.3.0]nonane
3) Spiranes（螺环）
5.6~5.7 Nomenclature of alkenes and alkynes
spiro[x.y] + the name of alkane
the number of carbon bridge, from small to large number.
8
6 5
9 1
7
4
6 5
7
2
3
8
7
8
5 4
3
1
8
2
1-methylspiro[2.5]octane
H
C
C=C C
H
C-C-C
C
trans-5,5-dimethyl2-hexene
2
9 3
1-methylspiro[3.5]-5-nonene
spiro[3.5]nonane
6
1
4
9 10 1 2
5
3
7 6 4
2-methylspiro[4.5]decane
C Ph
C-C-C C-C-C
2-methyl-1-phenyl3-hexyne
2) Cycloalkenes
1,5-cyclooctadiene
1) Simple alkenes and alkynes (containing only one
C=C or -C C-)
Suffix: -ene, -yne
Choose the longest chain that contains the C=C bond or the
C≡C as the parent body, and give the possible lower position
number to the C=C or the C≡C group.
Systematic name: ethene propene butene
Trivial name:
ethylene propylene butylene
(C2-C4 alkenes)
C
C -C=C
2-methylpropene
2-methylpropylene
isobutene
isobutylene
3) Molecules containing a few of C=C and C≡C
bonds
i. Choose the chain that contains the maximum
number of double and/or triple bonds as parent
body.
ii. Choose the chain with the greatest number of C
atoms as parent body.
H 3C
CH 3
3,5-dimethylcyclohexene
iii. Choose the chain containing the maximum
number of double bonds as parent body.
16
C-C C-C-C=C-C
C C
4-vinyl-2-hepten-5-yne
C C
C-C-C-C=C-C-C-C
C C
3,4-dipropyl-1,3-hexadien-5-yne
C C-C-C-C=C
C C 3-acetylenyl-1,5-hexadiene
C-C=C-C C
C
4-methyl-3-penten-1-yne
5.8 Nomenclature of alkyl halides (haloalkanes-RX)
Systematic name: prefix “fluoro-, chloro-, bromo-,
iodo-” + the name of alkane
Trivial name (C1-C4): the name of alkyl group +
fluoride, chloride, bromide, iodide
C-C-C
Cl
C
C-C-Cl
C
C
C-C-C-Cl
1-chloro-2-methylpropane
isobutyl chloride
Trivial name (C1-C4): the name of alkyl group + alcohol
OH
C-C-C
C
C-C-C
OH
2-methylpropan-2-ol
5.10. Nomenclature of ethers (ROR’)
Trivial name: list the names of both groups that attached to
the oxygen in an alphabetic order + ether
C-O-C=C
C-C-O-C-C
methyl vinyl ether diethyl ether
C
C6H5CH2O-C-C
benzyl isopropyl ether
Systematic name: name the simple OR group as a substituent,
the long chain as a parent body.
alkoxy groups (OR):
CH3O- C-C-O- C-C-C-O- C-C-C-C-Omethoxy ethoxy propoxy
butoxy
C5H11OC6H13Osuffix: -yloxy
pentyloxy
hexyloxy
OH
phenol
2-cyclopenten-1-ol
◆
Alcohols containing more than one OH group
Systematic name: suffix: -diol, -triol…
Trivial name: glycol, glycerol …
OH OH
CH2 CH2
Cl-C-C-C-OH
3-chloropropanol
C
C-C-C tert-butyl
OH alcohol
isopropyl
alcohol
OH
chain to which the OH group is directly attached, and give
the OH group the possible lower position number.
C
C-C-C-C-C
OH C
4,4-dimethylpentan-2-ol
2-chloro-2-methylpropane
tert-butyl chloride
C C-C-C=C
1-penten-4-yne
5.9 Nomenclature of alcohols
suffix: -ol
Systematic name: Select the longest continuous
OH
C-C-C
2-propanol
2-chloropropane
isopropyl chloride
OH
HO-C-C-C-OH
C C C
OH OH
glycerol
ethylene glycol propylene glycol
1,2-ethanediol 1,2-propanediol 1,2,3-propanetriol
e.g.
C-C-C-C=C
OC
4-methoxy-1-pentene
CH3OCH2CH2OCH3
1,2-dimethoxyethane
C2H5-O
CH3
p-ethoxytoluene
o
4H
O
furan
(呋喃)
O
o
tetrahydrofuran 1,4-dioxane
(四氢呋喃） （二氧六环）
5.11 Nomenclature of amines
THF
1) Simple amines
Trivial name: list the names of alkyl groups that are attached
to the nitrogen in an alphabetic order + amine.
Systematic name: list the names of small alkyl groups +
the name of parent chain + amine.
17
e.g.
C
NH 2
(C-C) 2 NH
cyclopentylamine
diisopropylamine
N-isopropyl-2-propanamine cyclopentanamine
N(CH3)2
aniline N,N-dimethylaniline
+
ethylmethylpropylamine
CH3
C-C-N-C-C-C N-ethyl-N-methyl-1-propanamine
R4N X -- quaternary ammonium salt (季铵盐)
Et4NOH--tetraethylammonium hydroxid
pyrrole
吡咯
1
pyridine
吡啶
N
H
8
N
3 2
6 7
C N(C2H5)2
C-C=C-C-C
4-(N,N-diethylamino)
-3-methyl-2-pentene
5
3) Heterocyclic amines
4
2) Amines with large alkyl groups or with other
functional groups in the molecules
C NH2
C-C-C-C-C-C
4-amino-2-methyl
hexane
NH2
H 2 NCH 2 CH=CHCH 2 OH
4-amino-2-buten-1-ol
N
CH3
N
quinoline 4-methylquinoline
喹啉
Chapter 6 Stereochemistry
2.4, 6.1~6.2 Introduction
Isomerism is a phenomenon that different compounds
have the same molecular formula, and such different
compounds are called isomers (not including
conformational isomers).
constitutional isomers (structural isomers)
构造异构
Isomers
Constitutional isomers (构造异构) have their
atoms connected in a different order.
Stereoisomers (立体异构) have their atoms jointed
in the same order, but differ in arrangement of their
atoms in space.
stereoisomers
立体异构
constitutional isomers (构造异构):
i. carbon-skeleton isomers:
◆
◆
C6H14
ii. position isomers:
C6H13Cl
Cl
Cl
Cl
iii. functional isomers:
O
O C C-C
C-C-C
C3H6O C-C-C-H O
iv. tautomers: CH3 C CH2 CCH3
互变异构
O
O
O
CH3C CH CCH3
OH
O
stereoisomers (立体异构):
cis/trans isomers
构型异构
(geometrical isomers)
configurational
isomers
optical isomers
(enantiomers)
构象异构
对映异构体
conformational
isomers
Configurational isomers are the stereoisomers for which
the1different arrangement of their atoms in space cannot
be interconverted with each other by rotations of atoms
about single bonds. Configurational isomers are different
compounds.
18
H
Cl
Cl
cis/trans isomers:
C C
(geometrical isomers) H
H H3 C
H
Cl
H
Cl
optical isomers:
(enantiomers)
CH3CH2
C C
H
CH3
Conformational isomers are the stereoisomers for which
the different arrangement of their atoms in space can be
interconverted with each other by rotations of atoms
about single bonds. Conformational isomers are the
same compounds.
H
H
CH3 CH3
H
H
C
C
Cl Cl
CH3
CH3
Cl
conformational:
isomers
H3C C
H
CH2CH3
CH3
Cl
C
H
CH
3
C
Cl
H
C
H
Cl
CH3
Enantiomers are chiral compounds which are related with
each other like an object and its mirror reflection.
◆
6.3 Designating the configuration of geometrical
isomers
◆
cis/trans and Z/E system (Zusammen/Entgegen)
H
CH3
C=C
H
CH3
H
H
Cl
Cl
3 rules used in designation of group priority:
Rule 1: The atom with higher atomic number has the higher
priority.
CH3
C2H5
Cl
Br
C=C
C=C
F
H
H
Br
(Z)-1-bromo-2-chloro(E)-3-bromo-2-pentene
1-fluoroethylene
Rule 2: If the two atoms attached to the carbon of the double
bond are the same, compare the atoms attached to them in order
of decreasing priority. The decision is made at the first point of
difference.
CHCl2 (Cl,Cl,H)
H3C
C=C
CH
2 Br (Br,H,H)
CH CH
trans-2-butene cis-1,3-dichlorocyclopentane
3
2
(Z)-2-bromomethyl-1,1-dichloro3-methylpent-2-ene
6.4 Conformations (构象)
Rule 3: Double and triple bonds that are part of the groups
attached to the double bond are treated as though they are
constructed from two or three single bonds, respectively.
(O,O,H) O
HC
(C,C,H) (C,H,H)
CH=CH2
C=C
CH(CH3)2
CH3CH
(O,C,H) OH (C,C,H) (H,H,H)
(Z)-isomer
(C,C,H) (C,C,C)
HC C
C=C
(CH3)3C
(H,H,H) (C,C,C)
(N,N,N)
C N
CH2OH
(Ο,Η,Η)
(E)-isomer
The different arrangements of the atoms in space that
result from rotation of a single bond are called
conformations.
◆ ethane (CH3CH3)
staggered conformation (交叉构象)
H
H
H
eye
H
H
H
front carbon
.
H
H
H
H
H
Newman projection
H
back carbon
19
eclipsed conformation (重叠构象)
◆
H
eye
H
H
Butane (CH3CH2CH2CH3)
HH
H
H
H
H
H
H
H
H
Energy changing curve
eclipsed
E
△E
E
staggered
H
H
CH3
H3 C
H
H
H
H
H
H
CH3
H
3
2
CH3
H
H
CH3
1
H3CH
H3CCH3
H
H
H
H
H
H
H
4
CH3
H CH
CH3 3
H
H
H
CH3
H
H
6
5
2
H
H
H
H
H
60
cyclopropane
60
300
◆
1
360
cyclobutane
4>2=6>3=5>1
4>2=6>3=5>1
4<2=6<3=5<1
◆
envelope
conformation
ring strain
potential E.
stability
cyclohexane
H
H
H
90
square
conformation
The relative stabilities of cycloalkanes:
cyclohexane
108
H
109
chair conformation
H
H H
H
H
H
H
88
H
butterfly
conformation
cyclopentane
◆
H
6
3 torsional barrier5
240
120
180
repulsive force:
potential E:
stability:
◆
H
△E
E
0
H3C CH3
ring strain = angle strain + torsional strain
◆
E
△E
1
CH3
CH3
H
H
CH3
6.5,6.7 Conformations and relative stabilities of
cycloalkanes
Energy changing curve
4
H
H
H
CH3 CH3
eye
torsional barrier
E 扭转能垒
staggered
H
H
CH3
eye
boat conformation
◆
~pentane
≈
≈
≈
~butane
<
<
>
~propane
<
<
>
Heat of combustion
(CH 2)n + 2
3O2
nCO 2 + nH 2O + heat
20
6.6 Conformations of cyclohexane
ring strain
flagpole
E
4× 157.4
(CH2)
kcal/mol
kcal
H
cyclobutane
actual data
calculated value
1
12 H
2
H
H
5H
H
8H
7
H
3
5H
H
4
H6
50%
H
3
H
H
H
H
H
H
H1
H2
50%
a CH3
less stable
CH3
H
H
H
93%
cis-1,4-dimethylcyclohexane
a
a
CH3
CH3
H
H3C
H
H
H
H
H
◆
e
H
H
H
H
H
H H
trans-1,4-dimethylcyclohexane
a
H
H
General rule: Normally, in the most stable
conformation of substituted cyclohexane, the
largest substituent will occupy an equatorial
position rather than an axial position.
6.9 conformations of cyclohexanes with two or
more substituents
CH3
H
CH3
H
only 7%
H with odd number--axial bond
H with even number--equatorial bond
◆
boat conformation
potential E.: chair < twist < boat < half chair
stability:
chair > twist > boat > half chair
H 11
H4
H10
H11
H
6
7H
12
H
8 9
H H
H
when a H is replaced by a methyl group:
6.8 Monosubstituted cyclohexanes
9
10 H
H
99%
chair conformation
△E = heat of combustion
ring strain of a cycloalkane = △E – n × 157.4
n = the number of the CH2 groups
H
H
H
H
-CH2CH2CH2CH2-
H
H
H
e
CH3
H
eH
H3C
e
CH3
H
the same stability
cis-1-tert-butyl-4-methylcyclohexane
◆
H
a
C(CH3)3
H
more stable
e
H3C
H
a
CH3
H
e
C(CH3)3
H
21
6.10~6.11 Chiral molecules (手性分子)
bicyclic and polycyclic alkanes
◆
Chirality (手性) or Handedness
H
H
10[H]
十氢萘
H
trans
1
H
<
H
H
H
cis
stability:
H
cis
,
mirror
decalin
naphthane
The property that an object and its mirror reflection cannot
overlap with each other is called Chirality or Handedness.
trans
The significance of chirality:
O
O
NMe
H
Me
HO
MeN
HO
H
Me
OH
HO
OH
OH
(-)-benzopyryldiol
(-)-benzomorphia
(+)-benzomorphia
anodyne
without the effect
of pain-relieving
not addict
(+)-benzopyryldiol
non-carcinogenic substance
carcinogenic substance
addict
Some important definitions in stereochemistry:
molecule (手性分子): A chiral molecule is the
compound which is not superposable on its mirror reflection.
9 Chiral
O
O
O
O
N
O
9 Enantiomer (对映体): If two chiral molecules are related
O
N
N
N
O
(S)-thalidomide
(R)-thalidomide
(S)-沙利度胺
(R)-沙利度胺
cause the congenital
sedative, stop vomiting
malformation of a foetus
O
like an object and its mirror reflection, they are called
enentiomers.
9 Racemate ( 外消旋体): When a pair of enantiomers is
mixed in the same amount, each accounts for 50%, we call
this kind of mixture—a racemate.
e.g.
Br
H
H
C
C
CH 3
Cl
Cl
Br
Chiral molecules
(optically active)
CH3
22
9 Diastereomers (非对映体): Diastereomers are
configurational isomers which are not related as
an object and its mirror reflection.
e.g.
CH3
H
Cl
C
C
9 Mesomer (内消旋体): The compounds have not only
stereogenic C atoms but also a symmetry element and can
overlap with their mirror reflections.
Cl H
H H
C
C
Cl
Cl
atoms or groups attached to it.
different atoms or groups in a chiral molecule.
Br
CH3
CH3
Cl
chiral C
chiral
Cl C
H
H C
Cl
Cl C
H
CH3
6.12, 6.17 Symmetry elements, R/S system, D/L
system and Fischer projection formulas
1) Symmetry elements
Chiral C atom: A carbon atom which is bonded to 4
stereogenic C
Cl
achiral Mesomer
optically inactive
Stereogenic C atom: A carbon atom which has 4 different
C
H C
CH3
CH3
CH3
diastereomers
H
CH3
CH3
CH3
a. the plane of symmetry
b. the center of symmetry
c. any n-fold (n = even number) alternating axis of symmetry
H3C
H C
Cl stereogenic C
H C
Cl
chiral C
CH3
achiral (a mesomer)
CH3
H
CH3
H
H
H3C
H
H
H
H3C
H
H3C
CH3
H
CH3
chiral
achiral
2) Designation of R/S configuration (relative
configuration)
General rules of nomenclature of chiral molecules by
R/S system:
i. First, determine the order of priority assigned to the
groups on chiral atoms.
*
CH3CHCH
2CH3
OH
the order of priority:
OH > CH2 CH3 > CH3 > H
H3 C
*
CH3CHCHCH=CH2 OH > CH=CH2 > CH(CH3)2 > H
OH
ii. Determine the relative position of the groups attached to
the chiral C atom
clockwise—R-isomer; counter-clockwise—S-isomer
e.g.
OH
O
C
CH
H
CH2OH
clockwise
R-glyceraldehyde
R-甘油醛
OH
O C
H
HC
CH2OH
counter-clockwise
S-glyceraldehyde
OH – hydroxy
(羟基)
CHO – formyl
(甲酰基)
CH2OH –
hydroxymethyl
(羟甲基)
S-甘油醛
23
3) Fischer projections
General rules:
i. The longest C chain should be written vertically
and the No.1 C should be written upside.
ii. All horizontal bonds connected with the chiral
C point forward and all vertical bonds point backward.
e.g.
H
CHO
CHO
C
CHO H
H2C
OH
OH
C
OH
H
OH
CH2OH
CH2OH
D-glyceraldehyde
iii. It is permitted to rotate a Fischer projection formula only in the
plane of the paper by 2n×90° (n = 1,2,3…, e.g.180,360…).
iv. We must always keep Fischer projection formula in the plane
of the paper, it is forbidden to flip them over.
CHO rotate 180
H in the plane
H of the paper
H
CH2OH
HO
HO
HO
(L)-Ribose
O
C OH
O
C H
H C
OH HgO H
CH2OH
(R)-(+)-glyceraldehyde
e.g.
H
HO
H
H
CHO
CHO
H
OH HO
H
OH
H
H
HO
OH
H
OH HO
CH2OH
CH2OH
D-glucose
L-glucose
CH2OH
CH2OH
C O
C O
HO
H
OH
H
H
H
OH HO
H
H
OH HO
CH2OH
CH2OH
L-fructose
D-fructose
6.13 Properties of enantiomers—optical activity
(D)
C
OH
CH2OH
(R)-(-)-glyceric acid
(D)
CH3
CH2Br
H C
+
OH Zn/H H
C2H5
C
OH
C2H5
(R)-1-Bromo-2-butanol (S)-butanol
(D)
(D)
The absolute configuration (D/L) of the chiral C keeps
unchanged during the configuration retention reaction,
but the relative configuration (R/S) and the rotation
direction may change. There is no direct correlation
among R/S, D/L system and the rotation direction.
◆
Specific rotation [α](旋光率)
[α ]
◆
Schematic diagram of a polarimeter (起偏器, 旋光仪)
(D)-ribose
Configuration retention (构型保持）
◆
4) D/L system (absolute configuration)
CH2OH
CH2OH
HO
H
OH
OH flip over HO
H
HO
H
OH
CHO
CHO
the same
compound
（核糖）
Fischer
projection
If OH or NH2 group attached to the chiral C with largest
position number is in the right of a standard Fischer
projection, the chiral compound is labeled by D, and if in
the left, labeled by L.
H
H
H
20
D
=
α
c.l
α - the observed rotation angle
c - the concentration of the solution
of a pure chiral compound
l - the length of the tube
20 - measuring temperature
D - sodium lamp with the wave
length of 589.3 nm.
optical purity or enantiomeric purity
optical purity=
α
× 100
[α ]
24
6.14 Molecules with multiple chiral centers
e.g.
◆
pure (S)-(+)-2-butanol: [ α ] = +13.52
pure (R)-(-)-2-butanol: [α ] = −13.52
The number of configurational isomers
4 3 2 1O
5
CH2 CH CH CHC H
OH OHOHOH
e.g.1
the measured value: α = - 6.76
6.76
optical purity = 13.52 × 100 = 50%
H
H
H
In the sample, 50% is the racemate, that means
(R)-(−)-2-butanol accounts for 75% and
(S)-(+)-2-butanol for 25%.
ee =
[S] − [R]
[S] + [R]
CHO
CHO
CHO
CHO
H
OH HO
OH HO
H
H
H
HO
HO
OH
OH
H
H
HO
OH HO
OH
H
H
H
CH 2OH
CH 2OH
CH 2OH
CH 2OH
Ⅱ
Ⅰ
100%
Ⅴ
12
3
4
5
HOOCCHCHCHCOOH
OHOHOH
COOH
OH
OH
OH
COOH
mesomer
H
H
H
the number of configurational
isomers < 23
COOH
COOH
H
OH
H
H
HO
H
OH
H
H
COOH
COOH
the same
mesomer
HO
HO
HO
COOH
H
OH
OH
H
HO
H
COOH
COOH
H
OH
H
COOH
the same
HO
H
HO
COOH
COOH
H
H
OH HO
H
OH
H
HO
OH
H
HO
H
COOH
COOH
Ⅲ
Ⅳ
CHO
CHO
CHO
CHO
OH HO
H
H
OH HO
H
H
HO
OH
H
H
H
H
OH HO
HO
H
OH HO
H
OH H
H
CH2OH
CH2OH
CH2OH
CH2OH
Enantiomer excess (对映体过量)
e.g. 2
the number of configurational
isomers = 23 (2n)
◆
Ⅵ
Ⅷ
Ⅶ
Designation of R/S configuration for molecules with
more than one chiral center
e.g.
HO
H
H
CHO
S H
R
OH
R
COOH
R
OH
OH
R
H
COOH
H
H
HO
OH
CH2OH
(2S,3R,4R)-arabinose
(2R,4R)-2,3,4-trihydroxy
pentanedioic acid
a pair of enantiomers
◆
Designation of R/S configuration for some mesomers
COOH
OH
OH
COOH
meso-tartaric acid
（酒石酸）
H
H
COOH
H R OH
HO S H
H S OH
COOH
(2R,3S,4S)-2,3,4trihydroxypentanedioic acid
COOH
H R OH
H R OH
H S OH
COOH
(2R,3R,4S)-2,3,4trihydroxypentanedioic acid
notice 2 points:
i. priority: R > S
ii. give the C labeled with R a possible lower position
number than the C labeled with S, when they are in the
equal position
6.15 Stereoisomers of cyclic compounds
e.g. stereoisomers of trimethylcyclopentane
Me
Me
R Me
Me H S
S
H
H
Me
H
H
H
Me
R Me
H H
R
Me
H
Me
S
Me
H
H
H
S
Me
Not
no stereogenic C atoms
H
Me
Me
H
R
H
Me H R
Me
S
Me
Me
H
Me
Me
H
H
H
Me
R
R
H
Me
Me
Me
S
H
H H
S
Me
left: (1R,2R)-1,2,4-trimethylcyclopentane
right: (1S,2S)-1,2,4-trimethylcyclopentane
25
6.18 Other chiral compounds
♠
♠
Compounds with chiral atoms other than C atoms
R1
Si
R4
R2
R4
R3
i. Compounds with chiral axes
R1
N⊕
R1
Ge
R2 R4
R3
Chiral molecules that do not possess a stereogenic atom
H
C==C==C
H
R2
R3
H
H
C==C==C
H
Cl
H
H
H
Cl
Cl
Allene (丙二烯)
H
C==C==C
Cl
H
H
H3C
CH3
H 3C
H
CH3
Cl Cl
H H
biphenyl
HOOC COOH
Cl
H
ii. Compounds with chiral planes
H
H H
H
C==C==C
e.g. hexahelicene (六螺并苯)
6.16 Separation of enantiomers—resolution
（拆分）
Identify the following pairs of compounds as identical,
enantiomers, diastereomers or structural isomers.
H
CH3
C=C=C
H
and
H
CH3
C=C=C
CH3
H
H
Br
CHO
Cl
H
and
H
Br
CH3
Cl
Cl
H
and
H
Cl
H
C
(+) acid + (-)base
Cl
H
CHO
a racemate a resolving
agent
B
A
H
CH3
Cl
CHO
OH
OH and H3C
H
CH3
+
CH3
(+)acid-(-)base
(-)acid-(-)base
(+)acid
(+)acid + (-)base H+ (+)acid-(-)base
(-)acid
(-)acid + (-)base H+ (-)acid-(-)base
separated
by physical
methods
H
CHO
D
26
e.g.
R
H
C
H3C
Br
C
O
H
CS
+
C
Br
CH3 O
OH
CH3
H
C
CH2CH3
CH3
Kinetic resolution of a racemate – an attracting research field
HO
O
HO
*
chiral catalyst
[O]
*
+
Chapter 7 Nucleophilic Substitution
Reactions
7.1~7.2 The general reaction
The covalent bonds may break in 3 ways:
isolated enantiomer
a racemate
A-B
N
Mn
R
O
R
Cl
N
O
R
R
a chiral salen complex
7.4, 7.7 Nucleophilic substitution reactions
1. General expression of the SN reactions
δ δNu: + R3C-X
H3C
-
CH2CH3
CH3
HCl
+
C O⊕
NH3
Br O
R-S
H
C
⊕
C O NH3
Br
CH3 O
S-S
H3C
H
C
H
C
H+
CH2CH3
C O
H3N
Cl CH3
Br O
H
H
S
C
C
+
C OH
CH2CH3
S-S HCl Br
H3N
CH3 O
Cl CH3
R-S
H
C
H
C
-
H2N
S
R
CH2CH3
+
H
C
separated by
physical methods
OH
+
R3C- Nu + X
-
X= Cl,Br,I
Nu: = any anions(OH-,OR,- NC , RC C ,
nucleophile
RCO2 , CH(CO2R)2 ... )
neutral molecules with unshared e-pairs:
..
..
.. .. ..
( H2O,
.. ROH,
.. NH 3, HNR 2, PR 3...)
R3C Z
homolysis（均裂）
free radical reaction
1
2
3
A. + B .
A: + B+
A+ + B:
1
2
3
R3C. + Z . C free radical 7e
R3C⊕ + Z: carbocation 6e
R3C: + Z⊕ carbanion 8e
heterolysis（异裂）
ionic reaction
intermediate
2. Reaction rates and potential energy diagrams of
SN1and SN2 reactions
◆ Two pathways:
SN2 mechanism:
Nu: + RX
δδNu R + X:
Nu ...R ...X
transition state
rate ∝ [ Nu: ] [ RX ]
rate = k [ Nu: ] [ RX ]
SN2—bimolecular nucleophilic substitution reaction
(one step, second order, via a transition state)
27
SN1 mechanism:
The potential energy curve of SN2 reactions:
δδNu ... R ...X
PE
R X
the energy of activation
（活化能）
rate ∝ [ RX]
E
the heat of reaction
（反应热）
Nu : + R X
NuR + X :
△H
fast
R⊕+ Nu:
R Nu
slow ⊕
R +X
step 1
carbocation
rate-determining step
rate
step 2
k [ RX]
SN1—unimolecular nucleophilic substitution reaction
(two or more than two steps, first order, via an
intermediate of a carbocation)
reaction process
The potential energy curve of SN1 reactions:
R ... X
PE
△E1
+
RX
△H
7.3, 7.5 Mechanism and stereochemistry of SN2
reactions
R1
Nu : + C X
R2
R3
R... Nu
△E2
R +X- +
Nu :
RNu + X -
δNu
R1
C Xδ
R1
Nu C
R2
R2 R3
R3
configuration inversion
（构型翻转）
e.g.
C2H5
C2H5
C2H5
C2H5
C
H
+ NaOHSN2
C
Br
HO
H
Br
H3C
CH3
HO
CH3
H
CH3
H
R
reaction process
enantioselective
7.8 Mechanism and stereochemistry of SN1
reactions
R3 C X + Nu :
H3C
H
3S 1R
Cl
+
H OH
3S 1S
H
OH
(1S,3S)-3-methyl
cyclopentanol
(1) R3C X
slow
R3 C Nu + X
R3C⊕+ X
(2) R3 C⊕+ OH fast R3C OH
H+
or (2') R3C⊕+ H2O fast R3C OH2
fast R3 C OH
+
(1R,3S)-1-chloro-3-methyl
cyclopentane
SN2 H3C
H
28
Racemization (外消旋化):
R2
R3
slow
X-
R1
+
R1
C
upside
front
Nu :
Nu:
C
X
CH3 H O
2
Br SN1
H3C
back
H
H3C
R2 R3
H
fast
Nu
R1
+
R1
C
C
R2
R2
R3
frontside:
configuration
inversion
2H H3C
S
H
+
Nu
R3
backside:
configuration
retention
H3C
H
⊕CH3
OH2⊕ H3C
+
CH3
H
OH
H3C
R
+ S
CH3
H
:OH2
downside
:OH2
CH3
OH⊕
2
CH3
S
OH
The general order of stability of carbocations:
3 C+ > 2 C+ > 1 C+ > +CH3
a racemate
4. The nature of the leaving group
For SN2:
SN2:
R1
δ
Nu C Xδ
-
1. The structure of the substrate
2. The concentration and reactivity of the nucleophile
for SN2 reactions.
3. The effect of the solvent
1. The effect of structures of substrates
-
7.6, 7.9~7.13 Factors affecting the rates of SN1
and SN2 reactions.
R2 R3
transition state
The key point for the SN2 mechanism is steric effect.
The general order of reactivity of RX in SN2 reaction is:
CH3X >1 RCH2X > 2 R1R2CHX > 3 R1R2R3CX
The nucleophilic substitution reaction of CH3X and
1°RX occurs readily in SN2 mechanism, except
some special 1°RX.
e.g.
CH3
CH3 CHCH2 X
CH2X
benzyl halide
CH3
CH3 C CH2 X
CH3
R
C C CH2 X
R'
allyl halide
For SN1:
The key point for the SN1 mechanism is the
stability of carbocations. The general order
of reactivity of RX in SN1 reaction is:
3 R1R2 R3 C X > 2 R1 R2CH X > 1 RCH2 X > CH3X
The nucleophilic substitution reactions of 3°RX
occur readily in SN1 mechanism, except some
special 3°RX.
e.g.
X
⊕
29
2. The effect of the concentration and reactivity of the
nucleophile (for SN2 reactions)
The strength of nucleophiles is determined by:
ii. For the atoms of the same group, in protic solvents (H2O,
ROH, RNH2…), the order of nucleophilicity is opposite
to the order of basicity.
The order of nucleophilicity in protic solvents:
◆
basicity
◆
polarizability of the atoms
◆
the volume of the nucleophiles
-
i. For the atoms of the same period, the order of nucleophilicity is paralleled with the order of basicity.
The order of nucleophilicity:
O
O
C2H5 O > HO > CH3 C O > H2O > CH3C OH
..
..
NH2 > OH > F , NH3 > H2O :
3. The effect of solvents on SN1 and SN2 reactions
aprotic solvents
O
HC-N(CH3)2
DMF
dimethyl
formamide
The order of nucleophilicity for SN2 mechanism:
NH2R > NHR2 > NR3
OCH2R > -OCHR2 > OCR3
-
i. For SN2 reactions
◆
In protic solvents:
-
H
nonpolar ~: alkanes, benzene,
toluene...
O
O
CH3C-N(CH3)2 CH3SCH3 [(CH3)2N]3P=O
DMSO
HMPT
DMA
dimethyl
sulfoxide
hexamethyl
phosphoric
triamide
In polar aprotic solvents:
The order of the strength of nucleophiles is paralleled
with the order of basicity:
F- > Cl- > Br- > I -
RO- > RS -
-
O
H
H
O H
Nu :
H
O
H
H
O H
solvation of an anion
◆
For the same substrates, under the same conditions,
the general order of the rates of S N2 reactions
in different solvents:
in polar aprotic solvents > in polar protic solvents
> in nonpolar solvents.
-
The solvation of a nucleophile will greatly reduces
its nucleophilicity in SN2
reactions.
In nonpolar solvents:
The rates of SN2 reactions will slow down.
ii. For SN1 reactions
Using a polar protic solvent will greatly increase the rate of
ionization of a RX in SN1 reaction.
OH2
+
★
-
nucleophicility: I > Br > Cl > F
polar ~: DMF, DMSO,
DMA, HMPT...
dimethyl
acetamide
-
iii. For the same atoms as the centers of nucleophiles, large
volume of the nucleophile will decrease its nucleophilicity for SN2 reactions.
◆
polar protic ~: H2O, ROH, RCOOH, RCO2NH2...
solvents
-
I > Br > Cl - >F , HS - > OH , H2S > H2O
R3C
H2O
OH2
OH2
solvation of a carbocation
In general, in a polar protic solvent, the rate of
ionization of a RX will increase, which is a ratedetermining step in SN1 reactions.
30
4. The effect of leaving groups
A weak basic ion cannot substitute the strong basic ion.
The best leaving groups are ions or molecules that
are the weak bases. The leaving groups have the
same effect on SN1 and SN2 reactions. The good
leaving groups can benefit both SN1 and SN2
reactions.
e.g.
basicity: X- < OH - , RORX + OH
X: + ROH
X: + ROR'
R X + :OR'
However, the following reactions take place readily.
The order of reactivity of RX for SN reactions is as follows:
RF << RCl < RBr < RI
Nu: + R H
+
RNu+ H
R R'
Nu:
◆
+
H
ROH H ROH X
⊕
H
+
H
ROR' X
ROR'
⊕
RNu + R'
◆
Summarization:
CH3X > 1 RX > 2 RX > 3 RX
SN2
SN1
SN2
SN2
SN1
weak nucleophiles (H2O, ROH, I- ...)
◆
polar protic solvents
substrates that are relative unhindered:
e.g. 1 RCH 2X, CH 3X
SN2
strong and small bases as nucleophiles
with a high concentration and reactivity
RX + R'OH
The general order for the rate of SN reactions of RX:
substrates that can form stable carbocations:
+
+
e.g. 3 C+,
CH2 , C C CH2
SN1
RX + H2O
The mechanism of SN reactions of 2°RX
CH3 strong Nu
CH3
C Br OH
configuration
HO C
H
H inversion
H2O
Ph
Ph
( S N2 )
polar aprotic or protic solvents
7.14 Intramolecular reactions and the
unreactivity of vinylic and aryl halides.
H2O
CH3 weak Nu
CH3
H2O
C
C⊕
Br
H
EtOH
Ph
H Ph
( SN1 )
CH3
HO C
H3C
H + H
Ph
C
Ph
a racemate
OH
O
Cl CH2 CH2 CH2 C OH + OH -H2O
H
+
CH2 CH2
CH2 C O
Cl
O
Cl
CH2 CH2
CH2 C=O
O
Unreactivity of
-C=C-X + OH-
3, 5 or 6 membered
sp2C-X:
-C=C-OH + X-
vinylic halide
ArX + OHaryl halide
ArOH + Xr.t.
芳香卤代物
31
7.15 Rearrangements of carbocations (additional)
1. Migration of hydride (Hˉ)
e.g. 1 1 ℃
e.g. 2 1 ℃
2℃
+
C-C-C-C-OH H
∆
+
C-C-C-C-OH2
H
H
+
C-C-C-C-OH H
C-C-C-C⊕
-H2O
H C
C
-H2O
+
H
⊕ -H
rearrangement C-C-C-C
⊕
C-C-C-C by H migration
H H
C
C C
H
C C + C C + C-C-C=C
H H
H
C
C
C
C C
C
H
C C
C
C
+
C
⊕
C-C-C-C
HCH
C C
C=CH2
C
3. Ring rearrangement
C
C
H+
⊕
C-C-C-C rearrangement
C-C-C-C H2O
by CH3 migration
C
C OH
C
H C
C
- H + C C C + CH2 C C C
⊕
C-C-C-C
C
C
C
CH
- H+
H
- H+
2. Migration of methyl (CH3−)
C
C
H+
C-C-C⊕
C-C-C OH
- H2O
C
C
3℃
+
CH3
H
CHCH3 H O, △
2
OH
H
⊕CH3 −H+
CH3
H
⊕
C-C-C-C
C
CH3
rearrange
CHCH3
⊕
CH3
CH3
+
CH3
CH3
The rearrangement of carbocations always occurs
when the 1,2-migration of a hydride ion or an
methyl group can lead to a more stable carbocation.
+ CH2 C C C
C
8.3, 8.6 E1 and E2 reactions
Chapter 8 Elimination Reactions
◆
E2 mechanism: bimolecular reaction, one step, second
order, via a transition state
8.1, 8.2 The general reaction
+
E2 :
δH
General expression of elimination reactions (E reaction):
β
α
C C base(B: ) C C + BH + :L
E
H L
L = a good leaving group
β−elimination or 1,2-elimination
δRO H
C
C C + RO
X δ-
C
Xδ
transition state
ROH
△
C C + ROH + X
Generally, the eliminations of 1°and 2°RX undergo by
E2 mechanism.
32
e.g.
◆
CH3
r.t.
CH3 CH2 C Br + C2H5OH HBr
CH3
E1 mechanism: unimolecular reaction, two steps,
first order, via a cabocation intermediate
CH3
CH3
CH3 CH2 C OC2H5 + CH3CH C
CH3
CH3
64%
30%
CH3CH2
C CH2
C2H5OH
CH3
6%
E1
SN1 E1
C
C
C C C slow C C C fast
B:
L
H L
H ⊕
C
C C C + BH
E1:
The elimination of 3°RX generally undergoes by E1 mechanism.
The formation of a carbocation is the rate-determining step for
E1 mechanism.
+
CH3 CH2 C CH3
CH3
8.4 The stereoselectivity of E2 reactions
δB H
δB H
C
e.g.
H3C
H5C2
C
Xδ -
X δ-
-OEt/EtOH
anti-(periplanar) conformation
H3C
- δ
δXδ B H X
δB H
C
Cl
R R
C C
CH2
H
H H
C C
H5C2
Z
H
CH3
C
H3C
CH3
R
H
+
C CH CH2
5C2
H
H5C2
H
major E
minor
H3C
C C
syn-(periplanar) conformation
H5C2 Cl CH3 H5C2
S
OEt/EtOH H5C2
S
H3C C C R
C C
+ H3C C CH CH2
H
H3C
H H CH3 △
H
Z
major
minor
The main point of the stereoselectivity of E2 reactions is
anti-elimination of the 2 leaving groups.
A comparison of cis/trans-1-bromo-2-methylcyclohexane:
H
H3C
H
cis- ~
H
◆
Br
HOEt/EtOH
H
△
H
H
Br
H
single bond
rotation
H
H
H
Br
H
H 3C
B
Br
E2 elimination of cyclic alkyl halides
H
+
CH 3
A
H
CH 3
trans- ~
H -OEt/EtOH
△
H3C
only product
H
33
8.5 The regioselectivity of E2 reactions
1. The effect of the structures of RX and the volume
of the bases (Zaitsev’s rule)
Zaitsev’s rule: The major product of an elimination
reaction is the olefins with more alkyl groups on the
carbons of the double bond (thermodynamically
favored product).
H
H CH2
B: + CH3 CH C Br ROH
CH3
CH3CH C
CH3
CH3
Relative stabilities of olefins:
R
R R
H
R R
C C > C C > C C >
H
R
H
R
R
R
H
R
R
R R
C C & C CH2 > H C C H
H
H R
+ CH3CH2C CH2
CH3
B:
EtONa 69%
B:
ButOK
27.5%
31%
72.5%
KOC2H5
H
CH3 H CH2
HOC2H5 , △
H3C C CH C CH3
K(OBut)
CH3
Br
HOBut, △
2. Hofmann elimination (Hofmann’s rule)
R3N + R'I
H
OH C C
+
NR3 △
If a terminal olefin is wanted, a large bulky
base should be used.
H
R3
R3
R1
C C
R4
C C
+ NR3 + H2O
+
R1
R4
△ R2
NR3
R2
OH -
Regioselectivity:
The order of β−Η elimination tendency is as follows:
+
For R C N ( CH3 ) 3
R = Y-CH2 > CH3 > R'CH2 > R2'CH
acidity of β-H
O
R
Y=C6H5, C C R , R'C , e-withdrawing groups
R
△
( CH3 )3 N + CH3OH
Hofmann elimination
98%
Stereoselectivity—anti-elimination:
AgOH
+
+ R3R'N I
R3R'N OH + AgI
or Ag/H2O
(CH3 )4 NOH
CH3
(CH3)3CCH=C(CH3)2+(CH3)3CCH2C=CH2
14%
86%
CH3
(CH3)3CH=C(CH3)2+(CH3)3CCH2C=CH2
2%
△
C C + NR3 + H2O
R=CH3
e.g.
CH3CH2CH2CHCH3
△
- +
HO N(CH3) 3
CH3CH2CH2CH=CH2
98%
+ CH3CH2CH=CHCH3+ N (CH3) 3 + H2O
2%
+
CH3
OHCH2CH2 N CH2CH3
△
CH3
CH3
+CH2 CH2 + H2O+ N CH2CH3 +
CH3
0.4%
CH CH2
93%
CH3
CH2CH3 N
CH3
The olefin formed by losing the most acidic β-H will be the
major product for Hofmann eliminations (Hofmann’s rule).
34
The regioselectivity of E2 reactions can be predicted as
following rules:
1. Common E2 reactions follow Zaitsev’s rule: The olefin
with more R groups on the carbons of the double bond is
the major product.
2. Hofmann eliminations and E2 reactions with large base
( t-BuO ) and the RX with a large steric hindrance for
2°β -H follow Hofmann’s rule: The olefin with less R
groups on the carbons of the double bond is the major
product.
3. A conjugated olefin is always preferred over an
unconjugated olefin.
e.g. E1 elimination of cyclic alkyl halides
H3C
CH3
H
H
Cl
Hb
+
H3C
EtOH
C
C C H2O
Ha
C
C C
CH3
H3C
47%
C
C C
H
CH3
product formed
+ by S 1 reaction
N
22%
Isotope effect: bond strength: D-C > H-C
Which elimination mechanism , E1 or E2, will have
isotope effect?
•
8.7 Regioselectivity and stereoselectivity of the
E1 reactions
Regioselectivity: The most stable olefin will be the
major product of E1 reactions.
Stereoselectivity: The process of E1 reaction has no
stereoselectivity.
C
C C
H
c
7.15, 8.8 The competition between nucleophilic
substitution and elimination reaction
SN2: for 1º RX, CH3X: small strong nucleophiles with
high concentration, polar aprotic solvents or
protic solvents (CH3COCH3, DMF, DMSO,
DMA, HMPT, ROH, H2O), r.t.; for 2º RX:
moderate nucleophiles with high concentration,
polar aprotic solvents or protic solvents
E2: for 2º, 3º RX: strong base with high
concentration, ROH as solvents, at relatively high
temperature; for 1º RX: large strong base with
high concentration
◆
SN1: 3°RX; weak nucleophiles, solvents as nucleophiles;
ROH or H2O as solvents; l.t.~r.t.
E1: 3°RX; weak base, solvents as bases; ROH or
H2O as solvents; at r.t. to relatively high temperature
In general,
SN2 reactions compete with E2 reactions, and
SN1 reactions compete with E1 reactions.
Br
C
C
C CHCH3
C C C
C C
H
C
C
+
C C
CH2 H
EtOH
C
H
C
C
b
H
B
A
a
product formed
C
C C C CC C
+ by S 1 reaction
+
C C
C
C
N
C
C
DC
C
General rules for nucleophilic substitution and
elimination of RX
a. CH3 X
B:b.
B:
CH3 B + X :- basicity: B:- >X :SN2
SN2
RCH CH2X
H
1
B:E2
small
strong B:
SN2
large
strong B:
RCH2CH2B+ X :B:- CH3O- , C2H5O
RCH CH2
E2, - HB,- X :B:- t-BuO:
35
R'
moderate baseB: RCH2CHB + X:c.
SN2
B: Cl -, Br , I -, CN,RS-, SH-, N-3, RCO-2
R'
strong base B:RCH CH R'
RCH CHX E2 -HB -X
B:- NH2 , RO- , OH , RC CH 2
ROH or H2O
SN1 + E1
R'
RCH2 CH + RCH CH R'
OR
(or OH)
solvent as a base BH
l.t. SN1 , HX
d.
R1
RCH C X solvent as a base BH
r.t. , SN1 + E1
H R2
3
strong base B:
E2 , HB, X
R1
RCH2 C B
R2
BH = ROH, H2O
R1
RCH2 C B
R2
+ RCH=CR'R2
RCH=CR'R2
Chapter 9 Synthesis Uses of Substitution
and Elimination Reactions
Which way is better for the target product (CH 3)3COCH 3?
(1) (CH 3)3COH
(2) CH 3OH Na
H2
NaH
(CH 3)3CONa CH 3Br (CH3)3COCH3
NaBr
SN2
(CH 3)3CBr
(CH
)
3 2C=CH2
CH 3ONa
NaBr
E2
9.3, 9.5 Preparation of alcohols and esters
H2 O
RX + H2O
ROH + HX
X = Cl, Br, I
RX + NaOH
H2 O
ROH + NaX
RX = 1 RX and activated 2 RX, such as
X
O X
X
C C CH C ,
CH C , C CH C
reaction rate: RI > RBr > RCl > RF
e.g. preparation of 2°ROH by SN2 mechanism:
O
X
DMF C-C-C-C
C-C-C-C +NaOCCH3
KOH
SN 2
OCCH3 H2O
O
O
O
+
C-C-C-C
KOCCH
C-C-C-C + HO CCH3
3
OH
OK
e.g. preparation of 3°ROH by SN1 mechanism:
C
C C X + H2O
C
H2O
SN1
C
C C OH + HX
C
9.4 Preparation of ethers
1. From alkyl halides (Williamson synthesis)
1 RX + NaOR' HOR' 1 ROR'
X = I, Br, OTs, OMs unsymmetric ether
O
O
S Ms: Mesyl CH3 S
Ts: Tosyl CH3
O
O 甲基磺酰基
对甲苯磺酰基
对甲苯磺酰基
CH3
甲磺酰基
O
S OR alkyl tosylsulfonate
对甲苯磺酸酯
O
36
◆
9.6 Preparation of alkyl halides
Intramolecular SN2 reaction:
H
OH
O
C C CH3
C C
KOH
H
Br
H
H
CH3
H2O
CH3 CH3
-KBr
epoxide
C
O
1. Replacement of OH group by reactions of alcohols
with HX
C
H
CH3
H CH3
Cannot be formed
2. From alcohols (intermolecular dehydration)
+
+
- H+
ROH
ROR
ROH2 - H O ROR
H
2
symmetric ether
acid = H2SO4, H3PO4, ZnCl2, BF3, Al2O3
+
1 ROH H
Mechanism:
i. 2 , 3 ROH , C C COH ,
CH2OH react
with HX by SN1 mechanism
C
C +
+
C C OH H C C OH2 - H2O
slow
fast
C
C
C
C C⊕
C
H
C
C
C C X +C C C
fast
C
SN1
E1
X-
A simple testing method for 3º, 2º and 1º ROH and CH3OH
C C COH ,
CH2 OH , 3 ROH
The clear solution turns turbid instantly.
Lucas reagent
2 ROH
HCl(conc.)/ZnCl2 The clear solution turns turbid after several
1 ROH , CH3 OH
At r.t., no obvious change.
When heated, the clear solution turns turbid.
ii. Common 10 ROH and CH3OH react with HX by
SN2 mechanism
+
⊕
X - RX
1 ROH H ROH
2
- H 2O
HX = HI, HBr, HCl/ZnCl 2
1 ROH+ ZnCl2
△
R⊕
O ZnCl2
H
Cl
RCl + [Zn(OH)Cl2]
2. Replacement of OH group by the reaction of alcohols
with PX3
3ROH + PX3
3RX + H3PO3 phosphorous acid
H3PO4 phosphoric acid
PX3 = PI3, PBr3, PCl3 (PCl5), P/I2, P/Br2
mechanism:
-
minutes.
H2O
RX+ H2O
ROH + HX
reactivity: HI > HBr > HCl, HF: nonreactive
nucleophilicity: I- > Br- > Cl- > Freactivity of alcohols:
CH2OH > C=C-C-OH
> 3 > 2 > 1 ROH
Br
R'
..
- Br
⊕
RCH OPBr2
R'RCHOH + P Br
H
Br SN2
1º, 2º ROH
R'RCHBr+ HOPBr2
37
mechanism and stereoselectivity:
3. Replacement of OH group by the reaction of alcohols
with TsCl/MX or MsCl/MX (M = Li, Na)
O
ROH + Cl S
O
1 or 2
CH3
step 1
H
C O Ts
C O H + Cl Ts HCl
R1 R
R1 R
2
2
config.
retention
step 2
H
H
Nu : + C O Ts TsO Nu C
SN2
R1
R1
R2
R2
config.
inversion
Sulfonate ions TsO- and MsO- are very good leaving
groups which can be easily replaced by the weak
base X-.
-
- HCl
LiX or NaX RX
ROTs
2 step SN2
1 step
X = Br, I
H
e.g
Br
H
R
H
S OH
H
R
1) ClTs
2)NaBr,acetone
CH 3
H
CH 3
(1R,2R)-1-bromo-2-methylcyclohexanol
(1S,2R)-2-methylcyclohexanol
mechanism I (without 3 amine or pyridine)
R
R
C
O
H
H R'
+
O O
R
S
-HCl
C
Cl step 1 H
Cl
R'
O
S
Cl
R
4. Replacement of OH group by reaction of alcohols
with thionyl chloride (SOCl2，二氯亚砜)
R OH + SOCl2
ether
△
step 2
H
RCl + SO2 + HCl
C Cl
intramolecular
attack
+ SO2
R'
Configuration
retention
mechanism II (with 3º amine or pyridine)
9.7 Preparation of amines
R 3NH +Cl +
R 3N+HCl
+HCl
N+
N
+ Cl -
1. By SN2 reaction of RX with NH3 or RNH2
free chloride ions
NH 3+RX
H
R 2NH
O
R
Cl-
C
H R'
S
Cl
O
SN2
Cl C
step 2
R
+ SO2 + Cl
H
RX
+ - NH 3
RNH 3 X
RNH 2+NH 4X
NH 3 R NH + X - RX
2
2
-NH 4X
R 3NH +X -
NH 3
R 3N
-NH 4X
R'
configuration inversion
38
2. Gabriel synthesis
C
O
O
C
C
NH 3
- H 2O
NH
O
phthalic anhydride
C
KOH
- H2O
O
C
O
C O Na
NaOH
H 2O
9.8 Preparation of hydrocarbons (dehalogenation)
O
C - +
NK
C
O
RX
O
C
O
脱卤化反应
RX
RX=CH 3X
1 RX
2 RX
C
+
2R-X + Zn + 2H
NH
C
O
phthalimide
(邻苯二甲酰亚胺）
9.10 Phosphorus and sulfur nucleophiles
负碳离子
R' + RX
R' R + X
X = Cl, Br, I, OTs, OMs
R
CN , RC C , R-
RS (mercaptide ion, RSH mercaptan), HS- (巯基)
(mercapto) and R3P can act as nucleophiles to
react with 1 and 2 RX in SN2 reactions.
R' X + S H
1 , 2 ( SR)
R' X + R3 P
e.g. HC CH NaNH2/NH3 HC C RX(1 )
1 equivalent acetylenyl
RC C
2RH+ZnX 2
O
The replacement of a leaving group with a carbanion
NaNH2/NH3
RH
Another useful reduction reaction of RX:
O
+ H2NR
9.9 Formation of carbon-carbon bonds
RC CH
Et2O
1°,2°
X = Cl, Br. I
NR -KX
C O Na
hydrozine (肼) O
O
NH 2NH 2
C NH
+ H2NR
EtOH, ∆
C NH
O
◆
LiAlH4 or NaBH4
CH3OMs
RS- mercaptide ion
烃硫离子
R' SH
( R'S R ) (sulfide 硫醚)
R' R3 P⊕X
phosphonium salt
季膦盐
RC CCH3 + MsO
9.11 Ring Opening of epoxides (环氧化物）
relative reactivity:
C
C
>
O
ROR’
1. Base-catalyzed ring opening
ROR' + R''ONa R''OH
ROR'' + NaOR'
Stereoselectivity: The nucleophile attacks the C atom
from the back side of the 3-membered ring.
Regioselectivity: The nucleophile attacks the C atom
with less steric hindrance.
e.g.
OH
H2O
R
H C
+ RO- ROH RO C C
SN2
O
O
RO
epoxide ROH
C C + ROOH
C
C
CH2
O
NH3
R
OH
H C CH2
OH
NH2
R
H C CH2
OH
Basic ring opening reagents: OH- , OR- , NaCN,
KI, LiAlH4 (H- ), RMgX (R- ), RLi (R- )
39
Mechanism:
2. Acid-catalyzed ring opening
H+
C C
O
+
CH2 CH2
O
H /H2O
HOCH2CH2OH
H + /HOR
HOCH2CH2OR
HX
+
Nu :
a R'
C C R
O+
H
R' b
HX = HI, HBr, HCl, HCN
CH3
C C
C
Nu
CH3
+
C CH2OH
CH2 Nu :
C
+
H3 C C C
C δ O+
H
C
C CH2 H C C
O
question:
H
C
HOC C Nu
R
Nu
R'
R
a
C C
R'
OH
R
Nu
R'
b
C C R
R'
R
OH
9.12, 9.13, 9.15 Synthesis of alkenes through
elimination reactions
Three kinds of elimination reactions to prepare alkenes:
dehydrohalogenation(-HX) of RX
dehydration(-H2O) of ROH
debromination(-Br2) of R1R2CBr-CBrR3R4
CH3
1) KI
+
2) H3O
CH3
Nu:
Stereoselectivity: anti-attack
HOCH2CH2X
Regioselectivity: The nucleophile attacks the C atom
which has more alkyl groups.
+
δ δ
C C
+O
δ H
CH2
O
HI
H
C
CH2I
OH
I
C CH2OH
H3C
H
1. Dehydrohalogenation of RX
a typical E2 reaction
For dehydrohalogenation: 2º and 3º RX, using strong bases
1º RX, using large strong bases
◆
2. Dehydration of ROH
2 kinds of dehydration reactions of ROH:
H + ROR+ H O intermolecular
2ROH
2
Mechanism and reactivity of alcohol dehydration
C H
fast
R C OH + H +
R'
C H
slow
R C OH
+ 2 H2O
R'
E1
+
C C
H
C C intramolecular
H OH - H2O, △
acid: H2SO4, H3PO4, Al2O3
C H
-H +
R C⊕
fast
R'
R
C C
R'
Reactivity: 3°ROH > 2°ROH > 1°ROH
dilute acid
conc. sulfuric acid
40
◆
◆
Regioselectivity (Zaitsev’s rule):
e.g. H3C H
CH3
OH H3PO4
H △ ,- H2O
CH3
+
84%
16%
H OH
CH
H
HC
H2SO4 H3C
+ 3 C C 2 5
C C
C-C-C-C-C
C2H5
H
H
△ - H2 O H
H
75%
25%
3. Debromination of vicinal dibromides
Br
acetone
C C + 2NaI
C C
- I 2 , -2NaBr
Br
The rearrangement of a carbocation during the
dehydration of some 1°and 2°alcohols
conc.
C C C
H
C
H C
H SO
C=CH2
C C + C C +
C-C-C-C- OH 2 4
H
△ - H2O H majorC H
H
minor
C
C
C
(CH3)3C
C H2C C
C-C-CHCH2 H3PO4
C=CH2 + C=C +
C CH
C
C OH H △ -H2O
C
H
C
minor
major
C H
rearrange
C-C-C-C
⊕
C
◆
C H
C-C-C-C
⊕C
Stereoselectivity—anti-elimination
H
Br
Br
H NaI
-Br2
Br
(R,R)-1,2-dibromocyclohexane
Br
C C
C C +M MBr2
Br
M Zn(AcOH or EtOH)
Mg(Et2O)
H
CH3
Br
H
CH3
Br
CH3
H S Br
Br S H
CH3
I-
or (R,R)-isomer
H3C
CH3
C C
H
H
cis-butene
9.14 Preparation of alkynes
1. Industrial production of acetylene
i. From calcium carbide CaC2
CaC2+ 2H2O
HC CH + Ca(OH)2
ii. From methane
2CH4
very h.t.
HC CH + 3H2
Br
H
NaI
H
cis-1,2-dibromocyclohexane
CH 3
CH 3
H
- H 3C
H H
Br I
C C
H
Br
H
Br stereo- H
CH 3
CH 3
CH 3 selective trans-butene
Br
2. Laboratory synthesis of alkynes
i. From dihaloalkanes
H H
B:
R C C R' △, - HB
X X
- X:
vic-dihalide
X
R C CH2R' 2B: , △
X
gem-dihalide
B:
H
R
C C
R'
X
B:
△ , -HB
RC CR'
- X:-
RC CR' + 2BH + 2X-
KOH/H2O,NaNH2/NH3
41
ii. From other alkynes
9.16 Oxidation reactions of alcohols and aldehydes
1. Oxidation of 1° alcohols to aldehydes and carboxylic
acids
[O]
[O]
RCH2OH
RCHO
RCOOH
R' X 1
RC C H NaNH2 RC C Na⊕ -NaX RC CR'
liq.NH3
'
'
RC C H RMgX RC CMgX RX 1 RC CR'
-MgX2
Et2O,-R'H
◆
CrO 3+
iii. From ketones
O
Cl
PCl5
2NaNH2
R C CH2R'
RCCH2R'
CR'
NH3 RC
-POCl3
Cl
-2NaCl
-2NH3
RCH=CHCH2CH2OH
RCH2 OH
RCH2 OH
Cu or Pd
△
H2CrO4
H2 O
PCC
RCH=CHCH2CHO
CH2Cl2
r.t.
O
RC H + H2
O
+
RC OH + HCrO3- + H3O
Chapter 10 Additions to Carbon-Carbon
Double and Triple Bonds
10.2 General addition reactions of C=C double bonds
General expressions:
+
+ HCl
N H CrO 3Cl
-
pyridinium
chlorochromate(PCC)
2. Oxidation of 2°alcohols to ketones
Jones oxidizing agent: CrO 3 in sulfuric acid
H2CrO 4, KMnO 4, NaOCl/H 2O/CH 3COOH
◆
O
OH CrO3/H2SO4
RCH CHCH2CR'
RCH CHCH2CH R'
CH3COCH3
O [O]
RC H
RCOOH
[O] H2CrO4, CrO3/H+, KMnO4/OH- (cold,dilute),
Ag2O/OH- , O2
10.3 Addition of HX to alkenes
C C +H X
add.reaction
elimination
(E1 or E2)
C C
H X
1. Rregioselectivity of the addition by ionic mechanism
add.reaction
sym. reagent
add.reaction
C C +Z Y
unsym. reagent
N
3. Oxidation of aldehydes to carboxylic acids
[O] = KMnO4/OH-, ∆; Na2Cr2O7 or K2Cr2O7/H2SO4;
H2CrO4 or CrO3/H2SO4
C C +Z Z
Sarrett oxidant (PCC)
C C
Z Z
C C
Z Y
Z2 = H2, Br2, Cl2
+
Z-Y = HI, HBr, HCl, H3O, H2SO4,
RCOOH, HOX (X2/H2O)
X-H
or
H-X
+
C-C=C-C
+
Cl
C-C-C-C
H
or X
X
H
X
Reactivity: HI > HBr > HCl
42
CH2 CHCH3 + HCl
C
C
C C + HCl
◆
AcOH
H2C CHCH3
H Cl
2-chloropropane
AcOH
Step 1
+
slow
δ δC C + H X rate determining
C
C-C-C tert-butylchloride
Cl H
-
X:
R'
C C
H H+
R''
CH2R"
CH2R"
+
R
R
R' C CH2 R''
⊕
X:-
C
R R'
+
R"CH2
X C
C X
R
R
R'
R'
a racemate
3. Regioselectivity of the free radical addition of HBr
C C C + HBr
ROOR
or hυ
C-C-C-Br
H
10.4 Addition of Br2 and Cl2 to olefins in nonpolar solvents
r.t.
C C + Br2 in the dark
CCl4
C C
Br Br
H
C C + X⊕
Step 2
Markovnikov’s rule: In the ionic addition of HX, the proton
always adds to the C atom of the carbon-carbon double bond
which has more H atoms.
2. Stereoselectivity of the ionic addition to an olefin
Markovnikov’s addition
H
C C + X - fast
⊕
◆
H
C C
X
anti-Markovnikov’s addition
the addition reaction via a free radical mechanism:
step 1
RO OR
2RO .
.+
ROH + Br .
step 2
RO H Br
H
.
b
HBr
a C-C-C-Br
C-C-C + Br .
.
step 3
C C C + Br
Br
.
b C-C-C HBr C-C-C H + Br .
a
Br
Br
The order of stability of carbon free radicals:
3°C. > 2°C. > 1°C. > .CH3
Notice: Under the same conditions HF, HCl and HI do not
react with alkenes in a free radical mechanism.
mechanism:
H H +
C
+ δBr
step 1
C
H H
δBr
Reactivity: F2 >> Cl2 > Br2 > I2
HH +
Cδ δ+
Br + Br
C+
δ
H
H
bromonium ion
Stereoselectivity:
+ Br2
in the dark
H Br +
CCl4
Br H
Br H
H Br
anti-addition
trans-vic-dibromide
step 2
a H
H
C
a
+ Br
Br
C
b H
b
H
Br
CH2
H2C
Br
43
e.g.
Br
Br
C C
H
a
H
H
- Br
R
R
cis-olefin
Br
H
H
C C R + R C
H
R
Br
Br
H
Ra b R
Br
C
Br
b
Br
b
⊕
C C
a R
Br
H Br
R
C C
R
H
trans-olefin
The common rule for the addition of a symmetric
reagent Z2 to a C=C bond:
Y syn-addition of Z2
a mesomer
X
anti-addition of Z2
a racemate
Y syn-addition of Z2
C C
Y
X anti-addition of Z2
trans
a racemate
Y
C C
X
H
cis
X
Br
C
H
R
C H
Br
R
mesomer
10.5 Addition of X2 in an aqueous solution
(Br2/H2O,Cl2/H2O) to olefins
mechanism:
step 1 R
slow
C CH2 + X X
R
X2 = Br2, Cl2
C C + XOH
X2 + H2O
H2O
HX
C C +
X OH
C C
X X
halohydrin 卤代醇
major
XOH = HOCl, HOBr
hypochlorous acid
hypobromous acid
10.6 Addition of other acids to olefins and acidcatalyzed hydration.
H2SO4
l.t.
+
C C
H2 O
C C
H OSO3H H△SO
2
4
C C
H⊕OH2
H+
ROH,H + C ⊕C
H OR
H
H
H3 O
a mesomer
RCOOH C C
H OCR
O
+
H2 O
C C
H OH
C C
H OH
C C
H OR
C C
△
RCOOH H OH
step 2
+
CH2 + X
X
halonium ion
OH
⊕OH2
+
C CH2
C CH2 − H
fast
X
R
R
X
R
R
Stereoselectivity: antiX
anti-addition
addition
Regioselectivity:
CH
XC
2
X adds to the C with
X
R
more H atoms
R
H2O
R
R
R
R C
C CH2
⊕
X
acid-catalyzed hydration
H+(dilute), l.t.
HO H
C C + H2O
C C
+ (conc.), h.t.
H
acid-catalyzed dehydration
10.8 Addition of diborane (B2H6)—hydroboration
The addition of diborane to a C-C double bond is
called hydroboration (硼氢化反应).
6 C CH2 B2H6/Et2O 2 ( C CH2 ) 3 B
or BH3/THF
H
44
H
C
mechanism:
D
C
H
H
B
S
S
C
R
+
δ- δ
+ H BH2
+
R
C
R'
D
R
R R
R1 C C H
C
D
H
R'
H B
S
S
C C
R
R'
H
tr.s.
B
B
C
H
R
O
D
C CH2D R'
RCOH
H
R'
C CH2D
R
+
D
R +
H
R'
R1 C C H
configuration retention
R
D
R
+ R R R H
1 C
C
D
H B
H
H
B
H
C
B
C
R
configuration retention
D
H
R'
D
R +
R1 C C H
Hydroboration:
steteoselectivity: syn-addition
regioselectivity: anti-Markovnikov's rule
H
B
H
D
R
H2O2
C
H
+
R1 C C
OH
R
H OH
R'
°
OH
C
1 alcohol
H
D
prepare 1° alcohols
10.7 Hydroxymercuration and demercuration
Hydroxymercuration (羟汞化反应):
R
H
C CH2
Hg(OAc)2,H2O/THF
-HOAc
R
H C CH2
HO Hg(OAc)
The key points for this kind of reactions:
i. The reaction follows Markovnikov’s rule. A method to
prepare 2°or 3°alcohols.
ii. There is no rearrangement of the C+ during the reaction.
Demercuration:
R
NaBH4/OH
H C CH2
HO Hg(OAc) -Hg,-AcO
R
H C CH2
OH H
10.9 Addition of carbenes (卡宾）
A comparison of three synthetic methods:
-
C
C-C-C=C
C
Carbenes (:CR2) are normally formed via 3 ways:
i. The elimination of N2 from diazo (重氮) compounds
(RR’CN2)
-
C H OH
1
C-C-C-C
C
C OH
1)Hg(OAc)2/H2O,THF
C-C-C-C
2)NaBH4/OH
C H
OH H
+
H2O, H C-C-C-C
3
CC
1)BH3/THF
2)H2O2/OH
2
C
H
R2
C
C C
C C
R2CN2 △ or hυ
Ph
" R2C:" H
2+
or Cu ,-N2
CH
Ph
H
+ its enantiomer
Formed by rearrangement of a C +
45
2. The α-elimination of chloroform (CHCl3) or
bromoform (CHBr3)
+ :CCl2
Cl Cl
CHCl3+NaOH
3. Simmons-Smith
CH 2I2+Zn(Cu) reaction
ICH 2ZnI
Carbenoid 类卡宾
CH 2
R
R
CH 2I2
C C
C C
R
H
H Zn(Cu) R
H
H
Epoxidation of small olefins used in industrial
production
CH2=CH2 + O2 Ag(cat.)
H2C CH2 or H2C CHCH3
or
O
O
250 ℃
CH2=CHCH3 + O2
ethylene oxide propylene oxide
10.10 Epoxidation of olefins (anti-hydroxylation)
O
O
+
R' RCOOH
C C
R'
H3O
C
C
R'
R epoxidation R' R a b R
R
H2O
OH
OH
R'
R'
C
R' R
C
R
+
R
C
C
'
OH
OH R R
glycols or vicinal diols
Mechanism and stereoselectivity
C C
O
O
Mn
O
O
C
O
C
OH
C C
O
H
O
HO
OH
2
Mn
O
O
syn-addition
10.11 Oxidation of alkenes (syn-hydroxylation)
C C
KMnO4(dilute)/OH
l.t.
C C
HO OH
1)OsO4
2)NaHSO3 or Na2SO3
C C
HO OH
C C
O
O
Os
O O
C
O
C
NaHSO3
O
Os
O
C C
HO OH
O
Strong reaction conditions:
R
R
C=CH2 KMnO4/OH, △
C=O + CO2 + H2O
R'
R'
KMnO4/OH
l.t. dil.
OH
H2 O
KMnO4/OH , △
H
RCH=CHR
+
RCHCHR
OHOH
O
2RC OH
Testing methods for multiple bonds
alkanes KMnO4/OH
deep purple
alkenes KMnO4/OH
alkynes deep purple
The deep purple color does
not disappear.
The deep purple color
disappears quickly.
46
10.12 Ozonization of olefins (Ozone-O3)
R
R'
C C
R''
+ O3
H
R O
R'' Zn or (CH3)2S
C
C
R' O O H H2O
10.13 Hydrogenation of alkenes and alkynes
1. Hydrogenation of alkenes
i. H2/M (M = Ni, Pt, Pd)
R
R''
C O+ C O
H
R'
◆
cat.(Ni,Pt or Pd)
RCH2CH2R'
RCH=CHR' H2 (pressure)
Determination of the location of the double bond
CH3
CH-CH=CH2
CH3
CH3
C=CHCH3
CH3
H3C
O
O
1)O3
+
HC
2)Zn/H2O 3 CH C H HC H
O
CH3
1)O3
C= O + CH3C H
2)Zn/H2O CH3
Stereoselectivity: syn-addition
up
H H
Cl
C
H5C2
down
CH2
H H
H
C
The rate of hydrogenation of alkenes
CH2=CH2 > RCH=CH2 > RR'C=CH2 >
RCH=CHR' > RR'C=CHR'' > RR'C=CR"R"'
ii. H2NNH2/H2O2
H2,Pt
H H mesomer
CH3 AcOH H3C CH3
H3 C
◆
Cl
Ni
CH3 + H5C2 C CH3
syn. Cl
H5C2
H
down
up
..
H H
H
H2N-NH2+H2O2 cat.Cu2+ N=N + N=N + H2O
..
..
..
H
hydrazine
cis-diimide trans-diimide
(二酰亚胺）
H H
Br
Br
syn-add. C C
C C + N N
+ N2
H
R
R H
Br R
Br
R
N N
H
iii. H2/catalyst (Pd/C)
H H
H2,Pd/C H C H +
H CH3
3
H CH3 H3C H
H3C
CH3 anti-add.
H H
2. Hydrogenation of alkynes
i. Thorough addition of alkynes to alkanes
R C C R' + 2H2 cat. RCH2CH2R'
cat. = Pt, Pd, Raney Ni
H
ii. Syn-addition of alkynes to olefins
H
H
cat.
C C
R C C R' syn-addi R
R'
(Z)-olefins
cat. = Ni2B(P-2), Pd/CaCO3 (Lindlar cat.),
Pd/BaSO4/Py (Cram cat.)
H H
iii. Anti-addition of alkynes to olefins
RC CR'
R
H
Na or Li
C C
R'
NH3 or RNH2 H
anti-add.
(E)-olefin
47
-80℃ CH2CHCH=CH2+ CH2CH=CHCH2
H
Br
H Br
80%
20%
+
10.14 Addition of conjugate dienes
CH2=CH-CH=CH2 HCl CH2CHCH=CH2 CH2CH=CHCH2
H
Cl
H Cl
mechanism
step 1 CH2=CH-CH=CH2 + HCl
CH2CHCH=CH2
H Cl
kinetically favored
40℃
40℃
1,2- ~
20%
H
⊕
CH CHCH=CH
2
Cl
-
H
⊕
step 2 CH2CHCH=CH2
1,2-add. Cl
CH2=CHCH=CH2 + HBr
1,4-addition
1,2-addition
1,4- ~
80%
2
⊕
CH2CH=CHCH2
H Cl 1,4-add.
CH2CH=CHCH2
H
Cl
thermodynamically
favored
10.16 Reactions of alkynes (additional section)
1. Addition of alkynes
i. Hydrogenation of alkynes (10.13-2)
ii. Addition of X2 to the triple bond
X X
X X
X2
2
C C
C C
CCl4 X
CCl4 X X
X2 = Br2, Cl2 anti-addition
There exists an equilibrium between 2 products.
40 ℃
CH2CHCH=CH2
CH2CH=CHCH2
H
HBr
Br
H Br
1,4rearrange
1,2-
iii.Addition of HX to the triple bond
H X
HX
H
R
C C HX H C C R
anti-add H
X
H X
HX=HCl,HBr,HI
haloalkene gem-dihaloalkane
H-C CR
following Markovnikov’s rule
C C
Br
l.t.
-C C-C-C=C + Br2 CCl -C C-C-CH C
4
Br
90%
H-C CR + HBr
H
R Br
h.t. or
R
C C + C C
hν or ROOR Br
H H
H
syn-add.
anti-add.
anti-Markovnikov’s rule
v. Hydroboration of the triple bond
iv. Addition of H2O to the triple bond
RC=CH
HO H
following Markovnikov’s rule enol form
（烯醇式）
RC CH3 tautomerization
O
keto form（酮式）
H-C CR
HgSO4/H2SO4
△ , H2O
The interexchange between enol form and keto form is
called tautomerization（互变异构）.
3 RC CR'
R' syn-add.
B 2H 6/Et 2O or R
C C
BH 3/THF, l.t. ( H
)3 B
H 2O 2/OH
AcOH
R
H
volume: R'<R
C C
R'
H
Z-olefins
RC=CR'
H OH
tautomerization
anti-Markovnikov’s rule
RCH 2 CR'
O
48
RC CH
diisoamyl
borane
H2O2
OH-
H
R
C C
H
OH
O
RCH2 C H
RC CR'
using diisoamyl borane to prevent
the following by-reaction
H
B
C C
R
H
11.1~11.3 Aromatic hydrocarbons
NH2
OH
CH3
9
1
2
3
5
4
8
9
1
5
10
4
7
6
8
2 7
3
6
OH
OH
HO
a
toluene aniline phenol o(m,p)-xylene styrene
8
1)KMnO4/OH
2)H3O
RCOOH + R'COOH
+
RCOOH + R'COOH
OH
NO2
Br
OH
CH3CHCH2CH2
OH OCH3
c
b
CH2CH3
d
e
HC=CH2
CH3
CH3
OH
7
6
2)H2O
bis-(2-isoamyl)borane
Chapter 11 Functional Groups and
Nomenclature Ⅱ
CH3
1)O3
H B
H C C H
R B
HB
C
(C-C-C ) BH
2
C
2. Oxidation of alkynes
10
1
2
5
4
3
a) 1,2-benzenediol(儿茶酚)
b) 1,3,5-benzenetriol（间苯三酚）
c) 1-methoxy-4-nitrobenzene
d ) 3-phenyl-1-butanol
e) 3-ethyl-4-(p-bromophenyl)-1-cyclohexene
p-cresol naphthalene anthracene phenanthrene
萘
蒽
菲
11.4 Aldehydes and ketones
Aldehydes: suffix — “-al” or “-carboxaldehyde”
As a substituente (-CHO) — “formyl”
e.g.
O
O
O
C H C
C-C-C- C H
CH3C H
C C
C C
a
c
b
a ) 3-methyl-4-phenylpentanal
b) 2-isopropylcyclopentanecarboxaldehyde
c ) acetaldehyde
O
C H
CN
d
HOOC
CHO
O
OHC-C-C-C-C-C-CHO
C H
f
e
d) 3-cyano-1-benzaldehyde
e) 2-formylbenzoic acid
f) pentane-1,2,5-tricarboxaldehyde
or 3-formylheptanedial
49
Trivial names are widely used for aldehydes with 1-5
carbon atoms:
Formaldehyde（甲醛）
Acetaldehyde
Propionaldehyde
Butyraldehyde
Valeraldehyde
Formyl (甲酰基）
Acetyl
Propionyl
Butyryl
Valeryl
Ketones: suffix — “-one” or the names of two alkyl
groups + ketone”
As a substituente (C=O) — “oxo”
O
H 3C C CH 3
acetone
HOOC
O
C C C
acetophenone
(methyl phenyl
ketone)
propiophenone
(ethyl phenyl
ketone)
11.6 Derivatives of carboxylic acids
Carboxylic acids: suffix–“-(o)ic acid” or “-carboxylic acid”
COOH
COOH
OH O
C-C- C OH
NC
O
CCH3
O
CCH3
2-acetylbenzoic
acid
11.5 Carboxylic acids
3-(p-cyanophenyl)-2hydroxypropanoic acid
3-cyclohexene-1,2dicarboxylic acid
Some trivial names for acids with low molecular weight:
formic acid (蚁酸) acetic acid (醋酸) propionic acid
butyric acid
valeric acid
oxalic acid (草酸)
maleic acid (马来酸, 顺丁烯二酸)
fumaric acid (富马酸, 反丁烯二酸)
1. Acid chlorides (acyl chlorides, 酰氯)
suffix – “-(o)yl chloride”
O
CH3C
2-methyl-2-butenoyl m-acetylbenzoyl
chloride
chloride
p. 490:
Table 11.3 The order of priority for selected functional groups
Suffix – “-(o)ic anhydride”
O
C
O
C-C-C
O
propanoic
anhydride
propionic
anhydride
C
O
C C
C C
O
O
2,3-dimethylbutenedioic
anhydride
O
C Cl
O
C Cl
C-C=C-C
3. Esters (酯)
suffix – “-(o)ate” or “-carboxylate”
2. Acid anhydrides (酸酐)
C-C-C
O
O
C-C-C-C C H
4-oxopentanal
O O
C-C-C-C-C=C
5-hexene-2,4-dione
Cl
Cl
C
O
O
C
O
4,5-dichlorophthalic
anhydride
4,5-dichlorobenzene1,2-dicarboxylic
anhydride
Cl
O
C
C O C C C C
CH3
O
C OCH CH2
OCH3
isopentyl 4-chlorobenzoate vinyl 2-methoxy-6-methyl-3cyclohexene-1-carboxylate
4. Amides (酰胺)
suffix – “-amide” or “-carboxamide”
O
C NH2
benzamide
C OC
C-C-C-C-N-C-C
N-ethyl N-methyl
-isopentanamide
O
CH3 HNC
O
C NHCH3
N,N'-dimethyl-2,5-cyclohexadiene-1,4-dicarboxamide
50
6. Nitriles (腈 RC≡N)
suffix – “-nitrile”
As a substituente (C≡N) – “cyano”
5. Carboxylate salts (羧酸盐)
suffix – “-(o)ate” or “-carboxylate”
COONa
Cl
NO2
sodium 2-chloro4-nitrobenzoate
C-C-C-C-C-C-COONH 4
C C
C
CN
propanenitrile
CN 3-cyano-1-cyclohexene
ethyl 3-cyanocyclopentanecarboxylate
ammonium 2-ethyl6-methylheptanoate
potassium 2-cyclohexenecarboxylate
COOK
O
C OC C
C-C-CN
11.7 Sulfur and phosphorus compounds
systematic names:
1. Sulfur compounds
thiols – mercaptans
thioethers – sulfides
(RSH, 硫醇)
(RSR, 硫醚)
-SH, mercapto, 巯基
-SR, alkylthio, 烷基硫基
trivial names:
C-C-SH
ethyl mercaptan
C-C-C-C=C
SCH 3
C
C-C-C-SH
isobutyl mercaptan
C=C-C-S-C=C
allyl vinyl sulfide
O
R-S-R
O
dialkyl
dialkyl
sulfoxide sulfone
亚砜
砜
C
C-C-C-C-SH
2-methylbutanethiol
SH
4-methylthio-1pentene
3-mercapto1-cyclopentene
C-C-S-C-C
diethyl sulfide
the names of sulfoxides and sulfones:
O
R-S-R
C-C-SH
ethanethiol
O
Cl-S-Cl
O
CH 3SCH 3
dichloro
sulfoxide
dimethyl
sulfoxide
thionyl chloride
二氯亚砜
O
O
R-S-OR'
R-S-Cl
O
O
sulfonyl chloride sulfonate ester
methyl methane~
methane~
O
R-S-OH
O
sulfonic acid
methanesulfonic acid
甲磺酸
O
R-S-NH 2
O
sulfonamide
methane~
(R=CH3: 甲磺酰氯) (R=R’=CH3,甲磺酸酯)
Some physical properties of sulfur compounds:
b.p.:
RSH < ROH
RSR’ > ROR’
The solubility in water: RSH < ROH
The acidity in water:
RSR’ < ROR’
RSH > ROH
2. Phosphorus compounds
O
CH3O-P-OCH3
OH
triphenyl dimethylhydrogen
phosphine phosphate
Ph3P
(二甲基磷氢酸酯)
51
12.3 Stability of radicals
Chapter 12 The Chemistry of Radicals
The energy required to break a covalent bond
homolytically is called bond dissociation energy.
12.1~12.2 Radicals
The mechanism of organic reactions can
be divided into 2 types:
a. ionic reactions
b. free radical reactions
A free radical is a species with an unpaired
electron.
i. To calculate △Ho(enthalpy, 焓)
Another example:
C
C-C-Cl + H-Cl
C
+103
+78.5
C
C C H + Cl-Cl
C
-58 (kcal/mol)
-91
△Ho = +32.5 kcal/mol
ii.To estimate the relative stability of free radicals
e.g.
C-C-C-H
+98
C C C
H
+94
C
C C C
H
+91 (kcal/mol)
12.5 Generation of radicals
The most useful starting compounds for
generation of radicals are peroxy ethers,
benzoyl peroxide and azo (偶氮) compounds.
R-O-O-R △ 2RO.
R-N=N-R
N2 2R.
△
O
O
O
.
RC-O-O-CR △ RC O
CN
CN
H3C C N N C CH3
CH3
CH3
azobis(isobutyronitrile)
(AIBN) (偶氮二异丁腈)
H CH 3 + Cl Cl
+104
CH 3 Cl + H Cl
+58
-83.5
-103 ( kcal/mol)
△Ho = 104 + 58 - 83.5 – 103 = -24.5 kcal/mol
endothermic
exothermic
The relative stability of carbon free radicals:
.
.
PhCH 2. >CH 2=CHCH 2. >3 C .> 2 C .> 1 C >CH
3
12.4 The structure of carbon free radicals
R .
C R''
R'
CH3 CH2 CH2 CH3 + Br2
sp2
HBr
C2H5 Br2
C .
ROOR hν
Br2
e.g. Br C C2H5
H
CH3 from
the left
(R)
H CH3
H5C2
C Br
from H
CH3
the right
(S)
X2 hν 2X. X = Cl, Br
O
O
RCR hν RC . + R.
CX4 hν . CX3 + X . X = Cl, Br
RS-H hν RS. + H.
O
NBr
N-bromosuccinimide
NBS
O
52
12.6~12.11 Some important radical reactions
The mechanism of free radical addition of olefins:
1
2 ROOR
1. Radical addition to alkenes (12.11)
△
H SR'
RCH-CH2
R'SH
HBr
H Br
ROOR RCH=CH2 ROOR RCH-CH
2
or hν
or hν
hν
CX4
CHCl3
or ROOR
H
RCHCH2Br
RCH CH2 chain-propagating
step
.
RCH-CH2Br
.
RO.
RCHCH2Br
chain-terminating
RCHCH2Br step
RCH CH2Br
OR
RCHCH2Br
HBr
RCH-CH2
H CCl3
RCH-CH2
X CX3
2. Kolbe electrolysis (decarboxylation reaction) (12.7)
O
O
1
e
.
R.
RR
RC O
anode RC O CO 2 coupling 2
3. Halogenation of alkanes (12.8)
r.t.
CH3Cl + HCl
in the dark
very slowly
CH4 + Cl2
CH4 + Cl2 △ or hν CH3Cl + HCl
fast
For the same alkane, the order of relative reactivity:
F2 > Cl2 > Br2 > I2
F2
explosion,seldom used
△ or hν
CH4 + Cl2 hν ClCH3+Cl2CH2+Cl3CH+CCl4
in excess
Mechanism:
1
2 Cl2
chain-initiating
△ or hν
ClCH3
step
.
Cl
CH4 HCl chain-propagating
Cl2
step
.
. CH3 .
Cl
CH3
chain-terminating step
ClCH3
CH3 CH3
H
(CH3)2C-CH2CH3
Cl2(1mol)
(1mol)Br2
hν hν
Br
(CH3)2C-CH2CH3
Cl2 no selectivity, not useful
△ or hν
alkane
ClCH2
I2
no reaction
H
CS
CH2CH3 H3C
Br2
hν
CH2Br
RCH=CHCH3
+
CH2CH3
CH2Cl
H Cl
3) +
+ (CH3)2C-CH(CH
R S
H
(CH3)2C-CH2CH2Cl
CH3
H
C
R
+
CH3
Cl
(CH3)2CCH2CH3
Br2
selective to different Hs:
△ or hν 3 R H >>2 R H >1 R H
△ or hν
chain-initiating
step
RO.
HBr ROH
Br.
Br2
hν
R + S isomers
RCHBrCH=CH2
+
RCH=CHCH2Br
53
4. Dehalogenation (12.9)
RBr+Bu 3SnH
AIBN
12.12 Reductions and radical anions
1. Birch reduction
RH+Bu 3SnBr
5. Autoxidation
e.g. antioxidant
+2Na+2ROH
trade mark
1010
H H
e source, H+ source
C OH C
1076
C C
C C
C
C
CH2CH2COOCH2(CH2)16CH3
C(CH3)3
[ HO
CH2CH2COOCH2] C
4
C(CH3)3
NH3(l)
H
reagents solvent H
substrate
Regioselectivity:
R
R
Li,NH3(l)
CH3CH2OH
1)Li,NH3(l)
COOH CH3CH2OH
+
2)H3O
COOH
R = alkyl, alkoxyl
mechanism:
eNa
H H
H
H H e
H .. .H
. Na
H OR
H
H
H H
H H
H-OR
2. Reduction of the double bond conjugated with a
carbonyl group
O
H H
O
1)Li,NH3(l)
2)H3+O
O
3(l)
CH=CHC-OH 1)Li,NH
2)H+3O
O
CH2CH2C-OH
Mechanism:
3.Regioselective alkylation of α,β-unsaturated
ketone by an enolate anion
O
R
O
O
Li
R'"X
R'"
R
R
R' R" NH3(l)
R' R"
e-
R' R"
Li
..
:O :
.
R
R' R"
O
R
e. H Li
O
R
R'
R' R"
+
OH
H3O
tautomerize
CH2 R"
R
O
R'
R
CH2 R"
R'
O
R'"X
R'"
R
R"
R' CH2
O
R
R'
H
H
R"
NH3
H
R"
O
R
CH2 R"
R'
54
A comparison of the following two methods :
Chapter 13 Benzene and Aromatic
Compounds
O
B
O
H strong base
H
+
H
H
CH3
CH3
CH3 BH
O
O
C-C=C C=C-C-Br
C=C-C
SN2
+
C
C
(1)
O
13.1~13.2 Benzene (C6H6)
Br2, r.t.
CCl4, in the dark
C6H6
KMnO4/OH
cold, dil.
+
O
2Li
NH3(l)
CH3
O
O
O
C=C-CBr
CH3
CH3
H3O
C-C=C
3H2/Ni
h.t. h.p.
H2/Ni
25℃
C
(2)
The ancient chemists determined the structure of benzene
based mainly on the following facts:
1) The addition reaction of benzene is very difficult.
2) In the presence of Lewis-acid, the H on the benzene
ring can be substituted by Br2 or Cl2, and there exists
only one formula structure of monosubstituted
benzene.
C6H6 + X 2
AlX3
Kekule structure of benzene:
H
H
H
H
H
H
Some experimental facts contradict Kekule structure:
X
X
C6H5X+HX
X
X
1,2-disubstituted benzene
13.3~13.4 Modern theories of the structure of
benzene
◆
Resonance theory:
◆
Molecular orbital theory:
All carbon atoms in benzene are sp2 hybridized.
The 6π electrons are delocalized in 6p orbitals.
H
H
sp2 H
The molecule of benzene is planar, and all of its C-C
bonds are of equal length.
cyclooctatetraene
unhybridized
p orbital
H
H
H
13.5~13.7 Hückel’s rule—The (4n+2) π-electron rule
55
E
π∗
Hueckel’s rules:
EAO
π
2-
πe 4
6
6
6
2
⊕
6
8
10
CnHn cyclic compounds with planar rings containing
(4n+2) of πes (n = 0,1,2… positive integers) are
aromatic compounds. They are more stable than their
corresponding linear polyenes.
CnHn cyclic compounds with planar rings containing 4n
of πes are antiaromatic compounds. They are less stable
than their linear polyenes.
CnHn cyclic compounds not in planar rings containing 4n
of πes are non-aromatic compounds. They have similar
stability with their linear polyenes.
Monocyclic compounds CnHn
13.8 Heterocyclic aromatic compounds
e.g.
..
N
4
1.35A
>>
1.50 A
~~
nonaromatic
antiaromatic
with large ring strain 8Cs not in a plane
alternate single and
less stable
double bonds
similar stability
5
3
6
N 2
..
O
..
..
S
..
pyridine
pyrrole
furan
thiophene
吡啶
吡咯
呋喃
噻吩
1
1.39 A
>>
..
N
H
..
N
H
aromatic
equal length of
all C-C bonds
more stable
5
4
6
3
7
8
N 2
1
imidazole quinoline
咪唑
喹啉
pyridine
N :
13.9 Polycyclic aromatic compounds
1. Condensed benzenoid aromatic compounds
..
N H
pyrrole
..
O ..
e.g. condensed ring or fused ring compounds:
naphthalene anthracene phenanthrene
furan
Chrysene 18 πes
benzo[a]pyrene 18 πes
苯并芘
Count only the π-es on the periphery of the aromatic ring,
don’t count the inside π-es.
◆
56
2. Other aromatic compounds without benzene ring
Another similar example:
+
⊕
⊕
⊕
azulene
naphthalene
...
⊕
stability:
+
+
>
⊕
an aromatic cation
an aromatic anion
large dipole
moment
13.11 Annulenes（轮烯）
Monocyclic conjugated polyenes with more than 10
carbon atoms in the ring are called annulenes.
According to Hückel’s rule, annulenes with 14, 18,
22 … πes in the ring are aromatic compounds.
H
H
H
H H
H
[10]-annulene
2 trans C=C all cis
1 trans C=C
e.g.
non-aromatic
[14]-annulene [16]-annulene (20，24…)
aromatic
non-aromatic
In general, an aromatic ion is more stable than its analogous ion.
13.12 Aromatic ions
H
strong B
(LiPh)
H
H
H
HH
H+
H
H NMR: 3 peaks
1 peak
H NMR: 4 peaks
H
H
H ⊕ H
H
1 peak
H
+
1
H H
H Ph3C+ClO4
H
H-
H
◆
Experimental phenomina:
δ -0.5 ppm
H
H
H
⊕
13.10 NMR and aromaticity
H H
H H
H H
H
H
5p–6πes
>
⊕
H
H
1
H
H H
H
stability:
H H
H
H
H
H H
H
H
7p–6πes
H
H
H
the H on the ring
δ 6.9~7.3 ppm
H
57
H
H
H
Chapter 14 Aromatic Substitution Reaction
H
H
H
HH
HH
H
H
H
[14]annulene
H
1H
NMR:
14.2 Electrophilic aromatic substitution reactions
outside H: δ 7.6 ppm
inside H: δ -0.1 ppm
General equation:
Y
Y
H+
+
+ E
E
A comparison with the electrophilic addition of HBr to olefins:
1H
NMR:
outside H: δ ~7 ppm
center H: δ -4.03 ppm
R2C=CH2 + HBr
R2C-CH3
Br
The curve of reaction energy:
General mechanism of electrophilic aromatic substitution:
E2
E
H
+ E
+
step 1
E
HE
step 2 :B
HB
fast
+
slow
E
+
H
E
H
E
+
H
H
D
D
D
per-deuterated benzene
+ E+
H/D isotope effect
E
+
D
D
H
E
+
D
H
H
E1
arenium ion (苯金翁离子)
σ−complex
H
H
H
+
Since △Ε1 >> △Ε2, the first step of the reaction
is a slow step—rate determining step.
arenium ion: a hybrid of 3 resonance structures
◆
14.3 Effect of substituents on reactivity and
orientation of electrophilic aromatic
substitution reactions
7 different cases of IE and RE of substituents:
i. Only with e-releasing IE on a benzene ring
e-r IE
R alkyl groups have weak e-r IE
a. Electronic effect of substituents
ii. Only with e-withdrawing IE on a benzene ring
e-releasing IE
Electronic
effect
induction
effect (IE)
e-w IE
e-w IE
+
e-withdrawing IE
NH3
CX3
+
resonance
effect (RE)
+
+
or NH 2R, NHR 2, NR 3
e-donating RE
X = F,Cl
e-accepting RE
The CX3 and the groups with positive
charges have strong e-w IE.
58
iii. Only with e-releasing RE on a benzene ring
e-r RE
e-r RE
C=C
C=C
C=C
E
H
+
E+
Phenyl and vinyl groups have weak
e-r RE on a benzene ring.
+
C=C
E
H
C=C
E
+
H
C-C
+
E
H
iv. With both e-releasing IE and e-releasing RE on a
benzene ring
e-r IE
e-r IE
O
S
e-r RE
e-r RE
The groups with negative charges have
a strong e-r effect on the benzene ring.
vii. With weak e-withdrawing IE and strong e-releasing RE
on benzene ring
Since e-w IE is weaker than e-r RE, the
general electronic effect is e-releasing.
This kind of substituents includes:
e-w IE
NH
.. 2
-NHR, -NR2, -NHCHO, -NHCOR,
-OH, -OR, -OCR, -OCH
O
O
e-r RE
b. Effect of substituents on reactivity of electrophilic
aromatic substitutions
The order of Eact (∆E1): Eact(Ye-w) > Eact(H) > Eact(Ye-r)
Reaction rate:
C6H5Ye-w < C6H6 < C6H5Ye-r
e-releasing groups—activating groups
e-withdrawing groups—deactivating groups
+ E
E
H
..
: OH
E
H
..
: OH
E
H
..
OH
E
H
Among 4 resonace structures, the 4th structure is relatively
stable, since every atom has 8 es in the valence shell.
For para-attack:
..
:OH
+E
..
: OH
..
: OH
..
OH
..
:OH
H E
H E
H E
+
Cl
para
..
: OH
+
Cl
+
..
: OH
+
FeCl3
For ortho-attack:
+
OH
OH
+ Cl2
Y
+
OH
Based on the effect of substituents on orientation,
substituents can be divided into 2 types:
• para-ortho directive groups—including all ereleasing substituents and the weak e-withdrawing groups which have at least one
nonbonding e-pair on the atom attached to the
benzene ring.
• meta directive groups—including all e-withdrawing groups without non-bonding e-pair on
the atom attached to the benzene ring.
+
The new coming group will be bonded to para or
ortho-position towards the original substituent.
c. Effect of substituents on orientation of electrophilic
aromatic substitutions
+
weakly activating: -CH 3, -R, -C 6H5, -C=CR 2, -C=CH 2
e-w IE
X = F, Cl, Br, I
.. Since e-w IE is larger than e-r RE,
:
X
.. the general electronic effect of a halogen
e-r RE atom is weakly e-withdrawing.
+
strongly activating: -O , -S , -NR 2, -NHR, NH 2, -OH
O
O
O
O
moderately activating: -OR,-SR,-OCH,-OCR,-NHCH,-NHCR
e-w RE
This kind of substituents, including
-CHO, -CO2R, -CONH2, -CO2H,
-SO3H, -CN and -NO2, have strong
e-w effect on a benzene ring.
vi. With strong e-withdrawing IE and weak e-releasing RE
on a benzene ring
+
i. Activating, para-ortho directive substituents
including following groups:
e-w IE
O
C R
+
d. General classification of substituents based
on their effect on reactivity and orientation
v. With both e-withdrawing IE and e-withdrawing RE on a
benzene ring
H E
Among 4 resonance structures, the 3rd structure
is relatively stable.
ortho
59
For meta-attack:
H
E
This kind of e-w groups will direct an incoming group
bonded to the meta-position towards the original substituent.
..
: OH
+
+E
..
: OH
+
..
:OH
+
..
:OH
+
H
E
NO2
H
E
NO2
+ HNO3
H2SO4
93%
NO2
3 resonance structures
meta
For ortho-attack:
+
NO2
+
+
NO2
+ HNO3
H E
H2SO4
NO2
+
The 2nd structure is relatively unstable.
NO2
70%
For meta-attack:
30%
For ortho-attack:
NO2
..
:Cl :
+
+E
..
: Cl:
..
: Cl :
E
H
+
E
H
E
H
+
..
:Cl:
+
E
H
E
H
+
+E
NO2
..
Cl :
+
+
+
NO2
+
NO2
Cl
Cl
Cl
+
+
H E
H E
NO2
E
H
iii. Deactivating, para-ortho directive subtituents (including
all halogen atoms)
For para-attack:
NO2
NO2
E
H
The 3rd structure is relatively unstable since the carbon
atom bearing a positive charge directly attached to the
e-withdrawing group.
moderately deactivating: -COOH, -COOR, -CONH 2
-COR, -CHO, -CHCl 2
+E
+
+E
strongly deactivating: -NH 3, -NR3, -NO 2, -CF3,
-CCl3, -CN, -SO 3H
NO2
NO2
E
H
+
+
+
NO2
+
ii. Deactivating, meta directive substituents
including following groups:
E
H
E
H
Among 4 resonance structures, the 4th is relatively stable,
since every atom has 8 es in the valence shell.
For para-attack:
+
..
: Cl :
14.4 Orientation in multiple substituted benzenes
..
: Cl:
+
+
+E
..
Cl:
+
..
:Cl:
+
..
:Cl:
H E
H
H E
H
E
E
Among 4 resonance structures, the 3rd is relatively stable.
NO2
..
: Cl:
..
: Cl:
E
H
+
E
H
+
..
:Cl:
+
+
+E
i. When the groups on a benzene ring direct the incoming group
to the same position, their directive effect can be reinforced.
OH
For meta-attack:
..
:Cl:
3 empirical rules:
3 resonance structures
CH3
CF3
NO2
NO2
E
H
NO2
p 846
Table 18.1
60
ii. When two groups on a benzene ring direct the incoming group
to different positions, the orientation of the incoming group
will be determined according to the following order:
14.5~14.7 Halogenation, nitration and
sulfonation of benzene
strongly activating groups > moderately activating groups
> weakly activating groups > deactivating groups
a. Halogenation (卤代反应) of benzene
NH2
CH3
NHCOR
major
General equation:
minor
COOH
CH3
Cl
X
iii. Because of steric hindrance the incoming group does not go
to the position between meta substituents if another position
is open.
b. Nitration (硝化反应) of benzene
Mechanism of halogenation:
General equation:
Step 1: polarization of X2 (X = Cl2, Br2)
X X + FeX3 fast
δ
+
δ
X X
+ HX
NO2
CH3
Br
Lewis acid
X2 = Cl2, Br2
Lewis acid: FeCl3, FeBr3, Fe/X2, AlCl3, ZnCl2
OCH3
CH3
Cl
+ X2
NO2
only HNO3, slow
+
X + [XFeX3]
FeX3
+
+ HNO3
+ H3O + HSO4
H2SO4 (conc.)
Step 2: formation of an arenium ion
+
Mechanism of nitration:
Step 1
+ NO2 slow
nitronium
ion
arenium ion
Step 3: loss of a proton
X
X
+
H
+ [XFeX3]
fast
Step 2
+ HX + FeX3
H
+
NO2
NO2
+
c. Sulfonation (磺化反应) and desulfonation
H NO2
+
+ X
X2 = F2, I2
H X
slow
+
+ HSO4
base
fast
+ H2SO4
Desulfontation reaction is useful in organic synthesis.
General equation:
SO3H
r.t.
+ H2SO4
+ H2O
fuming dil. H2SO4
or conc.
benzene sulfonic acid (苯磺酸)
Mechanism of sulfonation and desulfonation:
+ SO3
+
step 1
slow
SO3
HSO4
H3 O
- H2SO4
step 2
fast
H2 O
step 3
fast
CH3
CH3
CH3
Cl2/Fe
+
Cl
major
Cl2/Fe
SO3H
SO3H
Cl
minor
CH3
CH3
CH3
CH3
H2SO4 conc.
+
H SO3
e.g.
Cl dil. H SO
2
4
SO3H
Cl
o-chlorotoluene
61
14.8~14.9 Friedel-Crafts reactions (傅克反应)
The mechanism of Friedel-Crafts reaction:
+
Step 1
Alkylation(烷基化): introduce an R group to a benzene ring
Acylation(酰基化): introduce an acyl group (–COR) to a
benzene ring.
Step 2
R + AlCl4
RCl + AlCl3
+
Friedel-Crafts reactions include:
+ R
H R
slow
+
a. Friedel-Crafts alkylation
General equation:
Step 3
R
+ RX
AlCl4
+
AlCl 3
+ HCl + AlCl3
+ HX
e.g.
+
X
, C=C-X
RX =
HF
+
X = Cl, Br
R
R
H
AlCl3 is used in a catalytic amount.
Notice:
In the reaction, the initially formed carbocation can rearrange to
the more stable one.
C
C-C-C-C
+
C
C-C-C-C
CH3
H
+ H3C-CH-C-CH3
or BF3
OH H
+
major
+
minor
b. Friedel-Crafts acylation
General equation:
O
C-R
O
+ RCCl
AlCl3
benzene,
acyl chloride
H
+
C
C-C-C-C
+
C
C-C-C-C
H
2
- H2O
+
C
C-C-C-C
OH2
3
O O
AlCl3
+ R-C-O-C-R benzene,
acid anhydride
+ HCl
O
C-R
O
+ R-C-OH
AlCl3 is used in a stoichiometric amount.
Mechanism of acylation
Step 1: to form an acylium ion
O
R-C + AlCl4
acylium ion
+
O
R-C-Cl + AlCl3
Step 2: to form an arenium ion
O
C-OH
O
H CR
+
O
+ R-C
slow
step 2
e.g. to form a ring by acylation:
O
H2SO4
+
Step 3 and Step 4: to form a complex and to break O Al bond
+
δ
O
H CR
+
δ
O AlCl3
R-C
+ AlCl4
- HCl
step 3
O
R-C
H2O
step 4
62
c. Synthetic application of Friedel-Crafts reactions
Limits for synthetic application of Friedel-Crafts reactions:
i. When there is a substituent more electron withdrawing than
a halogen on the benzene ring, the Friedel-Crafts reaction
cannot occur.
Y
e.g.
R-X
O
AlCl3
Friedel Crafts reaction
+ R-C-Cl
(RCO)2O
Y = NO2, NH2, NHR, NR2
+
..
H2N
+ AlCl3
δ
δ
H2N
AlCl3
ii. Possible rearrangement of a carbocation (R+) may results
in another product rather than the target product.
C-C-C
+ C-C-C-Br
O
C-C-C
O
+ C-C-C-Cl
R
AlCl3
- HCl
C-C-C
C-C-C
+
C-C-C
1
2
7
6
3
5
4
Two kinds of Hs on the naphthalene:
Hs on the position 1, 4, 5, 8—α position
Hs on the position 2, 3, 6, 7—β position
Reactivity for electrophilic attack:
Hs on α positions > Hs on β positions
For irreversible electrophilic substitutions, such as
halogenation, nitration, the reactions mainly occur
on α position of naphthalene.
NO2
e.g.
HNO3
H2SO4
Br
Br2
For reversible electrophilic substitutions, such as sulfonation,
at low temp. the reaction mainly occur on α−position, while at
relatively high temp., the α-substituent can transfer to β-position.
e.g.
CH2-CH2CH3
Zn(Hg)
HCl
amalgamated zinc
Clemmensen reduction
14.10 Electrophilic substitutions of polycyclic
aromatic compounds
8
BF3
H2O
a. The reactions of naphthalene(萘)
<
Because of this, some di-substituted by-product will be
formed. In order to obtain mono-substituted product, benzene
is normally used in a great excess or even as solvent.
+ C-C-C
OH
minor but target
A very useful method is the Clemmensen reduction.
By this fast coordination reaction, the e-r group turns to be a strong
e-w group which causes the aromatic ring e-dificient.
reaction rate:
C-C-C
+
major
fast
iii. It is difficult to control mono-alkylation, since
AlCl3
160 C
SO3H
160 C
+ H2SO4
SO3H
60 C
Thermodynamically
controlled: β-position
Kinetically controlled:
α-position
General orientation rules for electrophilic multisubstitution of naphthalene:
i. With an e-releasing group or a halogen atom on α-position
of naphthalene, the reaction occurs on para or orthoposition towards the original group.
OCH3
OCH3
HNO3
H2SO4
+
OCH3
NO2
NO2
63
ii. With an e-releasing group on β position, the reaction mainly
occurs on the α-position adjacent to the original group.
Br
OCH3 Br2
FeBr3
OCH3
b. The reactions of anthracene(蒽) and phenanthrene(菲)
OCH3
+
9
1
5 10
4
8
Br
7
6
minor
major
iii. With an e-withdrawing group on α- or β-position, the
reaction occurs on the α-position of the unsubstituted ring.
The reaction will not occur on the deactivated ring.
9 10
8
NO2 NO2
NO2
NO2
HNO3
H2SO4
2
3
3 kinds of Hs for anthracene
α position: 1, 4, 5, 8
β position: 2, 3, 6, 7
γ position: 9, 10
2
5 kinds of Hs for phenanthrene
1, 8; 2, 7; 3, 6; 4, 5; 9,10
1
7
6 5
+
4
3
NO2
In general, the reactions easily occur at position 9 and 10 of
anthracene and phenanthrene.
e.g. The reactions of phenanthrene
Br
e.g.
Br
electrophilc
substitution
Br2
CCl4
Br2
CCl4
CrO3
H2SO4
Na/EtOH
or H2/cat
h.t. O2/V2O5
O
O
hydrogenation
O
oxidation
9,10 anthraquinone
9,10-蒽醌
9,10 dihydroanthracene
O
9,10-菲醌
I
+
+
Y
5 C
Ar-N NX
ArY
Ar-NH2 + NaNO2 + 2HX
-NaX, -2H2O
-X, -N2
sodium nitrite
arenediazonium salt Y = F, Cl, Br, I, CN,
HONO
OH, H, NO2,
芳烃重氮盐
nitrous acid (亚硝酸)
SO3, SCN, Ar
X
NaNO 2/HCl
H 2O , 5 °C
MI
- N2, - MX
-
General reaction:
NH 2
N 2Cl
9,10-dihydrophenanthrane
9,10-phenanthraquinone
14.11 Nucleophilic aromatic substitution (I)
via diazonium ions (重氮离子)
+
Na/ROH
or H2/cat
CuX(or Cu/HX)
- CuCl, - N 2
X = Cl, Br, CN
Sandmeyer reaction
+
HBF 4
N 2BF 4
F
- N 2,- BF 3
Schiemann reaction
M = Na, K
OH
H3O
- N2
+
NH2
NaNO2/HCl
H2O 5 C
N2Cl
H3PO2 or NaBH4
H2O
Cu, NaNO2
- N2, - NaCl
Cu, Na2SO3
- N2, - NaCl
H
NO2
SO3Na
SCN
Cu, KSCN
- N2, - KCl
/NaOH
- N2,- NaCl
thiocyanato
氰硫基
Bachmann reaction
64
e.g.1 To prepare 1,3,5-tribromobenzene
Br2/Fe
Br
Br
2Br2/Fe
14.12~14.13 Nucleophilic aromatic substitution (II)
Br
CH3CH2Cl + NaOH
1,2,4-tribromobenzene
Br
HNO3
H2SO4
NO2
Fe/HCl
NH2
3Br2
Br
NH2
N2Cl EtOH or Br
Br
Br NaNO2 Br
Br H3PO2
H2O
HCl, H2O
Br
Br
Br
5 C
e.g.2 To prepare multicyclic compounds
Z
NH2
NaNO2
HCl, H2O
5 C
Z
NaOH
- N2, - NaX
+
N2X
H 2O
CH3CH2OH + NaCl
H 2O
CH2=CHCl + NaOH reflux
X + NaOH
H 2O
a. Nucleophilic substitution by addition-elimination
mechanism
Aryl halides with at least one strong e-withdrawing group
(NO2) on the ortho- or para-position towards the halogen atom
◆
Z
General equation:
Cl
B
NO2
+ B
NO2
)
Z = CH=CH, CH2CH2, NH, CO, CH2
B = OH (Na2CO3/H2O), SH (NaSH/H2O), NH3, NH2R, OR (NaOR/ROH
e.g. Nucleophilic aromatic substitution of halogen atom:
H 2O
Na2CO3
Cl
NaSH
H 2O
NO2
OH
Mechanism of nucleophilic substitution by addition-elimination:
addtion
+ B
step 1
slow
NO2
NO2
SH
NO2
B
X B
X
NO2
NO2
elimination
step 2
fast
Bond energy:
I-Ar < Br-Ar < Cl-Ar < F-Ar
+ X
NO2
Elecronegativity:
I < Br < Cl < F
NO2
NO2
CH3NH2
NaOCH 3
CH3OH
NHCH 3
NO2
O2 N
◆
+ NaOH
H2O
Mechanism of nucleophilic substitution by elimination-addition
Step 1: elimination
Br
nucleophile
H
+ KNH2
NH3
- KBr
NH2
- Br
NH2
NH2-,NR2-
The molecular orbital of benzyne (苯炔)
Y
H
LiNR2
H
R
Br
- LiBr
NH2
NH3
- NH2
or NaNH2
+ LiR
Br
- NH 3
benzyne
NH2
Br
+ NH 2
Step 2: addition
OH-
350 C
NO2
meta-nitroaryl halides doesn’t undergo nucleophilic
substitution reaction by addition-elimination.
Simple aryl halides without NO2 group on the ortho- or paraposition of a benzene ring
OH
+
red crystals
b. Nucleophilic aromatic substitution by eliminationaddition mechanism
Cl
H5C2O OCH3 K
O2N
NO2
NO2
NO2
OCH3
NO2
NO2
◆
OC2H5
NO2 CH3OK
R- (carbanion)
sp2-sp2 orbitals overlap
with each other
H
H
Y group has only IE,
no RE on benzyne
65
The benzyne mechanism is proved by the following
experimental facts：
iii. The incoming group will be attached to either the position
of the leaving group or the ortho-position to the leaving group.
i. If two ortho-hydrogens are replaced by other groups, no
nucleophilic substitution reaction takes place.
Br
NH2
NaNH2
NH3
Br
CH3
CH3
KNH2
NH3
CH3
ii. When benzyne is formed in the presence of furan, the
product is a Diels-Alder adduct.
"
NH2
+
"
CH3
CH3
CH3
iv. If 14C-labeled bromobenzene is used as the starting compound,
2 kinds of labeled anilines are formed in an equal amount.
O
* Br NaNH2
NH3
+ O
formed in situ
*
* NH2
NH2
*
+
NH2
Diels-Alder adduct
Further reaction of the intermediate—benzyne:
The orientation of nucleophilic substitution for
substituted aryl halides:
Y
a
Y
Y
b
Y
orthosubstituted:
H
Y
metasubstituted:
Y: e-r IE
H
Y
H
Y
Y
NH3
- NH2
b
+ NH2
b
4-Y-benzyne
H
X
a
NH2 ortho product
Path a: Y—e-r IE
4-Y-benzyne
para product
NH2
III
NH2
Y
Y
a
meta product
Path b: Y—e-w IE
Y
Y
X
Y
NH2 NH3
- NH2
II
Y: e-w IE
H
parasubstituted:
Y
a
b
3-Y-benzyne
3-Y-benzyne
NH2
I
+ NH2
X
Y
NH3
NH2 - NH2
NH3
NH2 - NH2
Path b: Y—e-w IE
meta product
NH2 Path a: Y—e-r IE
IV
OCH3
X NaNH2
NH3
e.g.1
OCH3
+
e.g.3
OCH3
NH2
CH3
CH3
NH2
KNH2
NH3
" OCH3 "
OCH3
+
NH2
CH3 a
OCH3
NH2
Cl
b
+ NH2
a
b
NH2
e.g.2
major
2
NH3
CF3 a
b
+ NH2
b
a
NH3
NH2 - NH2
CF3
NH2
CH3
- NH2
NH3
NH2 - NH2
CH3
38%
NH2
CH3
62%
NH2
minor
CF3
CF3
Cl NaNH
NH2
NH3
NH3
- NH2
14.14 Some Additional useful reactions
CF3
major
NH2
CF3
NH2 minor
a. Reduction of nitro group
Reduce NO2 to NH2 by the following reductants:
Fe/HCl, Zn/HCl, Sn/HCl, SnCl2/HCl, H2S/NH3, Ni/H2 or Pt/H2
66
Compare the following reactions:
NO2
b. Reduction of carbonyl groups
Fe/HCl
Carbonyl groups of aldehydes and ketones can be reduced to
methylene groups (CH2) by the following three methods:
NH2
SnCl2/HCl
Fe/HCl
NO2
NH2
O
NHCCH3
Fe/HCl O2N
O
CH=CHCH 2CR
Zn-Hg/HCl
O
NHCCH3
Pt/H2
EtOH
Zn-Hg/HCl
R'CH2R
e.g.
NO2
NO2
NH2
O
R'CR
NH2
H2S/NH3 or
SnCl2/HCl
Fe/HCl
H2N
CHO
CHO
CH2OH
NH2
i. By Clemmensen reduction
For the compounds which are stable towards HCl acid
NH2
NO2
NH2
H2N
Cl
CHCH 2CH 2R
CH=CHCH 2CH 2R
+
- CH3COOH
c. Oxidation of the side-chain of benzene ring
ii. By Wolff-Kishner reduction
For the compounds which are stable towards bases
O
CH=CHCH 2CR (hydrazine 肼)
NH2NH2 , NaOH
(HOCH 2CH2)2O
CH=CHCH 2CH2R
(diethylene glycol 二甘醇)
iii. By Pd/H2
For the aromatic ketones in which the carbonyl group bonds
to benzene ring directly
A comparison:
O
CCH2CH3
H2/Pd
CH2CH2CH3
O
CH2CH2CCH3
alkyl
C-C-C-R'
alkenyl
C=C-C-R'
alkynyl
C C-R'
+
2) H 3O
O
C-R'
acyl
OH
CH2CH2CHCH3
R
H2/Pd
3°alkyl on the benzene ring cannot be oxidized under the
same condition aforementioned, since there is no H on the C
atom directly attached to the benzene ring.
◆
C
very h.t.
C-C-COOH
KMnO4
C
C
C-C-C
e.g.
CH2CH2CH3
CH 3
X
CH 3
X2/FeX 3
+
CH 3
Br
CHCH2CH3
O
NBr
ROOR
O
N-bromo-succinimide
NBS
d. Halogenation of the side-chain of benzene ring
X2
or hν
R = CH 2Cl, CHCl 2, CH 2OH, CHO, CH 2NO 2 ...
having at least one α-H on the benzylic C atom
+
KMnO4, OH
A comparison:
COOH
1) KMnO 4,OH,
14.15 Synthesis of aromatic compounds
Some noticeable points for synthetic applications:
X
CH 2X
a. Direct nitration of aniline or phenol is not a good
method for organic synthesis
X = Cl, Br
67
e.g.1
NH2 CH3COCl or
(CH3CO)2O
HNO3
H2SO4
+
O
C
NO2
+
- CH3COOH
minor
NH2
NH2
CH3O
+
+
HNR2
HNR2
HNO3
H2SO4
HNO3
H2SO4
O
C
N
C
O
c. If there is no other electrophiles, the carbocation formed
in the side-chain can form a 6- or 5-membered stable
cyclic compounds with the benzene ring.
minor
e.g.2
NR2
O2N
CH3O
HNO3
H2SO4
N
C
O
NO2
major
O2N
H3 C
HNO3
H2SO4
H3C
NO2
90%
+
H3O
b. If there is more than one benzene ring in a molecule, the
electrophilic substitution will occur on the one which is
more electron-rich
O
NHCCH3
NO2
O
NHCCH3
O
NHCCH3
- H+
C
C-C-C-C H2SO4
OH - H2O
NR2
NO2
NO2
C
C
C
+C
C
C
C C
C
C
d. An important skill in designing a synthetic route is the arrangement of the order in which the reactions should be carried out.
Compare 2 synthetic routes for preparation of o-nitrobenzoic acid:
Chapter 15 Addition to the Carbonyl Group
15.2 General mechanism of nucleophilic addition to the
carbonyl groups of aldehydes and ketones
a. Strong nucleophiles without catalysts (basic conditions)
CH3
COOH
COOH
1) KMnO4, OH,
HNO3
H2SO4
+
2) H3O
R'
NO2
R
HNO3
H2SO4
+
2)
+
+
H3O
separated by steam-distillation
b. Weak nucleophiles with acidic catalysts
(acidic conditions)
+
R'
C
H
+
R'
O
+
OH
C
R
R
HNu
NuH
C
R'
R
Nu
-H +
C
R'
R'
OH + R
C
R
HNu = H2O, HOR, NH3, HNR2
Nu
OH
C
R'
R C
+
O
Nu
+
R'
C OH + R
R'
R
O
Nu
R
H
NO2
NO2
R'
COOH
NO2
COOH
CH3
NO2 1) KMnO4, OH,
CH3
CH3
Nu
Nu
C=O
C OH
Nu
c. Reactivity of aldehydes and ketones towards
nucleophilic addition
R'
R
C
+
OH
OH
NuH
+
Two factors:
1) Electronic effect—The more electron-deficient
central C of an acyl group will benefit the
nucleophilic addition.
2) Steric hindrance—The less steric hindrance of
the central C will increase the reaction rate of
nucleophilic addition.
68
The general order of the reaction rate of the nucleophilic
addition of carbonyls is as follows:
H
C=O >
H 3C
H
H
H5C2
C=O >
O>
C=O >
a. Addition of water
Ph
C=O >
Ph
H3C
H3C
C O
C O
H3C
C=O
C
OH
R
H
C=O + H2O
C
H
chloral hydrate
OH
水合三氯乙醛
gem-diol
hydrate
O
H3C
CH3
C
O
D
CH3
C
NO2
B
A
OH
Cl3CCH
OH
H3C
R
Ph
C=O >
H5C2
H3C
H
hydrocyanic acid sodium bisulfite
H3C
Ph
C=O >
15.4 15.5 15.9 15.10 The addition of H20, ROH,
RSH, H2NX, HCN, NaHSO3
hypnotic
The study on the mechanism of this reaction:
16OH
O18
-H2O16
18
C-C-C
C-C-OH
16
H2O
C
16O
O16
+
H2O18
C-C-C
C-C-O18H2
C
+
HCl(gas)
+
+
H
R'OH R
R
OR'
H
OR'
C
R'OH H C OR' +H O H
OR'
3
acetal缩醛
stable in basic solution
OH
C
H
O
O
C
H
O
H
O
H
+
O
+
HOCH2CH2CH2CH2C
C
+
R'
+
R
C=O + HOR"
R'
R,R’ = alkyl
hemiketal
R
半缩酮
OR"
C
R
or
R’ = H
R' OH
hemiacetal
半缩醛
H
OR"
+
+
b. Addition of alcohols
R
R
..
or
H
C OR'
..
OH H2SO4(conc.) R
OH H2O H
C
C ..
H
OR'
+H
H
O
H
OR'
2
..
R
hemiacetal
C OR'
H
R
R
R
R'
CH H2SO4(conc.)
+
CH
H3O
HO R'
HO
C=O +
R
R
C
O
R'
O
R'
cyclic ketals 环缩酮
c. Addition of thiols (mercaptan RSH)
To make the following synthesis:
R
from O
O
COC2H5 to
OH
C-CH3
CH3
O
+
O
H
COC2H5
HOCH2CH2OH
O
O
CH3MgCl
COC2H5
O
O
R
+
C=O
H
2RSH
-H2O
R
R
C
SR Raney Ni(H2)
SR - 2RSH
R
R
CH2
thioacetal
R
R
R
S
H
C
HSCH2CH2SH R
S
-H2O
+
C=O
Raney Ni(H2)
-HSCH2CH2SH
R
R
CH2
cyclic thioacetal
"
OMgCl "
"
COC2H5 H5C2OMgCl
CH3
O
O
"
O
O
O
O
OMgCl "
+
H3O
O
CCH3
HOCH2CH2OH
CH3
O "
CH3MgCl
CCH3
OH
C-CH3
CH3
The reduction of C=O groups of aldehydes and ketones into
CH2 group:
Clemmensen reduction: Zn(Hg)/HCl, △
Wolff-Kishner reduction: NH2NH2/NaOH/(HOCH2CH2)2O, △
Reduction of aryl alkylketone: H2/Pd (neutral condition)
Reduction of thioacetals: Raney Ni(H2)
69
d. Addition of ammonia and its derivatives (H2NX)
NH 2NH 2
hydrazine
O 2N
H 2NNH
O 2N
H 2NNH
phenylhydrazine 2,6-dinitrophenylhydrazine
肼
苯肼
2,6-二硝基苯肼
O
H2NNHCNH 2
O
H2NCNH 2
carbamide(urea)
O
H2NNHCNHNH 2
semicarbazide
尿素
卡巴肼
C=C
RR'C=NR"
NRR'
hydroxylamine imine(Schiff base) enamine
羟氨
亚胺(西佛碱)
烯胺
C=N-N
O
C=N-NHCNH2
C=N-OH
hydrazone
semicarbazone
oxime
半卡巴腙
肟
腙
"R
R'
C
OH " - H2O
N H
X
R
C=NR"
R'
imine
Schiff base
The addition of 2°amines to carbonyl groups of aldehydes
and ketones
R
C=O + HN
R" addition
R'
2°amine
R
C=NX
R'
" H OH
"
C C N R" dehydration
-H2O
R'
R
C=C-NR'R"
R
enamine
e. Addition of hydrogen cyanide (HCN,氢氰酸)
OH
C
R= aryl, if another
H CN group on the C is
(CH3)
a methyl group
NaCN + H2SO4/H2O cyanohydrin
(KCN)
氰醇
R
OH
C=O + HCN
H
(CH3)
product
X
-NH2
-NHC6H5
-NHC6H3[2,6-(NO2)2]
O
-NHCNH2
not stable
CH
General expression of the reactions of aldehydes and ketones
with derivatives of ammonia:
R
R' C=O + H2NX
(H)
"R
R
OH " dehydration
C=O + H2NR" addition
C
R'
-H2O
R'
H
N
(H)
R"
1°amine
carbazide
氨基尿素
H2NOH
The addition of 1°amines to carbonyl groups of aldehydes
and ketones
R
hydrazone (orange)
Only aldehydes, aliphatic methyl ketones and
cycloketones can react with HCN.
◆
semicarbazone (colorless)
oxime (colorless)
-OH
using weak acid as catalyst
instead of strong acid
simple testing methods for aldehydes
and ketones
f. Addition of NaHSO3 (sodium bisulfite)
HCl
H2O
RCH2
R'
C=O
KCN
+
H3O
RCH2
R'
OH
C
CN
RCH2
OH
C
R'
COOH
α-hydroxy acid
acidification
H2SO4 RCH=C-COOH
dehydration
-H2O
R'
α,β-unsaturated acid
reduction
1) LiAlH4 RCH2 OH
C
2) H2O
R'
CH2NH2
β-amino alcohol
O
ONa
R
addition R C
C=O +
S
H
H OSO2H
Na O OH
(CH3)
(CH3)
R
H
OH
C
(white)
SO3Na
sodium α-hydroxy sulfonate
R= aryl, if another group on the C is a methyl group
+
H3O
R
C=O + NaHSO 3
H
R
H
OH
C
OSO2Na
OH
H2O
O
RCH + SO2 + H2O + NaCl
O
2
+
RCH + Na + SO 3
70
15.3 Oxidation and reduction of aldehydes
and ketones
a. Oxidation of aldehydes by mild oxidants
CuSO4/KNaC4H4O6
[O]=H2CrO4(CrO3/H+), KMnO4/OHO
[O]
(cold, dilute), Ag2O/OH-, O2
R-C-H
RCOOH
O
R-C-H
b. Oxidation of aldehydes, α-hydroxy ketones and
cyclic hemiacetals by weak oxidants.
O
R-C-H
CuSO4/citric acid/Na2CO3
blue
Benedict’s reag.
HO CHCOOH
KNaC4H4O6
salt of tartaric acid: HO CHCOOH
RCOONH4 + Ag
+
O OH
[Ag(NH3)2] /NH3
R-C-CHR
Tollen’s reag.
OH
C
O H
Fehling’s reag. deep blue
酒石酸
OO
R-C-CR + Ag
RCOONa + Cu2O (red)
RCOONa + Cu2O (red)
CH2-COOH
citric acid: CH -COOH
柠檬酸 CH2-COOH
C O + Ag
O
butanolactone
c. Oxidation of ketones
d. Reduction of aldehydes and ketones
Baeyer-Villiger reaction
O
R-C-OR
O
O
R-C-R + R'-C-OOH
or H2O2
O
O + R'-C-OOH
or H2O2
O
O
O
R'-C-OOH
or H2O2
O
O
hexanolactone (己内酯)
O
C=C-C-R
(H)
O
H
NaBH4
H
OH
C=C-CH-R
+
-NO2
-C=N
-CH2NH2 -NH2 -CH-NH2
ibid and -COOH, -COOR
-CH2OH
-CONH2,-COCl
-C=N-CHNH2
-COCl -CHO
-CH2OH
Na/CH3CH2OH
OH
C=C-CH-R
H2/Pd-C
O
CH-CH-C-R
-COOR
-CHO
-CH2OH
a. Preparation of organolithium and organomagnesium
compounds
Mg
HO OH
+
O O
R
H3O
R
R
C C R -Mg(OH) R' C C R'
R'
R'
2
R-X + 2Li
Et2O
R = alkyl, aryl
Pinacol
RLi + LiX
X = Br,Cl
X=I
片呐醇
R-X + Mg Et2O
RMgX
R = alkyl, X = Br,Cl
R = aryl, vinyl, X = I,Br X = Cl
Grignard reagents (格氏
试剂, Nobel prize in 1900)
15.6 15.7 16.10 Organometallic compounds
Organometallic compound: a compound that contains at least
one C-M or H-M bond
3 groups:
Organo-main group metal compounds: RC≡CNa, RLi, RMgX…
Organo-transition metal compounds: R2ZrCl2, R2Zn, R2Hg…
Organo-rare earth metal compounds: REuX(铕), RSmX(钐)
-C N
OH
C=C-CH-R
HOOCCH 2 CH 2 CH 2 CH 2 COOH
e. Bimolecular reduction of ketones by magnesium
O
C6H6
2 RCR' + Mg
LiAlH4
Et2O
OH
C=C-CH-R
+
Al[OCH(CH3)2]3
(CH3)2CHOH
epoxide (环氧化物)
O
HNO 3
OH
CH-CH-CHR
H2/Ni
(sp2)C-Cl bond is less reactive than (sp2)C-Br and (sp2)C-I bonds.
◆
e.g.
Cl
Br
Cl
+ Mg Et2O
MgBr
71
+
iii. With carbonyl compounds
b. Reactions of RLi and RMgX compounds
i. With acidic hydrogens
δ
+
δ
C=O + RMgX
H3O
HCl
C-OMgX
R
H2O
+
RH + HOMgX
R'OH
RMgX
O
H-C-H + R'MgX
+
+
δ
(t-Bu)2C-OH
t-Bu
Reactions with aldehydes and ketones:
RH + R'C CMgX
ii. With ethylene oxide
δ
H3O
t-BuLi
(t-Bu)2C=O
RH + R'OMgX
R'C CH
δ
H2C CH2 + RMgX Et2O RCH2CH2OMgX
O
or RLi
+
H3O
C-OH + MgCl2
R
RCH2CH2OH
+
H3O
R'CH2OH 1
O
R-C-H + R'MgX
+
H3O
O
R-C-R + R'MgX
+
H3O
RCHOH 2
R'
R2COH
R'
3
Reactions with esters and nitriles:
R'
R'MgX
..
-ROMgX R
C=O
R-C-OMgX
..
R'
fast
OR
O
R-C-OR + R'MgX
R'
R-C-OH
R'
R'
+
HO
R-C-OMgX 3
R'
iv. With allyl halides and benzyl halides
R-CH=CH-CH2X
RC=NMgX
R'
H3O R
C=O
R'
Reactions with CO2:
+
δ
C=C-X,
X = Br, Cl
CH 2R'
X or common sp3C-X + RMgCl
+
O
O
HO
RC-OMgX 3
RC-OH
δ
RMgX + O=C=O
◆
RCH=CHCH2R'
R'MgX
CH 2X -MgX
2
+
R-C N + R'MgX
R'MgX
-MgX2
The limits on the use of RMgX and RLi
To prepare RMgX or RLi reagents, the starting alkyl
halides should not contain the following active groups:
-OH, -SH, -NH2, -NHR, -CO2H, -SO3H, -C≡CH, -NO2,
-C≡N, C=O, C C
c. Lithium dialkyl cuperates (R2CuLi)
Preparation of R2CuLi:
R-X + 2Li
RLi + LiX
2RLi + CuI
R 2 CuLi + LiI
Reations of R2CuLi with RX: (coupling reactions)
O
R-R' + RCu + LiX
O
X = I, Br, OTs(-OSO 2Ar), -OCR
R2CuLi + R'X
e.g.
O
R'MgBr + HOCH2CR -R'H
OMgBr
BrMgO-CH2-CR'
R
O
R'MgBr
BrMgO-CH2-CR
+
H3O
OH
HOCH2C-R'
R
CH3
H
C=C
H
I
+ R2CuLi
I + R2CuLi
Et2O
R’ = methyl, 1° alkyl, aryl,
alkenyl, 2° cycloalkyl
CH3
H
Et2O
C=C
H
R
R
72
The advantage of R2CuLi reagents: The functional groups, such
as C=C, C≡C, C=O, C≡N, do not affect the coupling reactions.
15.8 The Wittig reaction
O
R'
RCCH2CH2CH=C
R"
O
R' R"2CuLi
RCCH2CH2CH=C
I
General reaction:
R"
R
C=O +
C=P(C6H5)3
R'
R"'
(H)
Reactions of R2CuLi with α,β-unsaturated carbonyl compounds:
phosphorus ylid
叶立德
δ
+
O
δ+
OLi H3O
R 2CuLi CH 3
CH-CH=C
CH 3CH=CH-CCH 3
CH
3
R
OH tautomerization
CH-CH=C
R
CH 3
CH 3
Preparation of phosphorus ylids:
O
CH 3CH-CH 2-CCH 3
R
Mechanism of Wittig reaction:
"
+
R"
R
C=O + Ph 3P-C
R'
R"'
R
R'-C
CH3
"
R"
C-R"'
O
R"
R
+ O=PPh 3
C=C
R'
R"'
RC
O
CH3
Ph
H
C=C
H + RC C=C Ph
RC
O
O
E-isomer
major
CH3
C=PPh3 + PhCHO
PPh 3
Stereoselectivity of Wittig reaction:
e.g.
R"
Ph3P-C-H X
R"'
R"
RLi
Ph3P=C
RH
R"'
LiX
R"
1°or 2° alkyl triphenyl+
Ph3P-C
alkyl halides phosphonium salt
R"'
O
R'C-R
R2CuLi
Et2O
+
R"
..
Ph3P + H-C-X
R"'
Reactions of R2CuLi with acyl halides:
O
R'C-Cl
CH 3Br
CH 3OH + PBr 3
Ph
H
Ph
+
C=C
C=C
H
H
Ph
H
cis 41%
trans 35%
Ph
H
C=PPh 3 + PhCHO
Ph
R
R"
C=C
+ O=P(C6H5)3
R'
R"'
(H)
BuLi
- BuH
- LiBr
+
Ph3P [CH -PPh ]Br
3
3
O
-OPPh 3
CH 2=PPh 3
CH 2
Methylenecyclopentane
亚甲基环戊烷
15.11 Conjugate addition of α,β-unsaturated
aldehydes and ketones
General reactions:
b
a. Nucleophilic addition
hybrid
b
H
+
C=C-C=O + Nu
4
+
+
C=C-C-O
R
δ+ δ
H
3 2 1
Resonance structures:
β α
C=C-C=O
R
(H)
a
C-C=C-O
R
R
(H) a
+
OH
C=C-C-R
Nu
1,2-addition, simple add.
OH tautomerization C-CH-C=O
C-C=C
R
R
Nu
Nu
1,4-addition, conjugate add.
δ
δ+ O
C C C
R
73
●
Effects of nucleophiles
RLi adds to α,β-unsaturated aldehydes and ketones
in the 1,2-addition manner.
OH
C=C-C-R
R'
1) R'Li
C=C-C=O
+
2) H3O
R
(H)
1,2-addition
R2CuLi adds to α,β-unsaturated aldehydes and ketones
predominately in the 1,4-addition manner.
RMgX adds to α,β-unsaturated aldehydes in the
1,2-addition manner, and to α,β-unsaturated ketones
in both 1,2- and 1,4-addition manner.
OH
C=C-C-H
R
1) RMgX
C=C-C=O
+
2) H3O
H
1,2-addition
OH
C=C-C-R + C-CH-C=O
R'
R'
R
1) RMgX
C=C-C=O
+
R' 2) H3O
1,2-addition 1,4-addition
O
C C-C-R
R' H
1) R'2CuLi
C=C-C=O
+
2) H3O
R
(H)
●
1,4-addition
CH3
C
1) PhMgBr
C-C-CH=CH-C=O
+
2) H3O
C
OH
C
C-C-CH=CH-C-CH3 100% 1,2-addition
C
Ph
O C 1) PhMgBr
CH3CH=CHC-C-C
+
2) H3O
C
OC
CH3CH-CH2C-C-C 100% 1,4-addition
Ph
C
tautomerization
HBr, 1,4-addition
OH
O
H
C-CH-C=O
Nu
R
1,4-addition
+
C-C=C-OH
Br R
OH
+
CH3OH
OH
+
Nu = NH 3 , RNH 2 , H 2 NX
General expressions:
O
R-C-B
Y
O
R-C-Y + B
O
+
R-C-Y + H
+
OH
R-C-B
+
OH
:B
R-C-Y
H
+
OH
OCH3
H
Chapter 16 Substitutions at the Carbonyl
Group
16.2 Nucleophilic substitution at a carbonyl
carbon
acidic
condition
C=C-C=O
R
(H)
H
C-C-C=O
Br R
+
1) Nu
2) H +
basic
condition
HBr, α,β-addition
e.g.
Addition of other nucleophiles:
Nu = CN
C-CH-C=O 1,4-addition
R
R'
b. Electophilic addition (HX, H3O+, ROH/H+)
Effects of steric hindrance:
C=C-C=O
R
1) RMgX/CuI
C=C-C=O
+
2) H3O
R'
O
R-C-B + Y
:OH
R-C-B
Y
Y
O
Y
- HY R-C-B
O
Y = Cl, OH, OR, NH 2, NHR, NRR', OCR
O
OCH3
OCH3
The order of basicity of leaving groups:
Weak: Cl- < RCOO- < -OH < -OR < -NH2 strong
The order of reactivity towards nucleophilic substitution:
reactivity increase
O
O
O
O O
O
R-C-Cl > R-C-O-C-R > R-C-OH > R-C-OR > R-C-NH2
stability increase
16.3 Synthesis of acyl chlorides
O
PCl5
R-C-OH - POCl3,- HCl
O
R-C-Cl
PCl3, SOCl2 (thionyl chloride, 二氯亚砜）
74
The reactions of acyl chlorides:
R'OH
O
R-C-Cl
P 2O 5
(CH 3CO) 2O
O
R-C-NH2 + NH4Cl
NH2R'
O
R-C-NHR' + R'NH3Cl
O
R'-C-OH
R'MgCl
-MgCl2
O
O
RCOOH + R'-C-Cl +
O O
RC-O-CR' +
O
RCOONa + R'-C-Cl
O
R-C-R' + R'Cu + LiCl
H
OH
OMgCl H +O
O
3
R'MgCl
R-C-R'
R-C-R'
R-C-R'
R'
R'
O
C NH2
O
C NH2 amidic
2NH3
C
O
CO
O
+
NH4
H3O
acid
C OH
酰胺酸
O
- NH3, - H2O
O
C
NH
C
O
imide
酰亚胺
16.5 Synthesis and reactions of esters
RCOOH + R'OH
1 ,2
O
RHC(CH2)n-C-OH
OH
H
+
C
O
R-C-Cl + HO-C-C
C
N
C
C
H
fumaric acid
-H2O
COOH
H
H
maleic acid
O
RC-OH + H-OR'
C
C
O
C
O
C
O
O
RC-O-H + HO-R'
model B
model A
O
18
RC-OH + HOCH 3
H
+
O
s CH3
H
RC-OH + HO-C
H
CH2CH3
+
O 18
RC-OCH 3 + H 2O
O s CH
3
RC-O-C
+ H2O
H
CH2CH3
for acids: HCOOH > CH3COOH, RCH2COOH >
R2CHCOOH > R3CCOOH
iii. From carboxylate salts and 1°alkyl halides
n = 2 γ-lactone
n = 3 δ-lactone
ii. From acyl chlorides or acid anhydrides
+
O
C
H
R-C-OH + HO-C-C
- H 2O
C
COOH
H
for alcohols: CH3OH > 1°ROH > 2 °ROH > 3 °ROH
water segregator
RCOOR' + H 2O
分水器 (p 661)
O
C
O
(CH2)n CH
R
O O
RC-O-CR'
- NaCl
The reactivity of esterification:
i. From carboxylic acids (esterification, 酯化反应)
+
COOH
C
C
HOOC H
Cl
N+
H
configuration retention
a. Synthesis of esters
H
(RCO) 2O + 2CH 3COOH
N
O O
R-C-O-C-R' + HCl
+
O
C
(RCO) 2O + H 2O
2RCOOH
NH3
R'2CuLi
16.4 Synthesis of carboxylic acid anhydrides
O
R-C-OH + HCl
O
R-C-OR' + HCl
H2O
iv. From nitriles (RCN)
O C
R-C-O-C-C
C
O C
R-C-O-C-C +
C
O
RCOONa + X-CH2R'
R-C-O-CH2R
- NaX
1
SN2 mechanism
RC N + 2H2O
H
+
Cl
N+
H
RC N + 2R'OH
H
+
O-H
R-C-NH2 - NH
3
OH
O
R-C-OH
O-R'
O
R-C-OR'
R-C-NH2
- R'NH2
OR'
75
b. Reactions of esters with H2O catalyzed by either
acids or bases
O
18
R-C-OR' + H-OH
H
For alkyl carboxylates: configuration retention
O 18
R-C-OH + HOR'
+
O
R-C-Cl
R' = 1 , 2 alkyl
H
O C
18
R-C-O-C-C + HO-H
C
H
O
C 18
R-C-OH + C-C-OH
C
+
R
- HCl
H
O-H
O
R-S-Cl
O
- HCl
Saponification (皂化反应):
O
R-C-ONa + R'OH
H 2O
H
OH
H3C
O-CR
O
carboxylate
S
H 3C
R' = 3 alkyl
to from a stable carbocation
O
R-C-OR' + NaOH
H
H
H
R
H3C
H
S
O-H
H
H
O-H
OH
O
R
R
H3C
O-S-R
H3C
H
O
sulfonate OTs - a good leaving group
For alkyl sulfonates: configuration reversion
16.6 Preparation and reactions of carboxylic
acids
Oxidation of aldehydes and 1°alcohols:
a. Synthesis of carboxylic acids
RCHO
Oxidation of alkenes:
H3O
KMnO4/OH
H3O
RCH2OH
KMnO 4
RCOOH
+
RCOOH
RCOOH + R'COOH
RCOOH + R'COOH
O3
Zn
H 2O
Oxidation of alkylbenzenes:
-
H 2O 2
RCH=CHR'
+
Ag2O or Tollen's
-
i. By oxidation
RCHO + R'CHO
CH3
KMnO4/OH
+
H3O
COOH
iii. By carbonation of Grignard reagents and RLi
ii. By hydrolysis of cyanohydrins and other nitriles
O
NaOH
R-C-H + HCN
(CH3)
RCH 2X + CN
SN2
OH
R
ONa
C
+
H3O
H
CN
(CH3)
RCH 2CN
+
H 3O
R
RX + Mg
RMgX
RX + Li
RLi
OH
C
COOH
H
(CH3)
RCH 2COOH
Advantage: Other functional groups in the starting compounds,
such as OH, NH2, COOR, COOH, will not affect
the reaction.
Limit: Only 1° RX can be used for this synthetic method.
CO2
CO2
+
O
H3O
RCOMgX
+
O
H3O
RCOLi
RCOOH
RCOOH
Advantage: The R group of starting RX can be 1°, 2°, 3°,
vinyl and aryl halides.
Limit: There should be no other functional groups in
the starting RX.
a comparison:
HO-C-C-C-C-Cl
HO-C-C-C-C-Cl
NaCN
1) Mg
2) CO 2
+
H3O
O
HO-C-C-C-C-C-OH
+
H3O HO-C-C-C-C-COOH
76
a comparison:
b. Synthetically useful reactions of carboxylic acids
malonic acid 丙二酸
General expression:
RCOOH
decarboxylation
α
RH + CO2
O
C
OH
Y-C-COO - CO
2
Y-C
(CH 2)n O + H 2O
C
O
5- or 6-membered ring
C OH
O
n = 2, 3
O
O O
Y = HC-, RC-, HOC-, NO2, -CN, F, Cl, Br
+
H3O
O
C
OH (CH 3CO) 2O
(CH 2)n
Y-C-H + CO2
Y-C-COOH
CH 3COOH + CO 2
HOOCCH 2COOH
i. Decarboxylation (脱羧反应)
O
C
Y-C-H
OH (CH 3CO) 2O
(CH 2)n
OH
C
O
n = 4, 5
(CH 2)n C=O + CO 2 + H 2O
5- or 6-membered ring
16.7 Synthesis and reactions of amides
ii. Substitution of α-H (Hell-Volhard-Zelinski reaction)
1) X 2/P
2) H 2O
RCHCOOH α-halo acid
X
X2/P, X 2/PX 3, X2/RCOCl, X 2/(RCO) 2O; X = Br, Cl
RCH 2COOH
a. Synthesis of amides
i. From acyl chlorides or acid anhydrides
O
O
R-C-NH 2 + NH 4Y Y = Cl, OCR'
O
..
R-C-Y + 2NH 3
or RNH 2, R2NH
ii. From carboxylic acids
OH
R2CHCHCOOH
OH
- H 2O
R2CHCHCOOH NH3 or RNH2 R2CHCHCOOH
X
NH2
+
HO
CN
R2CHCHCOOH 3
CN
R2C=CHCOOH
α,β-unsaturated acids
α-amino acids
2R-CN + 2H 2O2
O
C
OH
- H 2O
(CH2)n
(CH2)n
NH
CH2
γ-lactam
δ-lactam
CH2-NH2
n = 2 γ-aminoacid
n = 3 δ-aminoacid
c. Hofmann degradation (霍夫曼降解) of amides
NaOH/H2O
O
2R-C-NH2 + O2
b. Synthetically useful reactions of amides
Dehydration:
O
C
R2CHCHCOOH
COOH
dicarboxylic acids
iii. From nitriles
O
O
+ - H2O
R-C-ONH4
R-C-NH2
O
R-C-OH + NH3
O
RC-NH
X2
-X
O
RC-NHX
OH
- H2O
N-bromoamide - X
-
dehydrators: Al2O3, acid anhydrides
O
OH
RC-NH2
- H2O
-
1,2,3 R
Mechanism:
-
RC N
-
P 2O 5
- H 2O
RNH2 + 2NaX + Na2CO3 + 2H2O
X2 = Br2, Cl2
-
O
R-C-NH 2
O
RC-NH2 + X2 + 4NaOH
-
OH
RCN
RX + CN
3 R
olefins from E2 elimination
O ..
RC-N:
acyl nitrene
氮宾
configuration
retention
RN=C=O
OH RNH + CO 2 2
3
H2O
isocyanate
异氰酸酯
77
+
-
e.g.
O
- N2
RC-N=N=N
O
RC-Cl + NaN3
O ..
RC-N:
acyl azide
酰基叠氮
sodium azide
叠氮化钠
16.8 Synthetically useful reduction of carboxylic
acids and their derivatives
a. Reduction of acyl chlorides
-
configuration
retention
RN=C=O
2OH
RNH2 + CO3
H2O
H2/Ni or Pt
O
R-C-Cl
-
+
-
O
O
H2SO4
- N2 OH /H2O
RC-N=N=N
RC-OH + HN3
azide acid
acyl azide
RCH2OH 1
LiAlH4 or NaBH4
RCH2OH 1
O
R-C-H
LiAlH(O-t-Bu)3
RNH2
叠氮酸
b. Reduction of amides
d. Reduction of esters
O
LiAlH4
R-C-NH2
or NHR
NaBH4 cannot
reduce amides.
RCH2NH2
or NHR
O
LiAlH(OR")3
R-C-NR'2
CuO, CuCr 2O4
H2 175 C - ROH
O
R-C-H + HNR'2
CH=CHCH 2COOR
LiAlH 4
Et 2O
c. Reduction of carboxylic acids
RCOOH
H2 cat.
RCH 2OH
H2 cat.
CH=CHCH2COOH
H2O
B2H6
H2O
O
(i-Bu)2AlH
R-C-OR'
-78 C
e.g.
CH=CHCH2CH2OH
+
H3O
O
RO-C
O
R-C-H
O
O
NaBH4
RO-C
l.t. CH3OH
LiAlH(O-t-Bu)3
-78 C
LiAlH4
+
RCH2NH2
16.11 Preparation of aldehydes and ketones
a. Preparation of aldehydes
OH
H3O
RCHO
RCH2OH
iii. From nitriles
Cl
SnCl2
R-C N HCl R-C=NH
+
H
H2O
RCH=NH - NH
3
RCHO
iv. From terminal alkynes
Laboratory synthesis:
i. From 1° alcohols
R-C CH
PCC (Py/CrO3/HCl)
RCH2OH
Sarrett reagent
CH=CHCH 2CH 2OH
- ROH
ii. From acyl chlorides
O
R-C-Cl
H3O
CH=CHCH 2CH 2OH
+
H 3O
CH2CH2CH2CH2OH
e. Reduction of nitriles
R-C N LiAlH4
Et2O, reflux
H 3O
- ROH
NaBH4 can reduce aldehydes and ketones, but cannot reduce esters.
CH2CH2CH2COOH
LiAlH4
CH 2CH 2CH 2CH 2OH
+
Na/ROH
RCHO
R'2BH
H BR'2 H2O2
R-C=CH
OH
H
C=C
R
OH
H
RCH2CHO
enol
R’ = 2,3-dimethylpentyl or other hindered alkyl groups
78
b. Preparation of ketones
Industrial processes:
i. Formaldehyde
i. From alkenes
Ag
CH3OH
HCHO + H2
R
ii. Acetaldehyde
2CH2=CH2 + O2
CuCl2-PdCl2
2CH3CHO
iii. Other aldehydes (hydroformation or Oxo reaction)
Co 2 (CO) 8
H2
H
H
O
RCH-CH 2-C-H + RCH-CH 2
C
major
O H
h.t. H 2
HCo(CO) 4
2000 psi
synthetic gas 110~150 C
RCH=CH 2 + CO + H 2
"
RCH 2CH 2CH 2OH
C=C
R'
(H)
R
R
1) O 3
R' 2) Zn, H 2O
(H)
2
C=O
R'
(H)
ii. By Friedel-Crafts acylations
O
+ R-C-Cl
O
C-R + HCl
AlCl3
iii. From 2° alcohols
O
R-C-R'
OH
H2CrO4
R-CH-R'
HRh(CO)(PPh3)3
iv. From terminal alkynes
O
Hg(OCCH3)2 NaBH4
RC CH
H2O
R
HO
C=CH2
O
R-C-CH3
alkyl methyl
ketone
enol
v. From acyl chlorides and R2CuLi
O
δ
Et 2O
R2CuLi + R'-C-Cl
+
-78 C
δ
O
R'-C-R + RCu + LiCl
vii. From carboxylic acids and RLi
O
- R'H
R-C-OH + R'Li
H2O
vi. From nitriles and RMgX or RLi
+
R-C=NMgX
R'
RC N + R'MgX
or R'Li
H3O
O
R-C-R'
16.12 Derivatives of sulfur and phosphorus acids
H2 O
O
SOCl2
R-S-OH
or PCl3
O
O
R-S-Cl
O
R'OH
sulfonyl NH3
chlorides
O
R-S-OH
O
O
R-S-OR'
O
O
R-S-NH2
O
O
Cl-P-Cl
Cl
phosphorus
oxychloride
OLi
R-C-OLi
R'
O
R'Li
R-C-OLi
OH
- H2O
R-C-OH
R'
gem-diol
not stable
O
R-C-R'
Chapter 17 Enolate and Other Carbon
Nucleophiles
17.1 Introduction
The acidity of hydrogen:
OH
R-C-C- > HC CR > H2C=CR2 > H3CR
OH
R-C-C
B
O
R-C=C
O
R-C-C
H
+
H
+
OH
R-C-C-
OH
R-C=C-
keto form
enol form
enolate ion
烯醇离子
79
The order of acidity for the Hs of substituted methyl group:
H
O
O
CH3NO2 > CH3CH , CH3CR > CH3COOR > CH3CN
> CH3C CH > CH3
> CH3CH=CH2
O
C
OH
R-C-C
OH
R-C=C
O
C
H
CH2
a. Racemization of enolate anions
tautomerization
互变异构
Base-catalyzed enolization:
O
C
O
C
C-C
H
C
H
6-membered ring
β-dicarbonyl
compounds
H+
C-C
H
OH H2O
C=C
O
C-C
H
OH
Me
O
R
C-C-R
H
+
H
Et
Me
C=C
Et
OH
C=C
H
+
R
Me
O
R
C-C-R +
H
+
C=C
OH
slow
+
X
C-C-OH
- HX
X
fast
O
C-C
X
O
C-CH3
Cl2/FeCl3
O
C-CH3
Et
racemate
Cl2 hν
CH3
O
+
H
C-C-R
OH
C=C
enol form
OH X-X
-X
fast
O
S
C-C-R
H
Me
H
enol form
no racemization occurs
Cl2/H
Pr
no α-H
+
Cl
CH3
O
C-CH3
CH2Cl
O
C-CH2Cl
CH3
c. Haloform (CHX3) reaction (卤仿反应）
δ
General reaction:
H2O
enolate ion
+
Me
H
keto form
chiral
Et
O
O
C-C
a comparison:
Racemization via enolization:
Et
H2O
b. Halogenation
+
O
O OH
keto form
Acid-catalyzed enolization:
C-C
H
OH enol tautomer
17.3 Halogenation and alkylation of enolate
anions
17.2 Enols and enolate anions
enolization:
O
O
O
B
step 1
1) B
OH
R-C-C-X
X
1) B
2) X2
step 3
O
R-C-CH2X
O
R-C-CX3
The acidity of the α-Hs on the methyl group:
O
O
O
RCCH3 < RCCH2X < RCCHX2
step 1 < step 2 < step 3
O
O
3NaOH H3O
R-C-OH + HCX3
R-C-CH3 + 3X2 - 3NaX
Iodoform test: (碘仿反应)
O
3I2
H3O
RC-OH + CHI3 + 3NaI + 2H2O
3NaOH
yellow
e.g.
O
R-C-CH3
e.g.
O
OH
I2/OH
I2/OH
R-C-CH3
R-CH-CH3
oxidation
+
The rate of halogenation:
O
O
R-C-O + HCX3
R-C-OH + CX3
proton
haloform
transfer
+
2) X2
step 2
O δ
X-X
R-C CH2
O
RC-CX3
OH
+
O
RC-CH3
O
OH
RC-CX3
H3O
O
RC-OH + CHI3 + 3NaI + 2H2O
80
17.4 Alkylation of more stabilized anions
d. Alkylation
Active methylene compounds:
RCH 2-Y
B
R'
RCHY
R'X
SN2
RCHY
R'
LDA
R-C-Y
or NaH
Y-CH2-Y'
O O O
O
Y,Y': -CR, -CH, -C-OR, -CNR2, -C N
O O
O
-NO2, -SR, -SR , -SOR
O
O
R'
R-C-Y
R'
R'X
O
Y = PhC-, -COOR', -CN and other e-withdrawing groups
B = NaNH 2, NaOR, NaH, LiNR 2,
(LiN(i-Pr) 2) (LDA: lithium diisopropylamide)
X = Br, I
Y-CH 2-Y'
R' = CH 3 , 1 R
Some examples of synthetic uses of active methylene compounds:
i. To form substituted acetones
O
O
CH 3-C-CH 2-C-OC 2H5 ethyl acetoacetate
(乙酰乙酸乙酯)
1) NaOEt
2) RBr
M = K, Na
X = Br, I
R, R' = CH3, 1
+
O
R-C CH-Y'
H
+
Y
OY
H ,
R-C-CH-Y'
- H 2O
R'
CH 3COOH + RCH 2COOH
acidic decomp.
(酸式分解)
diethyl malonate
1) KO tBu
2) R'X
monosubstituted acetone
ORO
1) dil.NaOH
CH 3-C-C-C-OEt
2) H 3O
R'
- CO 2
O
CH 3-C-CHRR'
disubstituted acetone
2) H3O
- CO2
R
HOOCCCOOH
R'
- CO2
RCH2COOH
monosubstituted
acetic acid
RR'CHCOOH
disubstituted
acetic acid
The reactions with CH2I2 or BrCH2(CH2)nCH2Br (n = 0,1,2,3):
EtOOCCH2COOEt
1) NaOEt
EtOOCCHCOOEt
2) BrCH2(CH2)nCH2Br
CH2(CH2)nCH2Br
CH2
CH2
1) NaOH
NaOEt EtOOC
HOOC-CH (CH2)n
(CH2)n
C
CO
2
2) H3O
EtOOC
CH2
CH2
intramolecular
cycloalkanecarboxylic
acid
alkylation
+
R
HOOCCHCOOH
2
+
+
R
R
1) KOtBu
EtOOCCCOOEt
EtOOCCHCOOEt
2) R'X
R'
1) NaOH/H2O
1) NaOH/H O
2) H3O
- CO 2
O
CH 3-C-CH 2-R
e.g.
ii. To form substituted acetic acids
1) EtO
2) RX
O
O
CH 3-C-CH-C-OH
R β-keto acid
ketolytic decomp.
(酮式分解)
+
Y
R
C=C
R'
Y'
cis and trans isomers
Knoevenagel condensation
(诺文葛尔)
EtOOCCH2COOEt
1) dil. NaOH
O
O
KOH CH -C-CH-C-OC H
or H 3PO 4
3
2 5
2) H 3O
R
b path
b a
a path
+
R
Y-C-Y'
R'
R
1) MOBut
RX
Y-CH-Y' 2) R'X
SN2
O
R-C-Cl or (RCO)2O
aprotic polar solvent
O
RCR'
or R = H
stabilized anion
Y-CH-Y'
B = OCH 3, OC 2H5 , N(C 2H5)2
3 kinds of important reactions of active methylene compounds:
alkylation(烷基化), acylation(酰基化), and Knoevenagel condensation
Y-CH-Y'
B
- HB
81
17.5 Aldol condensation (羟醛缩合)
Step 3 acidification and Step 4 dehydration:
a. Self-condensation of aldehydes or ketones
O
General expression: 2RCH 2C-H
OH
O
O
O
H2O
RCH2CH-CHC-H
RCH2CH-CHC-H
OH
R
R
O
- H2O
RCH2CH=C-C-H
Step 4
R
O
R
RCH 2CH=CH-C-H
B
base = NaOH, KOH, NaOR, Al(OR)
3
Mechanism:
O
- HB
O
RCHC-H
e.g.
O
RCH=C-H
+
Step 1 enolization: RCH2C-H B
R' O
2RCHC-H B
O
O
RCH 2CH-CHC-H
R
O
2RCCH 2R'
O
O
CH 3CH=CHCH + CH 3CH 2CH=C-CH
CH 3
self-cond. of ethanal self-cond. of propanal
O
O
+ CH 3CH 2CH=CHCH + CH 3CH=C-CH
CH 3
OH O
- H 2O
CHCH 2CH
OH O
- H 2O
R'CH2-C-CH-CR
R R'
ketol 羟酮
O
CH=CHCH
O
γ
α O
CH3-CH CH3CH=CHCH
insert
-CH=CH-
O
R'CH2C=C-C-R
R R'
O
ε
CH3CH=CHCH=CHCH
e.g.
O
O
PhC-H + CH3-CH=CHC-H OH
γ-H is acidic
+
cross-cond. of ethanal and propanal
e.g.
O
O
OH
C-H + CH 3CH
B
RO
R' OH R O
- H2 O R
C=CH-C-C-H
R-CH-CH-C-C-H
R'
R'
aldol R'
The insertion of C=C double bond into the bond between the
α-C and the carbonyl C will not reduce the acidity of the H.
b. Cross-condensation of aldehydes
O
O
B
CH 3CH + CH 3CH 2CH
H3O
only one α-H
Step 2 nucleophilic addition:
O
O
RCH 2C-H
RCHC-H
aldol
羟醛
H
OH
O
PhCHCH2CH=CHCH
- H2O
O
PhCH=CHCH=CHCH
without α-H
c. Claisen-Schmidt reactions
O
1) NaOH
+ CH3CCH3
2) H3O
O CHO
furaldehyde (糠醛)
+
O
O CHCH2C-CH3
OH
- H2O
H
O C=C
H
CCH3
O
e. Condensation with nitroalkanes or nitriles
RCH2NO2 B
RCH2CN B
E-isomer as
major product
1) OH
CH3NO2 + PhCHO
+
2) H3O,
- H2O
d. Intramolecular aldol condensation
+
c
O
O
1) OH
CH3CCH2CH2CH2CH2C-H
2) H3O
a
- H 2O
b
PhCH=CH-NO 2
H2/Ni
PhCH2CH2NH2
CHO
O
CCH3 +
path a
major
RCHNO2 condense with aldehydes and
ketones which have no α-Hs
RCHCN
+
O
path b
CH3
CH3CN + PhCHO
H /Ni
1) OH
PhCH2CH2CH2NH2
PhCH=CH-CN 2
+
2) H3O,
- H2O
path c
82
e.g.
f. Perkin condensation—to synthesize cinnamic acid
O
1) CH 3COONa
-C-H + (CH3CO)2O
+
2) H3O,
1) CH3COONa
+ (CH3CO)2O
+
O CHO
2) H3O
CH=CH-COOH
cinnamic acid 肉桂酸
H
O C=C
COOH
H
Mechanism
O
CH3-C
O
O
NaOCCH3 CH2-C
PhCHO
O
O
CH3-C - CH3COOH CH3-C
O
O
O
Ph-CH-CH2-C
- H 2O
HO CH3-C O
Ph
H
O
C=C
H
17.6 Claisen condensation to form β-keto esters
a. Self-claisen condensation of esters
O
+
O
C
H3C
O
CH3COOH
Ph-CH-CH2-C
O CH3-C O - CH3COO
O
O
O
NaOC2H5
2CH3C-OC2H5
CH3CCH2COC2H5 + CH3CH2OH
H
Ph
H3O
C=C
COOH
O - CH3COOH H
C
ethyl acetoacetate
E-cinnamic acid
O
Mechanism:
e.g.
O
CH3C-OC2H5
O
O
CH3C-OC2H5 + CH2C-OC2H5
OC2H5
step 1
O
NaOC2H5
2R2CHCOC2H5
O
CH2C-OC2H5
b. Cross-Claisen condensation
O O
O
O
O
O
1) NaOC2H5
CH3C-OC2H5 + CH3CH2C-OC2H5
CH3CCH2COC2H5 + CH3CH2CCHCOC2H5
2) H3O
CH
+
O
O
O
O
- OC2H5
CH3C- CH2C-OC2H5
CH3C- CH2C-OC2H5
step 3
step 2
OC2H5
O
O
R2CH-C-CR2-COC2H5
3
O
O
CH3C- CH2C-OC2H5
OC2H5
+
step 4
O
O
O O
+ CH3CCHCOC2H5 + CH3CH2CCH2COC2H5
CH3
O
O
CH3C-CHC-OC 2H5 + C2H5OH
H
O
O
CH3C-CH2C-OC2H5
O
O
O
O
1) NaOC2H5
CH3C-OC2H5 + HC-OC2H5
H-CCH2C-OC2H5 + EtOH
2) H3O
+
O
O
CH3C=CH-C-OC 2H5
O
O
CH3CCH=COC 2H5
c. Intramolecular Claisen condensation—Dieckmann
condensation
e.g.
COOEt
+
CH2-COOEt 1) NaOC H EtOOC
2 5
EtOOC CH2
H
H-C
HO
OH
2) H3O
C=O
COOEt
O
CH2
COOEt
COOEt
EtOOC
- 3H2O
triethyl benzene1,3,5-tricarboxylate
H3 O
CH3
COOC2H5
NaOC2H5
path a
CH3
O
COOC2H5
CH2-C-OC2H5
b O
d. Resemble Claisen condensation
RCH2-Y + R'COOEt
O
Y = RC-, CN, NO 2,
1) B
+
COOEt
O
H3C O
CH-C-OC2H5
a
NaOC2H5 H3O
CH2
path b
CH2
+
OH
+
H
O=C
O
R'C-CHR-Y
2) H3O
base = NaOCH 3, NaOC 2H5, NaH, NaNH 2
83
+
O
O
O
O
1) NaNH2
CH3CCH2CH2CH3 + CH3CH2CH2C-OEt
CH3CH2CH2CCH2CCH2CH2CH3
2)
H
O
3
a
c
b
76%
pyrrolidine
吡咯烷
N
H
a. Acylation with acyl chlorides
+
acidity : H a > H b > H c
O
O
O
stability: CH 2CCH 2CH 2CH 3 > CH 3CCHCH 2CH 3 > CH 3CH 2CHC-OEt
N
H H
+
+
N
N
H2Cl
+
-
b. Alkylation with active RX (active alkyl halide)
R
O
N
H H
+
R-X
r.t.
c. Alkylation with α,β-unsaturated esters
X
N
N R
..
O
CH2=CHC-OEt
EtOH ,
N
N
- H 2O
O
O
RX = C=C-CH2-X , XCH2C-
+
N
H 2X
N
CH2-X , CH3I
+
R
+
H2O
β-diketone
+
X
..
N
- H 2O
-
+
+
N
H H
O
CR
O
H 2O
iminium ion
C-C=NR2
O
Cl
O
CR
+
..
NR2
C=C
enamine
OH
- H 2O
-C-C-NR2
H R'
O
RC-Cl
N
- H2 O
General expression:
H
..
N
+
O
17.7 Acylation and alkylation of enamines
O
..
-C-C-R' + HNR2
H (H)
piperridine
哌啶
N
H
O
CH2CH-C-OEt
O
CH2CH2C-OEt
O
H3O
N
H
17.8 Other carbon nucleophiles
b. Alkylation of dianions
O
O
NaH
CH3CCH2COC2H5
a. Alkylation of 1,3-dithianes (二噻烷)
H
SR Raney Ni
RC
H2
SR
-
+
H
RCHO + 2HSR'
- H 2O
RCH3
S
R
S
C Li
+
+
BuLi
- BuH
R'X
- LiX
17.9 Michael addition (conjugate addition )
S
S
R
O
R-C-R'
C
R'
Raney Ni(H 2)
RCH 2R'
+
dithiane (二噻烷)
H2O/HgCl 2
- HSCH 2CH 2CH 2SH
2
O O
O O
RX (1 equiv.)
RCH2CCHCOC2H5
CH2CCHCOC2H5
1 or 2
dianion
O
O
H3O
RCH2CCH2COC2H5
+
thioacetal (硫代缩醛)
O
HSCH 2CH 2CH 2SH S
S
R-C-H
H , - H 2O
C
R H
O O
BuLi
CH3CCHCOC2H5 or KNH
CH-Y
B
- HB
C-Y
C=C-Y'
-C-C-C-Y' H
Y
-C-C-C-Y'
Y H
O
Y, Y' = C , -C N, NO2
thioketal (硫代缩酮)
84
O
O
1) KOH
RC-CH=CHR' + CH 2(CO2Et)2
EtOH RCCH 2CHR'CH(CO 2Et)2
1) OH
2) H 3O
2) H 3O , , - CO2
e.g.2
+
Some examples of Michael addition:
+
e.g.1
O
(CH 3)2CHNO 2 + CH 2=CHCH=CHC-Ph
R4NOH
O
RCCHCHR'-CH 2COOH
Η
O
O
NO 2
(CH 3)2C-CH 2CH=CH-CH=CPh + CH 2=CH-CHCH=CPh
(CH 3)2C-NO 2
1,4-addtion
1,6-addition
e.g.3
+
O
C
1) NaOEt
2) H
+
CH2=CH
O
CH3
OC2H5
O C=O EtOH
CH3
+
+
O
NO 2
O
(CH 3)2C-CH 2CH-CH=CH-CPh + CH 2=CH-CHCH-CPh
(CH 3)2C-NO 2
H
H
- H2O
O
NO 2
O
(CH 3)2C-CH 2CH 2-CH=CHCPh + CH 2=CH-CHCH 2CPh
(CH 3)2C-NO 2
major product
OH
O
O
Michael addition + intramolecular Aldol condensation =
Robinson annulation
17.10 Synthesis (retrosynthetic analysis)
e.g.4
B
OH
COOEt - H O
2
CH3
O
+
+ BrCH 2COOEt
a. Reformatsky reaction
COOEt
CH3
O
COOEt
2)
CHO
=CR’COOR
e.g.1
CH=CHCOOEt
b. Mannich reaction—Aminomethylation (胺甲基化)
H
O
OH
HCl
PhC-CH2 + HCH + NR2 EtOH
- H 2O
or ketones
H3 O
1) Zn
+
H 3O
R
H
C=O BrZnO H
Br-Zn-C-COOR R'
R'-C-C-COOR
aldehydes
H
RH
H
Br-C-COOR Zn
H
+
COOEt
CH2
H
CH3
O
1) H3O
2)
,- CO2
e.g.
17.11 Other important reactions of carbonyl
compounds (additional paragraph)
COOEt
C CH3
O C=O
CH3
O
CH2
NaOCH(CH3)2
+ CH3CCHCOOEt
HOCH(CH3)2
O
CH3
HO H
- H 2O
R'-C-C-COOR
RH
R
COOR
C=C
R'
H
H H
HH
O
O
H+
HCCH 2CH 2CH + NCH 3 + HOOCCHCCHCOOH
- 2H 2O
O
CH 2-CH-CHCOOH
- 2CO 2 CH 2-CH-CH 2
H3CN C=O
H 3CN C=O
CH 2-CH-CHCOOH
CH 2-CH-CH 2
an intermediate for Belladonna and Atropine
颠茄
阿托品
O
PhCCH2-CH2NR2. HCl
e.g.2
O
H
OH
O
HCl
PhC-CH2 + HCH + PhCCH2CH2NR - H O
2
O
PhCCH2CH2
NR
PhCCH2CH2
O
OH
H
H
CH 3
O
HCl
+ 2HCH + 2HN(CH 3)2
OH
(CH 3)2NCH 2
CH 2N(CH 3)2
CH 3
85
e.g.
c. Darzen reaction – to synthesize α,β-epoxy esters
ClCH2COOEt
R"
R R"
+
R
H3O
NaOR
NaOR
C=O + ClCHCOOEt
R'-C-C-COOEt
HOR/H2O
R'
or NaNH2
O
(H)
- Cl
Ph
H
α,β-epoxy esters
R R"
R" tautomerize
R
R'-C-C=O
C=C
(H) H
R'
OH
R R"
- CO2
R'-C-C-COO-H
O
aldehydes
or ketones
d. Cannizzaro reaction—Disproportionation (歧化反应)
of aldehydes without α-H
2HCHO
2PhCHO
NaOH
PhCH 2 OH + PhCOONa
reduced
COOEt
Ph
H
C=C
H
Ph
Ph
H
H
Cl
C C
H
O COOEt
+
H
H3O Ph
NaOEt
H C-C COOH
HOEt/H2O
O
O
Ph-CH2CH
OH
General equation :
PhC
H
O
H
PhCH-CHO
Darzen reaction
Chapter 18 Pericyclic Reaction (周环反应）
oxidized
General equation:
σ
+
O
O 1) NaOH ,
R 3C-C-H + HCH
+
2) H 3O
H
C-C
O
O=C
18.7 The Diels-Alder Reaction
([4+2] cycloaddition)
CH 3 OH + HCOONa
NaOH
- CO2
NaNH2
ClCHCOOEt
- NH3
π
R 3 CCH 2OH + HCOOH
reduced oxidized
σ
diene dienophile
(双烯体) (亲双烯体)
adduct
concerted mechanism (协同机理）
b. Stereoselectivity of the reaction
i. For the dienes, they react in the s-cis conformation rather
than s-trans
a. Effect of substituents
200 C
+
20%
O
+
O
O
100 C
O
O
Me
Me
+
H
30 C
100%
O
O
maleic anhydride
Me
Me
s-cis
s-trans
ii. For a dienophile, the reaction is a syn-addition, the
configuration of the dienophile is retained in the reaction.
+
O
COCH3
H
COCH3
O dimethyl maleate
O
CH3OC H
CHO
high yield
H
+
H
O
COCH3
H
H
COCH3
O
OCH3
O C
H
COCH3
O dimethyl fumarate
H
COCH3
O
86
An empirical rule for Diels-Alder reaction of the conjugate
dienophile: the largest overlap of the conjugate unsaturated
bonds in the transition state.
iii. For cyclic dienes, if the dienophile is a conjugate
unsaturated system, the major product is the one in
an endo form (内式) rather than an exo (外式) form.
O
COCH3
cyclic
diene
conjugate
dienophile
H
H
O
+
COOCH 3
H
H
COOCH 3
endo-form
exo-form
minor
major
+
H
O
H
O
O
O
O
H
O
exo form
O
not observed
O
H
Two key points for Pinacol rearrangement:
+
◆ The originally formed C should be the more stable one.
◆ Normally the migration order is Ph and H prior to Me.
a. Pinacol rearrangement
H3C CH3
+
H3C CH3
H3C CH3
H
- H2 O
CH3-C C-CH3
CH3-C C-CH3
CH3-C C-CH3
+
HO OH
HO OH2
HO
+
Pinacol (频哪醇)
CH3
CH3
+
1,2-migration
CH3-C C-CH3
CH3-C C-CH3
HO
HO CH3
..: CH3
+
e.g.1
H3C H
CH3-C C-CH3
HO OH
H
+
- H2 O
H 1,2-migration
+
e.g.2
H3C H
H3C H
CH3-C C-CH3 + CH3-C C-CH3
+
+
HO
OH
minor
major
H3C
H3C
+
-H
CH3-C C-CH3
CH3-C C-CH3
H O
H OH
H3C +
CH3-C C-CH3
H :OH
..
CH3
CH3-C C-CH3
O CH3
Pinacolone (频哪酮)
-H
H
O
H
18.11 Rearrangements to electron-deficient
centers
O endo form
major
O
+
Mechanism of Beckmann rearrangement:
Ph 1,2-migr.
H3C CH3 +
H3C CH3
H, - H2O
Ph-C-C-Ph
Ph-C-C-Ph
+
HO OH
HO
Me 1,2-migr.
CH3
CH3-CH-C-CH 3
I OH
Ag+
CH3
+
CH3
- H H C-C-C-Ph
H3C-C-C-Ph
3
O Ph
HO Ph
+
+
major
CH3
CH3
+
Ph-C-C-Ph - H Ph-C-C-Ph
HO CH3
O CH3
+
R
R R
oxime
H
+
R'
R
OH
O
RC-NHR
amide
N
C
R
- H 2O
R'
R'C=N-R tautomerization
OH
OH
+
H
major product ?
b. Beckmann rearrangement
N
C
OH2
OH
N
C
R
N
C
H
+
R'
opposite to OH
R
N
+C
H2O
R'
H2O
+
N
C
- H+
R'
R'C-NR
O H
O
R'C-NHR formed by the migration of R group
O
RC-NHR' not formed in the migration
stereospecific reaction
87
A comparison:
HO
N=C
Ph H +
Mechanism of Baeyer-Villiger rearrangement:
O
PhC-NHCH 3
CH3
HO
CH 3
N=C
H
+
Ph
nucleophlic
O
O
addition
RCR + R'COOH
O
CH 3C-NHPh
General equation:
e.g.1
R
O
RC-O-R
O
O
RCR + R'COOH
or H 2O2
O
O
O + R'COOH
or H2O2
O
hexanolactone
己内酯
e.g.
H3C
O
CH3CH-O-CCH3
major
H3C O
O
CH3-CH-C-CH3 + CH3COOH
CH3CO3H
C6H5-C-C6H4-OCH3-p
C6H5-C-O-C6H4-OCH3-p
H2SO4
O
O
C6H5-C-C6H4-NO2-p CH3CO3H
H2SO4
O
C6H5-O-C-C6H4-NO2-p
O
a.For alcohols
4 methods for protecting alcohols:
ROH +
TsOH
O
dihydropyran
RO O
OH
R
c. Baeyer-Villiger rearrangement
TsOH
ROH
C2H5OH
1)NaH
HCl
ROCH2OCH3
2)ClCH2OCH3
H2O
chloromethyl methyl ether
ROH
C
R
R
OH
:OH
1,2-migration
O+
- R'COO
C
O-OCR'
O
R-C-OR
+
-H
O
RC-OR
+
An electron-rich R group benefits the migration.
The migrating order of R groups for Baeyer-Villiger rearrangement:
3°R > 2°R > 1°R > CH3
Chapter 19 The synthesis of Organic
Compounds
19.1 Introduction
retrosynthetic analysis of a target product
19.2~19.5 Protective groups for alcohols,
aldehydes and ketones, carboxylic
acids and amines.
The principle to choose a protecting group is to keep the other
functional groups in the starting compound intact during the
introducing and removing processes of a protecting group.
Problems:
ROH
H2
1) NaH
ROH
ROCH2Ph
Pd/C
2) PhCH2Cl
benzyl chloride
HC≡CCH2OH
RCH=CHCH2OH
b. For aldehydes and ketones
ROH
+
Et3N
Bu4N F
ROSi(CH3)3
H2O
(CH3)3SiCl
trimethyl silyl chloride
ROH
ROH
+
O
H
+ HO OH
RCR'
(H) ethylene glycol
+
O H3O
O
R
C
R' (H)
O
RCR'
(H)
88
An example:
c. For carboxylic acids
ClCH 2COOH
(LiPPh 2)
Ph 2PCH 2COOH
+
+
+
CH3OH or
1)NaOH/H2O
C2H5OH
RCO2Me
RCOOH
2)H3O
H
H
ClCH2COOH + EtOH
RCOOH
Ph2PCH2COOEt
ClCH2COOEt
1)NaOH/H2O
+
LiPPh2
- LiCl
Ph2PCH2COOH
2)H3O
RCOOH
RCOOH
RCOOBut
H+
PhCH 2OH
H+
HCl
H2O
RCOOCH 2Ph
RCOOH
H2
Pd/C
iv.For amines
O O
Et3N
RNH2 + t-BuOC-O-COBu-t
DMF
di-t-butyl dicarbonate
RCOOH
carbobenzoxy chloride
O
O
Na2CO3
PhCH 2OC-NHR
RNH 2 + PhCH 2OC-Cl
O
H2
- CO 2
HOC-NHR
RNH 2
Pd/C
19.6~19.7 Examples of Synthesis
e.g.
O
H2NCH- 2C-N(CH 3)2
H2NCH 2COOH
α-amino acid
O O
t-BuOC-O-COBu-t
Et 3N, DMF
- t-BuOH
- CO 2
HCl/H 2O
O
1)SOCl 2
t-BuOC-NHCH 2COOH
2)(CH 3)2NH
O
HCl
t-BuOC-NHR H O RNH2
2
Boc
- t-BuOH
- CO2
O
t-BuOC-NHCH 2CON(CH 3)2
Three general principles for designing the synthetic
route of a target organic compound:
1) Using the synthetic route as short as possible.
2) Using the synthetic route which can give a high yield
of the target product, without or only with a trace
amount of by products.
3) Using starting materials which are cheap and easily
obtained.
The example on page 1018:
O O
1) NaOEt, EtOH
OEt 2) Br(CH 2)3Br
3) H 3O , , - CO 2
O
+
TsOH
O
Br HO OH
O
+
O
BuLi
PPh 3 Br
O
O
O
H2SO 4
H 2O
O
OH
19.8~19.9 Carbon-Carbon bonds formation
and preparation of functional groups
O
PPh 3
Cl
CO 3H O
Br
O
CH 3CH 2CH O
O
PPh 3
O
- H 2O
All important reactions are summarized in the Tables of
21.1 and 21.2 of paragraph 8 and 9, which we have learnt
in preceding Chapters.
O
O
OH
spontaneous
89
Carbohydrates can be returned to CO2, H2O and energy by
metabolism in the bodies of living beings.
Chapter 20 Carbohydrates
20.1 Introduction and classification of carbohydrates
Cx(H2O)y + x O2 enzyme
General formula: Cx(H2O)y
Simple carbohydrates—sugars or saccharides (糖)
The suffix of the names of most sugars—“-ose”, e.g. glucose,
sucrose, maltose (malted milk)
Carbohydrates are synthesized in green plants by photosynthesis:
hν
x CO2 + y H2O
chlorophyll
Carbohydrates can be divided into 3 categories:
1) Monosaccharides—The simplest carbohydrates which
cannot be hydrolyzed into even smaller carbohydrates.
H
HO
H
H
CxH2yOy + x O2
CH2OH
CHO
CHO
CHO
CHO
CHO
OH
H
H
C O
H HO
OH HO
OH
H
HO
H
HO
H
H H
OH H
H HO
OH H
H
HO
OH
OH H
OH H
OH
OH H
OH
H
H
OH
OH
OH H
CH
CH2OH
2OH
CH2OH
CH2OH
CH2OH
CH2OH
D-glucose D-fructose D-ribose D-arabinose D-mannose D-galactose
阿拉伯糖
甘露糖
半乳糖
葡萄糖
果糖
核糖
aldohexose ketohexose
(2) Oligosaccharides which can be hydrolyzed to form 2 to 20
molecules of monosaccharides. Bi, tri, tetra,…-saccharides.
Bisaccharides: e.g. sucrose(蔗糖), maltose(麦芽糖),
lactose(乳糖) and cellobiose(纤维二糖)
H3O
1 mole of sucrose
H3O
aldopentose
20.2~20.4 Classification and structures of
monosaccharides
a. Classification
+
1 mole of maltose
x CO2 + y H2O + energy
2 mole of glucose
◆
+
1 mole of glucose + 1 mole of fructose
(3) Polysaccharides which can be hydralyzed to form more than
20 molecules of monosaccharide.
Polysacchrides: e.g. starch(淀粉) and cellulose(纤维糖)
b. D and L designations of open-chain monosaccharides
CHO
R
H
OH
CH2OH
CHO
S
H
HO
CH2OH
D-(+)-glycer- L-(-)-glycer- 甘油醛
aldehyde
aldehyde
To determine D and L designations:
If the highest-numbered chiral *C atom of a monosaccharide
has the same configuration as D-(+)-glyceraldehyde, it is
designated as a D-sugar, and the one whose highest-numbered
chiral *C atom has the same configuration as L-(-)-glyceraldehyde
is designated as an L-sugar.
◆
First, by the number of carbon atoms presenting in the molecule,
e.g. triose C3, tetrose C4, pentose C5, hexose C6 …….
Second, by whether they contain an aldehyde or a keto group.
A monosaccharide containing an aldehyde group is called an
aldose (醛糖), and the one containing a keto group is called a
ketose (酮糖).
e.g.
H
HO
H
H
CHO
CHO
H
OH HO
H
OH
H
H
HO
OH
H
OH HO
CH2OH
CH2OH
D-glucose
L-glucose
CH2OH
CH2OH
C O
C O
HO
H
OH
H
H
H
OH HO
H
H
OH HO
CH2OH
CH2OH
L-fructose
D-fructose
c. Cyclic structures and conformations of monosaccharides
In water, aldopentoses (戊醛糖), aldohexoses (己醛糖) and
ketohexoses (己酮糖) exist in cyclic forms of hemi-acetals or
hemi-ketals formed by intramolecular reactions of an OH group
with an acyl group to form a 5 or 6-membered ring.
90
CHO
H OH
OH H O HO
H
2
OH H
H
OH
H
H
O OH
OH
CH2OH
CH2OH
β-D-(+)-glucose
D-(+)-glucose
< 1%
64%
H OH
OH
OH
H H O H
CH2OH
H
HO
H
H
HO
α-D-(+)-glucose
35%
HO
H
HO
H
HO
H
H CH2OH O
OH
H
HO
HO
trans
H
OH
H
H
OH
H
H CH2OH O cis
β-D-(+)-glucose
α-D-(+)-glucose
α-glucose: The hemiacetal OH group is on the opposite side of the CH2OH group.
β-glucose: The hemiacetal OH group is on the same side of the CH2OH group.
Anomers(正位异构体): α-Glucose and β-glucose are diastereomers, this kind
of diastereomers are called anomers.
The above 3 kinds of weak oxidants can oxidize aldehydes,
α-hydroxy ketones, aldoses and ketoses.
e.g. aldose
HO
HO
H
H
CHO
H
H Tollen's
OH
OH
CH2OH
HO
HO
H
H
CHO
H
H
OH
OH
CH2OH
H
+
Fehling's
Benedict's
blue solution
HO
HO
H
H
HO
HO
H
H
COOH
H
H + Ag
OH
OH silver mirror
CH2OH
COOH
H
H
OH + Cu2O
OH
brick-red
CH2OH preciptate
Ketoses are oxidized by the weak oxidants via tautermerization
of keto form first to enol form, and then to aldo form.
There exists an equilibrium between the open-chain form and the
α and β forms of the cyclic hemiacetals. Since they have different
specific rotations (旋光率), as the equilibrium changes, the rotation
value of the aqueous solution will also change. This kind of
phenomenon is called mutarotation (变旋光).
20.5 Reactions of monosaccharides
a. Oxidation reactions of monosaccharides
i. By weak oxidants:
*
HO-CHCOOH
tartric
*
Tollen’s [Ag(NH3)2+OH-]
acid
HO-CHCOOH
Fehling’s CuSO4/KNaC4H4O6
CH2COOH
Benedict’s reagent CuSO4/citric acid/Na2CO3 HO-C-COOH
CH2COOH
e.g. ketose
CH2OH
C O
H Tollen's
HO
H
OH
H
OH
CH2OH
CH2OH
C O
H
HO
H
OH
H
OH
CH2OH
H
+
Fehling's
Benedict's
COOH
CHOH
HO
H + Ag
OH
H
H
OH
CH2OH
COOH
CHOH
HO
H
H
OH + Cu2O
H
OH
CH2OH
Reducing sugars: Sugars (containing a hemiacetal or a
hemiketal group) that can be oxidized by Tollen’s,
Fehling’s or Benedict’s reagent
Tautermerization (互变异构):
CH2OH
C O
CHOH
C-OH
O
C-H weak
oxidant
CHOH
C O
COOH
CHOH
C
OH
H
cyclic hemiacetal
OH
C O
C
O
H
weak
CHO
(CHOH)n oxidant
H2O
C-OH
OH
open-chain
H2O OH
C O
C
COOH
(CHOH)n
C-OH
aldonic acids
醛糖酸
O
H
91
Non-reducing sugars: Sugars (containing an acetal or a ketal
group) that cannot be oxidized by Tollen’s, Fehling’s or
Benedict’s reagent
C O
OR
C
H
iii. By HNO3
CHO
(CHOH)n
CH2OH
CHO
(CHOH)n
C-OH
OH
H2O
aldose
aldaric acid
糖二酸
open-chain
cyclic acetal
iv. By periodic acid (HIO4)
ii. By bromine water (Br2/H2O)
CHO
Br2
(CHOH)n
H2O
CH2OH
COOH
(CHOH)n
COOH
HNO3
H2O
COOH
(CHOH)n
CH2OH
CHO
H C OH
H C OH
CH2OH
configuration
retention
HCOOH
+
HCOOH
+
HCOOH
+
HCHO
3HIO4
H2O
aldonic acid
aldose
CH2OH
C=O
H C OH
H3C C OH
CH3
CH2OH
CH2
H C OH
CH2OH
CH2OR
H C OH
CH2OH
3HIO4
H2O
HIO4
H2O
HIO4
H2O
HCHO
+
O=C=O
+
HCOOH
+
CH3-C-CH3
O
CH2OH
CH2
CHO
+
HCHO
b. Reduction of monosaccharides
CHO
OH
H
OH
OH
CH2OH
D-glucose
H
HO
H
H
Ni/H2
or
NaBH4
H
HO
H
H
CH2OH
OH
H
OH
OH
CH2OH
glucitol
HO
HO
H
HO
CHO
CH2OH
HO
H
H
H
NaBH4 HO
H
H
OH
OH
HO
H
H
CH2OH
CH2OH
L-gulose
古洛糖
山梨醇
CH2OR
CHO
+
HCHO
alditols 糖醇
c. Reactions of monosaccharides with phenylhydrazine
Mechanism:
General equation:
H
CH2OH
CHO
CHOH or C O
(CHOH)n
(CHOH)n
CH2OH
CH2OH
aldose
ketose
3PhNHNH 2
H
C=NNHPh
C=NNHPh + PhNH2+ NH3 + H2O
(CHOH)n
CH2OH
phenylosazone
O
..
C
+ PhNHNH2
CHOH
HO H
- H2O
H-C-N-NHPh
CHOH
+
H
HC=N-NHPh tautermerize
CHOH
..
HC-NH-NHPh - PhNH HC=NH 2PhNHNH2 HC=N-NHPh
2
C O
- NH3, - H2O C=N-NHPh
C O-H
(苯脎)
92
During this reaction, the C-2 of aldose loses its chirality and the
configurations of other chiral C atoms in the molecule do not change.
CH 2OH
C=O
HO
H
H
OH
H
OH
CH 2OH
D-fructose
e.g.
D-glucose and D-mannose are diastereomers which differ only
in the configuration of the lowest numbered chiral C* atom.
The pair of diastereomers like this is called epimers
(差向异构体).
CHO
OH
H
OH
OH
CH2OH
D-glucose
H
HO
H
H
3PhNHNH 2
CHO
H
OH
HO
H 3PhNHNH 2
H
OH
H
OH
CH 2OH
D-glucose
CHO
HC=NNHPh
H
C=NNHPh 3PhNHNH 2 HO
HO
H
HO
H
H
OH
H
OH
H
OH
H
OH
CH 2OH
CH 2OH
D-mannose
CHO
H
H
OH
OH
CH2OH
D-mannose
HO
HO
H
H
epimers
甘露糖
OCH 3
CH 2 O
H
H
OCH 3 OCH 3
H3CO
H
H
pentamethyl β-D-glucoside
H
H3CO
d. Methylation of monosaccharides
H
CH2OH O
H2O
H
H
OH
OH
HO
H
H β
HO
HCl
- H2O
CH3OH
CHO
H
CH2OH O
OH H O HO
2
H
H
H
OH
H
OH
OH
HO
H
OH
CH2OH
α
D-glucose
HCl
- H2O CH
OH
H
HO
H
H
3
H
H
CH2OH O
H
H
OCH3
OH
HO
H
H β
HO
CH2OH O
H
H
H
OH
HO
OCH3
H
HO
H2O
methyl α-D-glucoside
methyl β-D-glucoside
This kind of acetals and ketals of monosaccharides are named
by suffix “-oside(糖苷)”.e.g. methyl glucosides, methyl fructosides.
20.6 Kiliani-Fischer synthesis and Ruff
degradation of monosaccharides
H
CH 2OH O
HO
H
H
OCH 3
OH
HO
H
H
(CH 3)2SO 4
NaOH, H 2O
methylation
O
O H OCCH 3
CH 2 O
(CH 3CO) 2O H3CCO
methyl β-D-glucoside
H
acetylation
H
OCH 3
H3CCO
OCCH
3H
H
O
O
methyl tetraacetoxy β-D-glucoside
OCH3
OCH
3
H
H
CH2 O
CH2 O
+
H3CO
H3CO
H3O
H
H
H
H
OCH3 CHOH
H3CO
OCH3 OCH3
H3CO
H
H
H
tetramethyl D-glucose
pentamethyl β-D-glucoside
b. To decrease the length of the carbon chain of an aldose
--Ruff degradation
a. To increase the length of the carbon chain of an aldose
O
C H HCN
H C OH
CH2OH
D-Glyceraldehyde
CN
1) Ba(OH)2
HO C H
H C OH 2) H3+O
CH2OH
CN
H C OH 1) Ba(OH)2
H C OH 2) H3+O
CH2OH
Epimeric
cyanohydrins
氰醇
O
O
C-H
C-OH
HO C H
HO C H Na-Hg, H2O
H C OH
pH
3-5
H C OH
CH2OH
CH2OH
苏阿糖D-(-)-Threose
O
O
C-OH
C-H
Na-Hg, H2O
H C OH
H C OH
pH 3-5
H C OH
H C OH
CH2OH
CH2OH
Epimeric
aldonic acids 赤藓糖 D-(-)-Erythrose
COOH
OH oxidative decarboxylation
H
OH
H2O2
Br2/H2O
CHO
OH
H
OH
CHO
H
HO
CH2OH Fe2(SO4)3
H
HO
OH
H
D-gluconic acid
OH + CO2
H
H
OH
OH
1)
H
COO
CH2OH
+2 H2O2
CH2OH
2)
H
OH Ca
D-glucose
H
HO
Fe2(SO4)3 D-arabinose
1) electrolytic
OH
H
H
OH
oxidation
CH2OH 2
2) Ca(OH)2
D-calcium gluconate
oxidation
H
HO
H
H
糖酸
93
8 D-stereoisomers of aldohexose with formula C6H12O6:
c. Fischer’s proof of the configuration of D-(+)-glucose
◆
◆
An aldohexose (C6H12O6): 4 chiral C atoms, the largest
number of stereoisomers—16(24), 8 structures of them
with D-configuration and another 8 with L-configuration
Suppose that the unknown monosaccharide with right rotation
of the plane-polarized light has a D-configuration (8 D-stereoisomers)
◆
◆
◆
CHO
OH
OH
OH
OH
CH2OH
D-(+)-Allose
1
H
H
H
H
CHO
OH
OH
H
OH
CH2OH
D-(-)-Gulose
5
H
H
HO
H
◆
The oxidation of unknown compound by HNO3 gave an
optically active aldaric acid containing 6 C atoms, ruling
out the possibility of structures 1 and 7.
CHO
H
OH
OH
OH
CH2OH
D-(+)-Altrose
2
HO
H
H
H
CHO
H
OH
H
OH
CH2OH
D-(-)-Idose
6
HO
H
HO
H
End-group interchange reaction of the unknown
compound gave another different monosacchride,
ruling out the structure 4.
CH2OH
CHO
H end-group HO
H
H interchange HO
H
OH
H
OH
H
OH
OH
CH2OH
CHO
D-(+)-Mannose
4
b. Maltose (麦芽糖)
H
a. Sucrose (蔗糖)
H
CH2OH O
H
H
H
OH
HO
H
OH
α-D-glucose
sucrose
+
OH
CH2OH O
H
H
H
OH
HO
H
OH
α-D-glucose
HO
HO
OH
+
H3O
CH2 O
H
HO CH OH
2
HO
HO
HO
H
HO
HO
H
H
20.7 Disaccharides
H
O
CHO
H
H
H
OH
CH2OH
D-(-)-Talose
8
CHO
OH
H
H
OH
CH2OH
D-(-)-Galactose
7
H
HO
HO
H
CHO
CH2OH
OH end-group
H
OH
H interchange HO
H
OH
H
OH
OH
H
OH
CH2OH
CHO
D-(+)-Glucose
3
First, Ruff degradation, and then Kiliani-Fischer synthesis
to increase a C, a pair of epimers were obtained, which
were oxidized by HNO3 to afford 2 optically active aldaric
acids with 6 C atoms, ruling out the structure 8.
CH2OH O
HO
H
H
OH
HO
H
HO
HO
H
H
H
HO
H
H
First, Ruff degradation, and then oxidation by HNO3
gave an optically active aldaric acid containing 5 C
atoms, ruling out the structures 2, 5 and 6.
H
CHO
H
H
OH
OH
CH2OH
D-(+)-Mannose
4
CHO
OH
H
OH
OH
CH2OH
D-(+)-Glucose
3
H
HO
H
H
HOH2C
HO
O
H
HO CH OH
2
H
CH2OH O
H
H
OH
HO
H
HO
+
H3O
H H CH2OH O
O
H
H
OH
OH
HO
H
H
maltose
H
CH2OH O
H
H
OH
OH
HO
H
H
β-D-glucose
HO
OH
β-D-fructose
94
d. Lactose (乳糖)
OH
c. Cellobiose (纤维素二糖)
H
CH2OH O
+
H
H
CH2OH O
H3O
H
O
H
OH
HO
H
H
OH
H
OH
HO
H
H
cellobiose
H
HO
CH2OH O
H
H
OH
OH
HO
H
H
HO
2
2 β-D-glucose
Chapter 21 Amino Acids, Peptides and
Proteins
21.2 Amino acids
Definition: Amino acids are carboxylic acids that contain
amino groups.
NH2
General molecule of α-amino acids:
R-CH-COOH
Except the simplest α-amino acid—
glycine(甘氨酸), the α-carbons in all
of α-amino acids are chiral carbons.
Only L-enantiomers of α-amino
acids are found in nature.
H2N
COOH
H
R
L-α-amino acids
21.3, 21.4 Chemical reactions of amino acids
a. Acid-base chemistry of amino acids
An intramolecular acid-base reaction to form a
dipolar ion, also called as a zwitterion.
R O
H2N-CH-C-OH
neutral form
CH2OH O
H
H
OH
OH
HO
H
H
β-D-galactose
H
R O
+
H3N-CH-C-O
dipolar ion (偶极离子）
zwitterion (两性离子）
H
OH
CH2OH O
H
H
OH
HO
H
H
O
H
+
H3O
CH2OH O
H
H
OH
OH
HO
H
H
lactose
H
HO
CH2OH O
H
H
OH
OH
HO
H
H
β-D-glucose
Category:
According to the position of amino group, amino acids
can be divided into:
α, β, γ ... ω amino acids
According to the numbers of amino groups and carboxylic
groups, amino acids can be divided into:
neutral amino acids—
the number of the NH2 = the number of COOH
acidic amino acids—
the number of the NH2 < the number of COOH
basic amino acids—
the number of the NH2 > the number of COOH
A zwitterion can react either with an acid to form a
cation or with a base to form an anion.
R O
+
H3N-CH-C-OH
cation
pH < 2
+
H 3O
pKa1
R O
+
H3N-CH-C-O
zwitterion
pH ≈6
R O
OH
H2N-CH-C-O
pKa2
anion
pH > 10
The concentration of each form depends on the pH
value of the solution. In a basic solution, amino acids
mainly exist in an anionic form, and in an acidic
solution, amino acids mainly exist in a cationic form.
95
When the pH value of the solution is equal to the
average of pKa1 and pKa2 , the concentration of the
zwitterion is at its maximum value, and this pH value
is called the isoelectric point (pI, 等电点).
+
pKa = -log Ka = -log
-
pKa1 + pKa2
pI =
2
Write the major existing form of glycine (molecular
formula: H2NCH2COOH) in aqueous solution at the
following pH values.
[H3O ][A ]
[HA]
For neutral amino acids: pI = 5.6 ~ 6.3
For acidic amino acids: pI = 2.8 ~ 3.2
For basic amino acids: pI = 7.6 ~ 10.8
b. Esterification of the COOH group and amidation
of the NH2 group
R O
+ R'OH
H2N-CH-C-OH
R O
O O
H2N-CH-C-OH + R'C-O-CR'
O
or R'C-Cl
H+
RCH
(CH2)n + H O
2
m ≥5
- (n-1)H2O
Δ
H3N+CH2COO-
pH = 2
H3N+CH2COOH
i. α-amino acids (intermolecular dehydration):
O
lactams
H
N
O
C
RHC
+ 2H2O
C
CHR
N
O
H
H
R-CH-N-H HO-C O
+
C
CHR
O
H-N
OH
H
ii. β-amino acids (intramolecular deammoniation):
RCH=CHCOOH + NH 3
21.6 Peptides (肽) and proteins (蛋白质)
R' O
R''
R O
R' O
R'' O - 2H2O
R O
+
+
NH2CHC-NHCHC-NHCHCOOH
NH2CHCOH NH2CHCOH NH2CHCOH
HN C
N-terminus
n = 2 or 3
iv. ω-amino acids (intermolecular dehydration):
n H2N-(CH2)m-COOH
pH = 6
R-CH-CH-COOH
H2 N H
Δ
iii. γ or δ-amino acids (intramolecular dehydration):
O
RCH-(CH2)n-C
HN-H
OH
H2NCH2COO-
c. Dehydration and deammoniation of amino acids
R O
+
+ H2O
H3N-CH-C-OR'
O
R
+ O
R'C-NH-CH-COOH R'C-OH
pH = 11
O
O
H2N(CH2)mC-[NH(CH2)mC-](n-2)NH(CH2)mCOOH
polyamides
amide bond or C-terminus
peptide bond
tripeptide
The intermolecular dehydration of amino groups and carboxyl
groups produce condensation polymers by forming amide bonds,
also called peptide bonds. These polymers are called peptides or
proteins.
e.g.
H3C O
O
O
H2NCHC-NHCHC-NHCH2COH
OH
CH2
Alanine-Tyrosine-Glycine
Ala-Tyr-Gly
(丙氨酰-酪氨酰-甘氨酸)
96
polymers of amino acids
molecular mass > 10000
proteins
molecular mass < 10000
peptides
Peptide—polymers of amino acids with molecular masses smaller
than ten thousand
Protein—polymers of amino acids with molecular masses larger
than ten thousand
+
proteins H3O
+
peptides H3O
or enzyme
a mixture of α-amino acids
or enzyme
2. Ammonolysis of α-haloacids
21.5 Preparation of amino acids
1. Strecker synthesis
RCHO
There are two critical differences between proteins and
artificially synthesized polymers:
1) The molecules of a particular protein have the same
molecular mass and contain the same number of
amino acids connected in the same sequence.
2) Proteins are formed by a combination of many
different amino acids, while artificial polymers are
formed only by 1~3 different monomer units.
X
X2
NH3
RCHCOOH excess
PX3(cat.)
X = Br or Cl
RCH2COOH
NH2
NH2
+
NaCN
HO
RCH-CN 3 RCH-COOH
NH4Cl,H2O,-NaCl
3. By Gabriel synthesis
Mechanism:
OH
- H 2O
RCHNH 2 Δ RCH=NH
+
HCN
NH 4Cl + NaCN
- NaCl
RCHO + NH 3
NH2
RCHCOOH
aminonitrile
NH 2
RCHCN
+
H3O
NH 2
RCHCOOH
O
O
NH
KOH
X
+
- KX
N K + RCHCOOR'
O
O
phthalimide
邻苯二甲酰亚胺
COOH
+
H
O
O
C
H
RC
H
N
O2N
N
O2
2 O
p
+3
e
t H
s
N
O2
N
H2
+
H
O
O
'C
H
R
C
N2
H
C-terminal amino acid:
H
O
O
C
H
R
C
N2
H
+
H
O
C'
OH
O
CR
H
H2
N
+
C
H OH
O
C
C
OH
H
CR N
H
N
C
OH
'
CR
H
N
C
OH
C
H
N
H
N
C
O
'H
R
C
H
N
OC
H
RC
H
O2N
N
N2
1 O
p
e
t
s
H
N
C
O
'H
R
C
H
N
C
OH
RC
.N
.
H2
+
O2
N
F
The studies are normally undergone by 3 steps:
ⅰ.To determine the composition of peptides and
proteins.
ⅱ.To determine the N-terminal amino acid by Sanger’s
reagent--2,4-dinitrofluorobenzene (DNFB),and the
C-terminal amino acid by a special enzyme—carboxypeptidase(羧肽酶）
N-terminal amino acid：
e.g.(Sanger’s reagent)
+
R
H3O
+ R'OH + H2NCHCOOH
H
N
C
O
'H
RH
C
N
OC
H
RC
H
N
O2N
21.7 Sequencing peptides and proteins
R
NCHCOOR'
O
SN2
COOH
O
carboxypeptidase
R''
O2
N
R''
97
ⅲ.To determine the sequence of amino acids in a particular
peptide or protein by Edman degradation and by the above
mentioned hydrolysis reaction of C-terminal amino acid using
carboxypeptidase as a catalyst.
E.g. Edman degradation
H
N
OC
H
C
H
N
OC
H
'
C
R
H
N
C
OH
RC
H
N
C
SH
N
h
P
H
N
C
OH
C
H
N
OC
'
H
RC
H
N
S
=
C+ C
OH
RC =
h
. P
.
N
H2
R''
R''
C
S
H
N
C
OH
C
H
N
O
+
H3 '
OC
RH
C
N
H2
+
O
HC
C
HN NH
(phenyl isothiocyanate)
R''
21.8 Laboratory Synthesis of Peptides
In order to selectively form a new amide bond between 2
α-amino acids, generally, 5 steps must be made:
1) to protect the NH2 group in which reaction is not desired;
2) to protect the COOH group in which reaction is not desired;
3) to activate the COOH group in which reaction is desired;
4) to form a new amide bond between α-amino acids;
5) to remove protective groups.
1. General methods to synthesize peptides and proteins
in laboratory:
1) to protect the NH2 group in which reaction is not desired.
separated by high-performance liquid
chromatography and then identified
3
R
O
OC
2H
C
R
N2
H
O
+ 2
H
H
- O2
H
/
H H
O
O +O3
3 a
R
N H
+ ) )
H 1 2
O
O
C
2H
C
R
N
H2
H
H
O
O
O
O
C
C
2H
1H
R
C
C
R
H
H
N
N
C
OC OH
2
2H
C
R
C
R
N
N
H2
H2
+
+
H
H
O
O
O
O
C
C
2H
H
1C
C
R
H RH
N
N
OC OC
1H
1H
C
R
C
N RN
H2
H2
+
O
H2
H
O
O
C
2H
R
C
N
H2
+
H
O
O
C
1H
R
C
N
H2
2) to protect the COOH group in which reaction is not desired
Δ
protect activate
protect
3) to activate the COOH group in which reaction is desired
l
C
H
+
H
O
O
C
'H
R
C
H
N
C
OO
H2
C
h
P
C
/
d
P
,
H H2
O
O
C
'H
R
C
H2
.N
.
+
l
C
C
OO
H2
C
h
P
t-Bu
H
3
O
R
O
O
2
O
C
H
O
H
/
C
C
H H
H
O
O
C
N
+
a
H
H3 N
N
C
- )) O
H
'C
C 12 R
OH
'
N
R
C
N
H2
H2
3
R
O
C
OH
2
C
R
H
N
C
O
H
'C
R
H
N
C
OO
H
O
t
E
+
O2
C
+
3
R
O
C
O
2H
R
C
.
.
N
H2
+
t
E
O
OC
O
C
O
H
'C
R
H
N
C
O O
t-Bu
O
3
H
N
C
O H
N
) C
D
D
(
+
3
R
O
OC
2H
C
R
H
N
C
OH
'
C
R
H
N
C
OO
N
C
N
-
R
O
+ OC
2H
3 R
C
H
N
C
O H
'
C
R
H
N
C
O O
-t-BuO(-),-CO2
combined step:
- -
+
H3
R
O
C
O
2H
R
C
N
H2
+
H
O
O
C
H
'C
R
H
N
C
O O
t-Bu
t-Bu
t-Bu
- -
4) to form a new amide bond between α-amino acids
dicyclohexylcarbodiimide
t-Bu
t-Bu
- -
t
E
O
OC
O
C
O H
'
C
R
H
N
C
O O
di-t-butyl dicarbonate
l
C
H
t
E
O
OC
l
C
+
H
.O
.
.
.
O
C
H
'C
R
H
N
C
OO
H
O
O
C
O
u
B
+
H
O
O
C
'H
R
C
H
N
C
OO
C
u
O
B
-B
t
O
+3
F H
NM
t3D
E
'H
O
R
2
HO
.H
NC C
.
+
u
B
t
O
O C
O
O C
O
u
B
t
t-
2. Solid phase synthesis of peptides and proteins
See next page: equations.
5) to remove protective groups
98
H
H
O
O
O
O
2
2
R
C
R
C
D
D
D
P
D
O
C
OH
N
P OC
H
O
C
R
C
N
O
'H
H2
C
R
N
H2 +
H
P
O
C
OH
RC
H
N
OC
H
2C
R
H
N
-
H
+
BOCNHCHC
BOC-NHCHC
1
3
e
u
n
i
t
n
o
c
.
.
.
P
O
C
OH
RC
H
N
OC
H
2C
R
H
N
O
R
1
3
O
R
BOCNHCHC
BOC-NHCHC
1
2
+
H
P
O
P OC
H
C
H
N
-
O
R
O
2
R
BOC-NHCHCO-
H2NCHC
99