Untitled - Chem254REELMWG7

when dealing with this method of reduction, as the reagents
are often difficult to handle for inexperienced organic
chemists. Although methods have been developed for running
this reaction in a standard household microwave oven.4
The Clemmensen reduction is another well-known
method of reducing aryl ketones and aldehydes. The reaction
uses a zinc-mercury mixture in concentrated hydrochloric acid
to remove the double bonded oxygen from the carbonyl group
similar to the Wolff-Kishner reduction.1 Also similar to
Wolff-Kishner, Clemmensen is not readily used in most
organic laboratories due to the complexity of the procedure. A
modified sort of Clemmensen reduction uses acetic anhydride
and zinc instead of the zinc-mercury mixture and is much
more practical to carry out and still obtain a high yield.5
There are a variety of different ways of reducing
atoms, but the products can often be a racemic mixture which
is not acceptable for drug companies.6 Therefore, the need
exists for a reliable and stereoselective reduction that produces
one exclusive product of a single conformation. Biological
reasons for the study of these reductions include the search for
mechanism under which enzymes can successfully reduce
compounds stereoselectively.7 In this experiment, we will be
examining how successful certain condition are when an
attempt is made to produce only one diasteriomer of an
alcohol product.
4-t-butylcyclohexanone is an unsymmetrical ketone
containing a carbonyl functional group which can be reduced
using various reducing agents. Subsequent experiments were
conducted using sodium borohydride and ammonia borane in
two different solvent systems to determine its effectiveness as
a reducing agent and to discover the stereochemical outcome.
Despite the possibility of attack from both the top and bottom
face of the carbonyl group by a hydride ion, it is clear that an
axial attack will lead to the major product with the hydroxyl
group in the equatorial position on the newly formed sp3
hybridized carbon center.
Results and Discussion
[R] - crude
+
OH
OH
O
R1 - 23% Yield
1. NaBH4 CH3OH
2. HCl, H 2O
77.5%
22.5 %
R2 - 11% Yield
NH3-BH3, EtOH
86.8%
13.2%
R3 - 37% Yield
NH3-BH3, Et 2OH
94%
6%
Table 1. Experimental Results based on GC analysis.
The reduction of 4-t-butylcyclohexanone with
sodium borohydride at 0o C resulted in 4-t -butylcyclohexanol
in 22.5% axial, and 77.5% equatorial conformations. Under
identical conditions, Lansbury and McLeay8 reported the
reduction of 4-t-butylcyclohexanone with sodium borohydride
resulted in 20% axial and 80% equatorial conformations . The
data of this particular experiment matched Group II, and
therefore showing that this experiment’s findings are accurate.
The findings of the Lansbury-McLeay experiment were
furthermore supported by Group II experiment.
[R]
+
OH
OH
O
4-tert-butylcyclohexanone
[R] =
trans-4-tert-butylcyclohexanol
1. NaBH4 CH3OH
2. HCl, H 2O
or
cis-4-tert-butylcyclohexanol
Major
Minor
Product from axial
hydride attack
Product from equatorial
hydride attack
NH3-BH3, EtOH
or
NH3-BH3, Et2OH
Figure 1. Major and Minor Stereoisomeric Products and Site of Nucleophilic Attack.
Using sodium borohydride as the reducing agent, the
major product in the reduction of 4-t-butylcyclohexanone was
trans-4-t-butylcyclohexanol (77.5%) and the minor product
was cis -4-t-butylcyclohexanol (22.5%). As indicated in
2
Scheme 1, the major product was a result of an axial attack of
the hydride ion to the bottom face of the carbonyl group of the
ketone. This was also determined by the use of 1 H NMR
spectroscopy. Despite the thermodynamic stability from the
hydroxyl group of the major product being in the equatorial
position on the newly formed sp3 hybridized carbon center, it
is not the reason that trans-4-t-butylcyclohexanol is the major
product. To understand why a more thermodynamically stable
product would not determine the amount of product, it has to
be considered that hydride addition is non-reversible. The
resulting major product is then determined by the mechanism
of the reaction. Figure 3 gives the view of the transition state
down the C1-C2 bond as a Newman projection of trans-4-tbutylcyclohexanol and Figure 2 gives the view of the
transition state down the C1-C2 bond as a Newman projection
of cis -4-t-butylcyclohexanol. It can be seen that trans-4-tbutylcyclohexanol is formed during the axial attack from the
hydride ion on the bottom face of the carbonyl group. Trans-4t-butylcyclohexanol is formed as the major product because
there is no energy barrier to overcome in its formation as in
the formation of the minor product, cis -4-t-butylcyclohexanol.
This energy barrier arises due to the eclipsed conformation
between Hb and the adjacent C=O bond that would result from
an equatorial attack of the hydride ion.
Ha
Ha
-
!
BH 3
Hx
O
!-
O
!-
Hb
Hb
Hx
!BH 3
Figures 2 and 3. Newman Projections of the transition state under Sodium Borohydride Reduction.
The major product each time was trans-4-t -butylcyclohexanol
when using NaBH4 vs. BH3 -NH3 , and BH3 -NH3 with
CH3 CH2 OH as the solvent vs. BH3 -NH3 with Et 2 O as the
solvent. Scheme 2 represents a proposed mechanism for the
reduction of a ketone by ammonia borane.
3
Equatorial Attack
H
Hx b
BH3
+
O
Na
C
OH
Na
+
Ha
Ha
Ha
Ha
HCl
Hb
Hb
-
O
O
Hb
HO
-
BH3
BH3
Minor: cis-4-t-butylcyclohexanol
Ha
-
BH3
!BH3
Hx
Hx
+
-
O
!
Hb
Ha
Hb
O
HO
Ha
+
Hx
Na
+
-
O
BH3
!-
Hb
-
Hx
Axial Attack
Ha
Hb
C
Hx
+
Na BH3
O
HO
!
BH3
Ha
Ha
Ha
-
O
Hb
O
BH3
HCl
Hb
-
Hb
OH
BH3
Major: trans-4-t-butylcyclohexanol
Scheme 1. Mechanism of Reduction with Sodium Borohydride in MeOH
4
Equatorial Attack
H
Hx b
BH2
O
+
NH3
C
Ha
Ha
Ha
Ha
Hb
Hb
-
O
O
H3N
+
HCl
BH2
H3 N
Hb
HO
-
BH2
+
Minor: cis-4-t-butylcyclohexanol
Ha
+
H3 N
BH2
!BH3
Hx
Hx
+
O
!-
Hb
Ha
Hb
O
Ha
+
Hx
-
H3N
+
O
BH2
Hb
Hx
Axial Attack
Ha
O
O
-
BH2
+
NH3
Hb
Ha
+
HCl
Hb
O
BH2
H3N
!BH3
Ha
Ha
Hb
C
Hx
!-
-
Hb
OH
BH2
+
H3 N
Major: trans-4-t-butylcyclohexanol
Scheme 2. Mechanism of Reduction with Ammonia Borane
Summary and Conclusions
Ammonia borane effectively reduces cyclic ketones with
predictable stereochemistry and predictable solvent effects.
While yields were less than desirable, the stereoselective
reduction of 4-t-butylcyclohexanone with ammonia borane in
Et2 O resulted in a primary alcohol that was a 16:1 trans to cis .
This ratio is a significant increase over the sodium
borohydride reduction completed in this experiment which
provided an alcohol in 6:1 trans to cis . Past investigations into
the temperature dependence of stereoselectivity8 regarding
reductions with sodium borohydride indicated that lowering
the temperature of the reaction would only increase the ratio to
7:1. Solvent effects were significant and predictable. When
EtOH was used in the ammonia borane reduction in place of
Et2 O, the product ratio fell to 6:1. The addition of a protic
solvent resulted in hydrogen bonding, as indicated in Scheme
1, which made the passing of the oxygen through the eclipsed
position with Hb significantly more difficult. In all three
reductions performed in this experiment, a single
recrystallization did not effectively eliminate the minor, cis
products. In most cases, recrystallization only resulted in a
1% increase in the major products produced. The low impact
of recrystallization on eliminating the minor stereoisomer
makes more remarkable the high stereoselectivity observed by
ammonia borane. Chemists seeking to synthesize a single,
major stereoisomer would benefit from the use of ammonia
borane in that fewer purifications by recrystallization or
chromatography would be required. In both reductions
involving ammonia borane; the workup was completed with
only water.
This likely contributed to the low yield.
Completing an acidic workup before collecting the alcohol
product would significantly increase the yield by decreasing
the loss of the ionic product to the aqueous extraction layer.
These results coupled with the ammonia borane’s controlled
reactivity and handleabilty illuminate its value as a
5
stereoselective reducing agent. Future research into the
impact of hydrogen bonding through the use of selectively
deuterated solvents and reactants would further illuminate and
help to quantify the effect of hydrogen bonding on the ratio of
the stereoisomers produced.
Experimental Section
Purpose:
1. To determine the stereo-selectivity of the reductions for the
indicated reaction and rationalize the selectivity with sodium
borohydride and ammonia borane.
2. To study the reaction with a different reducing agent (NH3 BH3 , ammonia borane) and solvents (methanol, ethanol, and
diethyl ether) to compare the diastereoselectivity and yield
that results.
again in the ice bath, and another addition of sodium
borohydride (0.0310 g, 0.819 mmol) was added. The reaction
was then stirred for an additional 15 min and retested via TLC.
TLC confirmed that there was still starting material present.
Another portion of sodium borohydride (0.0300 g, 0.793
mmol) was added when the contents of the flask were at 0 °C
then stirred at rt for another 15 min. The mixture was tested
via TLC and there was no longer any starting material,
indicating that the reaction was complete. To the mixture, HCl
(1M, 0.5 mL) and ice water (5 mL) were added to a 50 mL
Erlenmeyer flask. The contents of the flask were then
transferred to a seperatory funnel, where the organic products
were extracted with diethyl ether (2 x 10 mL). The organic
layer was dried with anhydrous magnesium sulfate. After the
dried sample was filtered via gravity filtration, the organic
crude product was evaporated over the steam bath, with small
samples being reserved for GC and HMR testing to yield a
white crude solid (1.2348 g) as trans-4-t-butylcyclohexanol Rf
0.36 (77.5%) and cis -4-t-butylcyclohexanol Rf 0.70 (22.5%).
1
H NMR (400 MHz, CDCl3 , !H ) 3.55 (m, 1H, H-4A), 4.05 (p,
1H, H-5A), 1.05 (m, 1H, H-4/5B), 0.07 (s, 9H, H-4/5C), 1.65
(s, 1H, H-4/5D).
Procedure:
Sodium Borohydride Reduction Procedure:
4-t-butylcyclohexanone (0.213 g, 1.38 mmol),
methanol (8.0 mL), and a stir bar were added to a 50 mL
Erlenmeyer flask. The mixture was cooled to 0 °C in an
ice/brine bath and sodium borohydride (0.0372 g, 0.983
mmol) was added. The mixture was allowed to stir for 30 min
at rt. Throughout the 30 min mixing process the mixture
remained clear and colorless. After 30 min, the reaction was
measured via TLC (5:1 petroleum ether: ethyl acetate eluent).
The reaction was compared to 4-t-butylcyclohexanone, the
starting material. The reaction sample that was analyzed using
TLC still showed starting material, hence the reaction was
determined to be incomplete. The mixture was reduced to 0 °C
Ha (Figure 4)
Ha (Figure 5)
Jaf
10Hz
Jaf
3Hz
Jaf
Jaf
10Hz
10Hz
Jaf
3Hz
Jae
3Hz
Jae
3Hz
Ja f
3Hz
Jae
3Hz
Jae
3Hz
Jae
3Hz
Jae
3Hz
Jae
Jae
Ja e
Jae
Jae
Jae
Ja e
Jae
Jae
Jae
3Hz
3Hz
3Hz
3Hz
3Hz
3Hz
3Hz
3Hz
3Hz
3Hz
Triplet of Triplets
Hb
Hf
He
Pentet
Hb
He
Hf
H dO
Ha
(H c )
He
He
Ha
H dO
Figures 4 and 5. 1 H NMR Analysis
6
Hf
Hf
(H c )
The crude product was recystallized in petroleum
ether (<1.0 mL) to yield the major product trans-4-tbutylcyclohexanol and the minor product cis -4-tbutylcyclohexanol. (total purified yield of both diastereomers:
0.0504 g, 0.3226 mmol, 23.4%) with mp 61.9-64.1 °C (lit9 6270 °C).
(Total purified yield: 0.0776 g, 0.4966 mmol, 37.6.6%) with
mp 71.7-74.4 °C (lit 1 62-70 °C).
Reduction using Ammonia Borane with Ethanol as a solvent:
4-t-butylcyclohexanone (0.210g, 1.36 mmol) and
ethanol (8 mL) were added to a 50 mL Erlenmeyer flask and
cooled to 0 °C in an ice/brine bath. Once at 0 °C, ammonia
borane (0.054 g, 1.75 mmol) was added. The mixture was
removed from the ice bath and allowed to warm to rt, while
being stirred for 30 min. The ammonia borane dissolved
completely resulting in a solution that was clear and colorless.
After 30 min, the reaction was measured via TLC (5:1
petroleum ether: ethyl acetate eluent) and compared to the 4-tbutylcyclohexanone starting material. The TLC showed that
no starting material was left, hence the reaction was complete.
Water (3.0 mL) was added to the completed reaction and
stirred for 15 min. The reaction was then diluted with CH2 Cl2
(15 mL) and the organic layer was separated via a seperatory
funnel. A second dilution of water (5 mL) and CH 2 Cl2 (15
mL) was added, and the extraction was repeated. The organic
layer was then dried with magnesium sulfate, and then filtered
via gravity filtration. The organic layer was then evaporated, a
small sample being reserved for 1 H NMR and GC testing,
yielding a white powdery crude product (0.1072g) as trans-4-tbutylcyclohexanol
Rf
0.39
(86.8%)
and
cis -4-tbutylcyclohexanol Rf 0.56 (13.2%). 1 H NMR (400 MHz,
CDCl3 , !H ), 3.55 (m, 1H, H-4A), 4.05 (p, 1H, H-5A), 1.05 (m,
1H, H-4/5B), 0.07 (s, 9H, H-4/5C), 1.65 (s, 1H, H-4/5D).
The crude product was recystallized in petroleum
ether (<1.0 mL) to yield a flaky white solid; the major trans-4t-butylcyclohexanol and minor cis -4-t-butylcyclohexanol.
(total purified yield of both diastereomers: 0.0233 g, 0.1491
mmol, 10.9%) with mp 68.5-71.1 °C (lit 9 62-70 °C).
Reduction using Ammonia Borane with Diethyl Ether as a
solvent:
4-t-butylcyclohexanone (0.210 g, 1.36 mmol) and
diethyl ether (8 mL) were added to a 50 mL Erlenmeyer flask
and cooled to 0 °C in an ice/brine bath. Once at 0 °C,
ammonia borane (0.054 g, 1.75 mmol) was added. The
mixture was removed from the ice bath and allowed to warm
to rt, while being stirred for 30 min. The ammonia borane did
not completely dissolve, resulting in a solution that was
slightly opaque. After 30 min, the reaction was measured via
TLC (5:1 petroleum ether: ethyl acetate eluent) and compared
to the 4-t-butylcyclohexanone starting material. The TLC
showed that no starting material was left, hence the reaction
was complete. Water (3.0 mL) was added to the completed
reaction and stirred for 15 min. The reaction was then diluted
with CH 2 Cl2 (20 mL) and the organic layer was separated via
a seperatory funnel. A second dilution of water (5 mL) was
added, and the extraction was repeated. The organic layer was
then dried with magnesium sulfate, and then filtered via
gravity filtration. The organic layer was then evaporated, with
a small sample being reserved for 1 H NMR and GC testing,
yielding a white powdery crude product (0.4029 g) as trans-4t-butylcyclohexanol Rf 0.43 (94.0%) and cis -4-tbutylcyclohexanol Rf 0.65 (6.0%). 1 H NMR (400 MHz,
CDCl3 , !H ), 3.55 (m, 1H, H-4A), 4.05 (p, 1H, H-5A), 1.05 (m,
1H, H-4/5B), 0.07 (s, 9H, H-4/5C), 1.65 (s, 1H, H-4/5D).
The crude product was recystallized in petroleum
ether (<1.0 mL) to yield a flaky white solid; the major trans-4t-butylcyclohexanol and minor cis -4-t-butylcyclohexanol.
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8
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9
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2
Acknowledgement. This work was completed under
the careful guideance of Dr. Christopher Callam and Teaching
Assistant Erica Campbell of the Ohio State University.
7