MROV 2014 - Repositorio

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MROV 2014
University of Puerto Rico
Río Piedras Campus
Collage of Natural Sciences
Department of Chemistry
SYNTHESES AND CHARACTERIZATION OF FERROCENYL CHALCONES
Myrna R. Otaño Vega
A Thesis Submitted in Partial
Fulfillment of the Requirements for the
Degree of Master in Science
February 28, 2014
All Rights Reserved
MROV 2014
ACCEPTED BY THE CHEMISTRY DEPARTMENT OF THE UNIVERSITY OF
PUERTO RICO IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE
DEGREE OF MASTER IN SCIENCE
THESIS DIRECTOR
CHAIRPERSON
CHEMISTRY DEPARTMENT
February 28, 2014
MROV 2014
In loving memory of Antonio Vega Latorre, Felicita Cuevas Avilés,
Demetrio Otaño Colón, Ana L. Nieves Vega, Adolfo Irizarry De León,
Jorge Vega Latorre and Eladio Chaparro Rosario.
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To: Eduard Irizarry, Héctor Otaño, Myrna Vega, Juan A. Otaño, Héctor Otaño Jr.,
Jacky González, Eliut Irizarry, Herminia Jiménez, Elvin Irizarry and Keila Reyes.
MROV 2014
Dedication
I want to dedicate this thesis dissertation to my grandmother, Rosa D. González for
making my dreams her dreams. To my father Héctor Otaño Cuevas for holding me and
guiding me throughout this phase of my life, for giving me his love, passing me his spirit
of service and inspiring me to be better every day.
To my mother Myrna Vega
González, for showing me how to fight for all that I want, tough, strength, courage, and
unselfish love. To both of you, I dedicate all my triumphs because of you I have gotten
to be what I am today; both of you are the best team. To my brothers Héctor Otaño
Vega and Juan A. Otaño Vega, for loving me and holding me but mainly for believing in
me. To my aunts and uncles for making me understand that there are no obstacles that
cannot be won and, to Milagros and Rafy Colls for giving me a room in your home,
taking care of me, giving me food and support when I needed. To Eliut Irizarry Mercado
and Herminia Jiménez Martes for your unconditional love and support and for allowing
me to stay close to both of you in the perfect place to stay, my new Home. To Jacky
González Arroyo, Elvin Irizarry Jiménez and Keila Reyes López for your advices,
patience and love. With all of you I had wonderful and happy moments which have
helped me grow each day of my life.
Finally, to my other Me, the person who gave me the space to develop my skills and
help me reach my goals at the perfect time, who cares for me, and believes in me, who
smiled, cried and celebrated all my triumphs and failures; the person who made me
accept that everything pass with a purpose and who continuously teaches me to see
only the good things in life. To my love, my husband Eduard…
MROV 2014
Acknowledgements
I would like to thank my parents, family and husband for your patience and support
throughout this adventure. Also, I want to thank the people who became my second
family, the people who smiled and cried with me throughout this journey and
experienced with me the hardest part of graduate school, my laboratory partners and
friends Johanna Fajardo Tolentino, Juan C. Aponte-Santini, Sara M. Delgado Rivera
and the undergraduates students Jonathan Rojas, Jesús Dones, Emmanuel López,
Julio A. Cedeño, Giovanni Rodríguez, Adrián Burgos, Fernando Correa, Edmarie
Santiago, Israel Méndez, María Rodríguez, and Raúl E. Martínez.
I want to especially thank the undergraduate students Ingrid Lehman Andino,
Ninoshka M. Lafontaine, Adriana Rodríguez Vázquez, Nicole Z. Hernández, Stephanie
Ramos de Dios, and Josué Rivera Hernández for your contribution and support in all
aims of this project. Your commitment makes possible the successful completion of this
project. Also, I want to recognize to Cristina Díaz Borrero and Wanda Cuadrado, M.S.
for their contribution of the very beginning of this project. Especially, I want to thank to
Joaudimir Castro, Ph. D. for your time, comments, advices and corrections.
Also, I want to thank to my friends Luis F. Padilla Morales, Rafael Ramos Franco,
Mara G. Morales García, Barbara Casañas Montes, Elizabeth Valentín Nevárez,
Mariana López-Cepero Montes, Ivan Olivo, Vanessa Morales, and Ileana Ortega for
your support and affection. Especially, thanks to Viviana León Morales, Alejandra Cruz
Montañez, and Raúl Rodríguez, Ph. D., for the discussion of NMR results and synthetic
procedures. Also, my gratitude to Dr. José A. Prieto for your helpful discussions in
NMR and FT-IR results of this project and to Dr. Ana R. Guadalupe for your teaching
and expertise in the electrochemistry area.
MROV 2014
In addition, I want to thank Allan Rodríguez, Kenette Rivero, and Richard Rivera
Ocasio for your help in the X-ray crystallography area and Rocio Cardona Couvertier
Ph. D., María del Mar García, and Yanira Enriquez for your collaboration in the
electrochemical and UV-Vis experiments, all of you are wonderful persons, thank you!
My sincere thanks to David J. Sanabria Ríos, Ph. D. and Gerardo Torres, Ph. D. for
your commitment and collaboration in the bioactivity testing and molecular modeling,
respectively; your knowledge and expertise were a key aspect in the culmination of this
project.
I want to thank to the American Chemical Society (ACS) and Society of Graduate
Students in Chemistry (SEGQuim) for giving me the tools to be strong during these
years and for allowing me to do something else besides studying, help others. Thanks
to Pfizer Fellowship which supported me economically for two years and to the
Chemistry Department for giving me the opportunity to be a Teacher Assistant during
my years in the graduate program. Also, I want to thank to José Terrón and Edwin
Viera for all your efforts and dedication in the printing of all my documents and posters.
Finally, I want to thank my Thesis Committee for your advice and support during
these years but especially, thanks, to Dr. Ingrid Montes González for teaching me all
the new things that I know, for giving me the opportunity to create and for teaching me
to open my mind to new possibilities and experiences. Thank you for giving me the
opportunity to be part of your research group, for your support and for teaching me that
nothing is impossible, is only the way to believe that stop us.
“La ciencia es orgullosa por lo mucho que ha aprendido; la sabiduría es humilde porque no sabe más.”
William Cowper
MROV 2014
Biography
Myrna Raquel Otaño Vega (Rakel) was born on July 22, 1982 in Mayagüez, Puerto
Rico. Her parents are Héctor Otaño Cuevas and Myrna Vega González and she is the
only daughter of this marriage of 35 years. Also, she is the first grand-daughter to
graduate from the University. She lived most of her life in the “Ciudad del Grito” Lares,
town in which she grow and studied her primary to high school years. In this stage of
her life, Myrna participated in all types of competitions: singing, speaking, dancing and
playing the typical Puerto Rican instrument: Cuatro. All these activities were forming
and giving her the character and personality that she stands today.
Also, Myrna
actively participated with her parents and brothers in the activities of the Historical
Museum of Lares and the Church community activities.
In 2000 she obtained her high school degree from the Domingo Aponte Collazo
School and was admitted to the University of Puerto Rico, Río Piedras Campus. During
her years as an undergraduate student she had the opportunity to excel in different
roles within the institution, where she implemented all her skills as the versatile person
that she is, and where she had the opportunity to develop new skills. Myrna worked as
a student facilitator in the Dean’s Office and Department of Biology of the Natural
Sciences Faculty and was part of the Student Exchange Program where she had the
opportunity to study a semester at Hayward University, California. She participated in
the Mentoring Program of the organic chemistry course for "Majors" in the laboratory
area and also was an undergraduate researcher under the guidance of Dr. Ingrid
Montes in the Chemical Education and Organic Synthesis areas.
Since 2004 she has been an active member of the American Chemical Society
which active participation in festivals and other community activities as part of Río
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Piedras Chapter. Myrna is also an active member of the ACS-Puerto Rico Chapter
occupying the Secretary position in 2011 and 2012.
Actually, she occupies the
Alternate Councilor position of the Puerto Rico Chapter in a term of three consecutive
years.
Myrna initiated her graduate study in Organic Synthesis in 2006, under the guidance
of Dr. Ingrid Montes González. She has had numerous presentations in local and
national ACS meetings, SERMACS and World Chemistry Conference, IUPAC. Myrna
received for two consecutive years the Pfizer scholarship which supported her as a
graduate student.
Also, she was a Teaching Assistant in the organic chemistry
laboratory for seven years. She is the co-author of one scientific publication in the
Journal of The Electrochemical Society in 2010 and is an author of one publication in
Acta Crystallographica published in 2014. As a graduate student she was part of the
Society of Graduate Students in Chemistry (SEGQuim) from the UPR Río Piedras as a
public relations officer and secretary from 2008 to 2010. In 2011 she wrote an article
for one of the most circulated newspaper in the country, “El Nuevo Día”, entitled " Mmm
... nadie huele como tú" as part of the celebration of the International Year of Chemistry.
Also, in 2011 she got married with Eduard Irizarry Jiménez and permanently lives in
Lares, Puerto Rico.
MROV 2014
Table of Contents
List of Abbreviations
List of Figures
List of Tables
List of Schemes
Abstract
Chapter 1. Introduction, Specific Aims and Overview
1.1. Ferrocene
1.2. General Applications
1.3. Biomedical Applications
1.4. Ferrocenyl Derivatives
1.4.1. Chalcones
1.4.2. Ferrocenyl chalcones
1.5. Synthesis
1.5.1. Classic Aldol reaction (Claisen-Schmidt) and the solvent-free
approach
1.6. Objective of the project
1.7. Hypothesis, specific aims and overview
1.8. References
Chapter 2. Synthesis and Characterization of ferrocenyl chalcones from
acetylferrocene.
2.1. Introduction
2.2. Experimental
2.2.1. Glassware and instrumentation
2.2.2. Chemicals
2.2.3. General Procedures
1. General procedure 1 for the preparation of the acetylferrocene
derivatives.
2. General procedure 2 for the preparation of the 1,1’diacetylferrocene derivatives using a solvent-free approach.
2.2.4. Results
A. Synthesis of ferrocenyl chalcones from acetylferrocene using classic
Claisen-Schmidt aldol reaction.
B. Synthesis of ferrocenyl chalcones from acetylferrocene using
Claisen-Schmidt aldol reaction following general procedure 2
(Solvent-free medium).
C. Characterization of ferrocenyl chalcones from acetylferrocene.
1. Nuclear Magnetic Resonance: Proton (1H) and 13Carbon Spectra
of the new derivative 1-ferrocenyl-3-(3,4-dichlorophenyl)prop-2en-1-one.
2. Spectroscopy data summary
3. X-Ray crystal structures of three ferrocenyl chalcones from
acetylferrocene.
4. Electrochemical and UV-Vis properties of some ferrocenyl
chalcones.
2.3. Discussion
2.4. Application
2.5. Conclusion
Pages
1-2
3-6
7-8
9-10
11-12
13-32
14
15
15
18-19
18
19
20-23
20
23
24
28-32
33-95
34
42-64
42
43-44
45-46
45
46
46-64
46-49
49-51
52-64
52-53
54
62
63-64
65-77
78-79
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2.6. References
2.7. Appendix I
Appendix II
Appendix III
80-83
84-89
90-93
94-95
Chapter 3. Synthesis and Characterization of Ferrocenyl Chalcones from
1,1’-diacetylferrocene
3.1. Introduction
96-140
97-107
3.1.1. Bridged ferrocene
102
3.1.2. Resurge the 1,1’-bis-ferrocenyl chalcone
105
3.2. Experimental
108-123
108
3.2.2. Chemicals
109
3.2.3. General Procedures
110-111
1. General procedure 1 for the preparation of the 1,1diacetylferrocene derivatives using a solvent free approach
2. General procedure 2 for the preparation of the 1,1’diacetylferrocene derivatives using the alcoholic medium.
3.2.4. Results
A. Syntheses of ferrocenyl chalcones form 1,1’-diacetylferrocene using
Claisen-Schmidt reaction.
B. Characterization
of
bis-ferrocenyl
chalcones
from
1,1’diacetylferrocene.
1. Nuclear Magnetic Resonance: Proton (1H) and 13Carbon
(13C)
2. Infrared Spectroscopy
3. Spectroscopic data summary
110
110-111
111-123
111
115-120
115-116
117
118
4. X-Ray crystallographies of two ferrocenyl chalcones from
1,1’-diacetylferrocene.
C. Characterization of [5]ferrocenophanes from 1,1’-diacetylferrocene.
1
1. Nuclear Magnetic Resonance: Proton ( H) and
(13C)
2. Spectroscopic data summary
13
Carbon
3.3. Discussion
3.4. Conclusions
120
121-123
121-122
123
124-133
133
3.5. References
134-136
3.6. Appendix IV
137-140
Chapter 4. Synthesis and Characterization of Non-symmetric Ferrocenyl
Chalcones
4.1. Introduction
141-164
142-145
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4.2. Experimental
145-154
145
4.2.1. Chemicals
146
4.2.3. Procedures
147-150
A. General procedure for the synthesis and characterization of 1’acetyl-1-ferrocenyl-3-(3-fluorophenyl)prop-2-en-1-one
(Fc-4)
chalcone from acetylferrocene.
B. Attempted synthesis of 1’-carboxylic-1-ferrocenyl-3-(3-fluorophenyl)1-oxo-prop-2-enoic acid (Fc-4a).
C. Attempted synthesis of 1’-ethenil-1-ferrocenyl-3-(3-fluorophenyl)
prop-2-en-1-one chalcone (Fc-4b).
4.2.4. Results
A. Characterization of 1’-acetyl-1-ferrocenyl-3-(3-fluorophenyl)prop-2en-1-one from acetylferrocene
Spectra
147
148
149
150-154
152-154
152-153
154
154
4.3. Discussion
155-156
4.4. Conclusions
156
4.5. References
157-158
4.6. Appendix V
159-164
A. Characterization of the reduction of Fc-4b’ using Red-Al as
reducing agent.
Spectra
B.
160-162
160-161
162
Characterization of the reduction of Fc-4b’ using NaBH4 as
reducing agent.
163-164
1. Nuclear Magnetic Resonance: Proton (1H) and
Spectra
163-164
13
Carbon
Chapter 5. Synthesis and Characterization of Curcumin Derivatives
165-204
5.1. Introduction
166-170
5.2. Experimental
171-175
171
5.2.2. Chemicals
171-172
5.2.3. Procedures
172-175
A. Synthesis of 1-ferrocenyl-3-(4-hydroxy-3-methoxyphenyl) prop-2-en1-one and 1,1’-bis-ferrocenyl-3-(4-hydroxy-3-methoxyphenyl)prop-2-
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en-1-one.
B. Attempted syntheses for the preparation of 1-ferrocenyl-3-(4hydroxy-3-methoxyphenyl)prop-2-en-1-one and the Curcumin
analogue
1. Attempted procedure for the synthesis of ferrocenyl
chalcone using DIMCARB
2. Attempted procedures for the preparation of 3-methoxy-(4tetrahydro-2H-pyran-2-yloxy)benzaldehyde and the aldol
condensation with acetylferrocene
3. Attempted procedure for the removal of tetrahydropyranyl
protecting group (preparation of 1-ferrocenyl-3-(4-hydroxy-3 methoxyphenyl)prop-2-en-1-one.
5.2.4. Results
A. Physical properties and yields
B. Characterization of 1-ferrocenyl-3-(4-hydroxy-3-methoxyphenyl)
prop-2-en-1-one
and
1,1’-bis-ferrocenyl-3-(4-hydroxy-3methoxyphenyl)prop-2-en-1-one.
Spectra
173-175
173
174
175
175-188
176-183
176-179
180
181
4. UV-Visible Spectroscopy
182
5. Cyclic Voltammetry
183
C. Characterization of THP derivatives
184-188
1
13
1. Nuclear Magnetic Resonance: Proton ( H) and Carbon
Spectra of 3-methoxy-(4-tetrahydro-2H-pyran-2-yloxy)
benzaldehyde
Spectra
184-185
186-187
188
5.3. Discussion
189-196
5.4. Conclusion
197
5.5. References
198-199
5.6. Appendix VI
200-204
Final Remarks
205-209
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List of Abbreviations and Acronyms
AcFc
Acetylferrocene
ACN
Acetonitrile
AcOEt
Ethyl acetate
CDC
Centers for Disease Control and Prevention
CDCl3
Chloroform-d
CFU
Colony-Forming Units
CH2Cl2
Dichloromethane
CHO
Benzaldehyde
CLSL
Clinical and Laboratory Standards Institute
CMPE
Cyclopenthyl methyl ether
Cp
Cyclopentadienyl
Cps
Substituted cyclopentadienyl
CV
Cyclic Voltammetry
DiAcFc
DIMCARB
N,N-dimethylmethanamine dimethylcarbamate
DMSO
Dimethyl Sulfoxide
EDG
Electron-donating group
EtOH
Ethanol
EWG
Electron-withdrawing group
FT-IR
Fourier Transform Infrared Spectroscopy
GC
Glassy Carbon
MIC
Minimum Inhibitory Concentration
MW
Microwave
NMR
Nuclear Magnetic Resonance
PEG
polyethylene glycol
ppm
parts-per-million
PPTS
pyridinium p-toluenesulfonate
PTC
Phase Transfer Catalyst
1
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PTSA
p-toluenesulfonic acid
pyr
pyridyl
ROMP
Ring-opening metathesis polymerization
r.t.
Room temperature
TBAP
Tetrabutylammonium Perchlorate
THP
3-methoxy-(4-tetrahydro-2H-pyran-2-yloxy) or tetrahydropyran
THF
Tetrahydrofuran
TLC
Thin Layer Chromatography
TSB
Tryptic Soy Broth
Van
Vanillin
Δ
Changes
2
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List of Figures
Pages
Chapter 1. Introduction: Introduction, Specific Aims and Overview.
Figure 1.1. Molecular structure of ferrocene.
13-32
14
Figure 1.2. Molecular structure of a Tamoxifen.
16
Figure 1.3. Molecular structure of a (Z)-ferrocenylhydroxyTAM.
16
Figure 1.4a. Molecular structure of ferrocenyl carbohydrate.
Figure 1.4b. Molecular structure of ferrocenyl dicarbohydrate.
16
16
Figure 1.4c. Molecular structure of acetylferrocene derivative (Fc-1).
17
Figure 1.5a. Molecular structure of Licochalcone C (anti-bacterial chalcone).
18
Figure 1.5b. Molecular structure of Crotaorixin (anti-malarial chalcone).
Figure 1.5c. Molecular structure of Cardamonin (anti-HIV chalcone).
18
18
Figure 1.5d. Molecular structure of an anti-inflammatory chalcone.
18
Figure 1.6. Molecular structure of Ferroquine (anti-plasmoidal chalcone).
19
Figure 1.7. Molecular structure of ferrocenium tetrafluoro borate salt
19
(anti-cancer chalcone).
Figure 1.8. Molecular structures of ferrocenecarboxaldoxime
and ferrocene-1,1'-dicarboxaldoxime (Topoisomerase II inhibitor chalcones).
Figure 1.9. Molecular structure of ferrocenyl hydrazines (anti-bacterial
activity).
Figure 1.10. Molecular structure of Ferrocenyl Chalcone from
Acetylferrocene (AcFc).
Figure 1.11.Molecular structure of Ferrocenyl Chalcone from 1,1'diacetylferrocene (DiAcFc).
Figure 1.12. Molecular structure of non–symmetric ferrocene derivative.
Figure 1.13. General molecular structure of curcumin (a) and its derivatives
(b -f).
Figure 1.14. Molecular structure of curcumin ferrocenyl chalcone.
Acetylferrocene.
Figure 2.1. Molecular structures of ferrocenyl chalcones: series 1 (Fc-1) and
1’ (Fc-1’).
Figure 2.2. 1H NMR spectrum of the new ferrocenyl chalcone 3-(3,4dichlorophenyl)-1-ferrocenyl-prop-2-en-1-one chalcone in CDCl3 obtained
from a Bruker spectrometer at 500 MHz (AV-500) at room temperature.
Figure 2.3. 13C NMR spectrum of the new ferrocenyl chalcone 3-(3,4dichlorophenyl)-1-ferrocenyl-prop-2-en-1-one chalcone in CDCl3 obtained
Figure 2.4. X-ray crystal structure of 3-(2-bromophenyl)-1-ferrocenyl-prop-2en-1-one.
3
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25
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26
26
33-95
38
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Figure 2.5. X-ray crystal structure of 1-ferrocenyl-3-(3-nitrophenyl)-prop-2en-1-one.
Figure 2.6. X-ray crystal structure of 1-ferrocenyl-3-(2-methoxyphenyl)prop2-en-1-one.
Figure 2.7. Cyclic voltammetry at platinum working electrode of ferrocenyl
chalcones at 1x10-3 M concentration in 0.1 M TBAP/acetonitrile in a potential
window between (-500 – 1600) mV.
62
Figure 2.8. UV-Vis spectra of ferrocenyl chalcones prepared in acetonitrile.
64
Figure 2.9. Comparison of LUMO orbital energies of para-substituents and
benzaldehyde calculated by Spartan Program.
Figure 2.10. Comparison of the electron density of 2-methoxybenzaldehyde
(a) and 4-methoxybenzaldehyde (b) from Spartan 04 program.
Figure 2.11. Electrostatic potentials of nitrophenyl derivatives obtained by
Spartan 04 program.
Figure 2.12. Molecular structure of ferrocenyl chalcone and its polarization of
the α, ß-unsaturated ketone.
Figure 2.13. General molecular structure of ferrocenyl chalcones.
66
Appendix II. X-ray crystallography data, UV-Vis and Electrochemical
properties.
Figure 2.1A. Carbon labeling for the analyses of the ferrocenyl chalcones Xray crystallography.
Chapter 3. Synthesis and Characterization of Bis-ferrocenyl Chalcones from
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63
67
68
69
72
91-94
91
96-140
Figure 3.1. Molecular structures of 1,1’-disusbtituted ferrocene.
97
Figure 3.2. Molecular structure of water soluble ferrocenyl derivative as anti
cancer agent.
Figure 3.3. Molecular structures of possible by-products proposed by
Mashburn, Cain and Hauser.
Figure 3.4. Molecular structures of different ferrocenophane whereas m
denotes the length of the bridge and n the relative location from m.
Figure 3.5. 1H NMR of 1,1’-bis-ferrocenyl-3-(4-methoxyphenyl)prop-2-en-1one in CDCl3 obtained from Bruker spectrometer at 500 MHz (AV-500) at
room temperature and following the general procedure #1.
Figure 3.6. 13C NMR of 1,1’-bis-ferrocenyl-3-(4-methoxyphenyl)prop-2-en-1one in CDCl3 obtained from a Bruker spectrometer at 500 MHz (AV-500) at
room temperature and following the general procedure #1.
Figure 3.7. Infrared spectrum of 1,1’-bis-ferrocenyl-3-(4-methoxyphenyl)prop2-en-1-one from region of (500 – 4000)cm-1.
Figure 3.8. X-ray crystal structure of 1,1’-bis-ferrocenyl-3-(2-pyridyl)prop2en-1-one (Fc-2c).
Figure 3.9. X-ray crystal structure of 1,1’-bis-ferrocenyl-3-(4methoxyphenyl)prop-2-en-1-one (Fc-2n). Also shown the recrystallization
solvent: 2-methyl-2-butanone.
Figure 3.10. 1H NMR of [5]ferrocenophone-3-(2-pyridyl)-1,5-dione (3a) in
CDCl3 obtained from a Bruker spectrometer at 300 MHz (DRX-300) at room
temperature following the general procedure #2.
98
4
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102
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MROV 2014
Figure 3.11. 13C NMR of [5]ferrocenophone-3-(2-pyridyl)-1,5-dione (3a) in
CDCl3 obtained from a Bruker spectrometer at 500 MHz (AV-500) at room
temperature following the general procedure #2.
Figure 3.12. Possible mechanisms of attack of the second enolate after the
first condensation.
Figure 3.13. Proposed transition state for the ferrocenophane derivative of 2pyridyl in alcoholic-aqueous medium.
Figure 3.14. Distance between the acetyl group and the β-carbon of the α,βunsaturated ketone for intramolecular Michael addition on 4-BrPh, 4OCH3Ph, 2-OCH3Ph, 4-pyr and 2-pyr derivatives.
Figure 3.15. Molecular modeling of the HOMO-LUMO gap energy difference
of intermediary A of some di-chalcones pbtaining from Spartan 04 and
Gaussian 03.
Appendix IV
Figure 3.1A. General molecular structure of ortho- 1,1’-bis- ferrocenyl
chalcones.
Figure 3.2A. Carbon labeling for the analyses of the ferrocenyl chalcones Xray crystal structure.
Chalcones.
Figure 4.1. Molecular structure of ferrocenyl bioiosteres for the treatment of
schizophrenia.
Figure 4.2. 1H NMR of the new ferrocenyl chalcone 1’-acetyl-1-ferrocenyl-3(3-fluorophenyl)prop-2-en-1-one in CDCl3 obtained from a Bruker
spectrometer at 500 MHz (AV-500) at room temperature.
Figure 4.3. 13C NMR of the new ferrocenyl chalcone 1’-acetyl-1-ferrocenyl-3(3-fluorophenyl)prop-2-en-1-one in CDCl3 obtained from a Bruker
Figure 4.4. Infrared spectrum of 1’-acetyl-1-ferrocenyl-3-(3fluorophenyl)prop-2-en-1-one from region of (500 – 4000)cm-1.
Appendix V
Figure 4.1A. 1H NMR of the reduction of Fc-4 with Red-Al in CDCl3 obtained
Figure 4.2A. 13C NMR of the reduction of Fc-4 with Red-Al in CDCl3 obtained
from a Bruker spectrometer at 500 MHz (AV-500) at room temperature
Figure 4.3A. Infrared spectrum of reduction of Fc-4 with Red-Al from region
of (500 – 4000) cm-1.
Figure 4.4A. 1H NMR of the reduction of Fc-4 with NaBH4 in CDCl3 obtained
Figure 5.5A. 1H NMR of the reduction of Fc-4 with NaBH4 in CDCl3 obtained
Figure 5.1. Molecular structure of curcumin.
Figure 5.2. General structure of curcumin(a) and its derivatives.
Figure 5.3. Molecular structure of 1,1’-bis-ferrocenyl-3-(4-hydroxy-3-methoxy
phenyl)prop-2-en-1-one (Fc-5b).
5
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129
130
137-140
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141-164
143
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153
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159-164
160
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165-204
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MROV 2014
Figure 5.4. Molecular structure of the new derivative: 1-ferrocenyl-3-(4hydroxy-3-methoxyphenyl)prop-2-en-1-one (Fc-5a).
Figure 5.5. 1H NMR of the new ferrocenyl chalcone 1-ferrocenyl-3-(4hydroxy-3-methoxyphenyl)prop-2-en-1-one in CDCl3 obtained from a Bruker
Figure 5.6. 13C NMR of the new ferrocenyl chalcone 1-ferrocenyl-3-(4hydroxy-3-methoxyphenyl)prop-2-en-1-one in CDCl3 obtained from a Bruker
Figure 5.7. 1H NMR of 1,1’-bis-ferrocenyl-3-(4-hydroxy-3-methoxyphenyl)
prop-2-en-1-one in CDCl3 obtained from a Bruker spectrometer at 500 MHz
(AV-500) at room temperature.
Figure 5.8. 13C NMR of 1,1’-bis-ferrocenyl-3-(4-hydroxy-3-methoxyphenyl)
prop-2-en-1-one in CDCl3 obtained from a Bruker spectrometer at 500 MHz
(AV-500) at room temperature.
Figure 5.9. Infrared spectrum of 1-ferrocenyl-3-(4-hydroxy-3-methoxyphenyl)
prop-2-ene-1-one from region of (500 – 4000) cm-1.
Figure 5.10. UV-Vis spectra of 1-ferrocenyl-3-(4-hydroxy-3methoxyphenyl)prop-2-en-1-one ferrocenyl chalcones prepared in
acetonitrile.
170
Figure 5.11. Cyclic voltammetry with GC electrode of ferrocenyl chalcones at
1x10-3M concentration in 0.1M TBAP/acetonitrile in a potential window
between (-500 – 1600) mV.
183
Figure 5.12. 1H NMR spectrum of 3-methoxy-(4-tetrahydro-2H-pyran-2yloxy)benzaldehyde obtained from a Bruker Spectrometer at 500 MHz at
room temperature.
Figure 5.13. 13C NMR spectrum of 3-methoxy-(4-tetrahydro-2H-pyran-2yloxy)benzaldehyde obtained from a Bruker Spectrometer at 500 MHz at
room temperature.
Figure 5.14. 1H NMR spectrum of 1-ferrocenyl-3-(3-methoxy-4-tetrahydro2H-pyran-2-yloxy)phenyl)prop-2-en-1-one obtained from a Bruker
Spectrometer at 500 MHz at room temperature.
Figure 5.15. 13C NMR spectrum of 1-ferrocenyl-3-(3-methoxy-4-tetrahydro2H-pyran-2-yloxy)phenyl)prop-2-en-1-one obtained from a Bruker
Spectrometer at 500 MHz at room temperature.
Figure 5.16. Molecular structure of DIMCARB adduct.
Figure 5.17. Molecular structure of pyrrolidine adduct.
184
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List of Tables
Pages
Acetylferrocene
Table 2.1. Timetable for Claisen-Schmidt condensations of ferrocenyl
chalcones Fc-1 colored based on the green chemistry principles.
Table 2.1.1. Timetable for Claisen-Schmidt condensations of ferrocenyl
chalcones Fc-1 colored based on the green chemistry principles.
33-95
Table 2.2. Data of ferrocenyl chalcones synthesized from acetylferrocene
using the alcoholic medium approach.
Table 2.3. Data of ferrocenyl chalcones synthesized from acetylferrocene
using the solvent-free approach.
Table 2.4. 13C NMR displacements and FT-IR frequencies of ferrocenyl
chalcones.
48
Appendix I. Physical properties and purification methodology
Table 2.1A. Data of previously reported ferrocenyl chalcones from
acetylferrocene in alcoholic medium.
36
37
50
72
84-89
85
Table 2.1.1A. Data of previously reported ferrocenyl chalcones from
acetylferrocene in alcoholic medium. (cont.).
Table 2.2A New ferrocenyl chalcones from acetylferrocene synthesized in
alcoholic medium.
Table 2.3A. Results of ferrocenyl chalcones which were not reported in
literature using the solvent-free apporach.
Table 2.4A. Results of ferrocenyl chalcones using solvent-free approach
which were previously reported in the literature.
Table 2.5A. Thin Layer Chromatography (TLC) conditions for ferrocenyl
chalcones.
86
Table 2.6A. Recrystallization solvents for ferrocenyl chalcones.
89
Appendix II. X-ray crystallography data and UV-Vis and Electrochemical
properties.
Table 7.2A. Experimental bond lengths of 2-BrPh, 3-NO2Ph and 2-OCH3Ph
ferrocenyl chalcones from X-ray crystallography obtained by Mercury
Program.
Table 8.2A. Experimental bond angles of 2-BrPh, 3-NO2Ph and 2-OCH3Ph
ferrocenyl chalcones from X-ray crystallography obtained by Mercury
Program.
Table 9.2A. Electrochemical parameters of ferrocenyl chalcones.
Table 10.2A. Absorption coefficients for the most prominent bands of
ferrocenyl chalcones.
Appendix III. Anti-bacterial activity of 3-NO2Ph, 4-BrPh, 3-ClPh and 4-ClPh
ferrocenyl chalcones against B. cereus bacteria
Table 2.11A. Average (n=2) of the percentage of antibacterial inhibition of
7
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88
88
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93
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ferrocenyl chalcones in Ethanol.
Chapter 3. Synthesis and Characterization of Bis-ferrocenyl Chalcones
from 1,1’-diacetylferrocene
Table 3.1. Timetable for Claisen-Schmidt condensations of 1,1’-bisferrocenyl chalcone (Fc-2).
Table 3.2. Results of 1,1’-Bis-ferrocenyl chalcones using solvent-free
approach.
Table 3.3. Results of the condensation of the p-substituted benzaldehyde
and 1,1’-diacetylferrocene using the solvent-free media.
Table 3.4. Results of the condensation of 1,1’-diacetylferrocene and
benzaldehyde using the classic alcoholic medium.
Table 3.5. Molecular modeling information for the intermediary and the
enolate of the alcoholic reaction obtained using Spartan 04 and Gaussian
03.
96-140
107
112
113
114
128
Appendix IV
Table 3.1A. 1,1’-bis-ferrocenyl chalcones δ tendencies in 13 C NMR and σ in
FT-IR for ortho- position derivatives.
Table 3.2A. Experimental bond lengths of 2-pyridyl and 4-OCH3Ph bisferrocenyl chalcones from X-ray crystallography data obtained by Mercury
Program.
Table 3.3A. Experimental bond angles of 2-pyridyl and 4-OCH3Ph bisferrocenyl chalcones from X-ray crystallography data obtained by Mercury
Program.
137-140
Chalcones.
Table 4.1. Results for the synthesis of Fc-4 and its oxidation and reduction
using the Iodoform reaction and NaBH4 or Red-Al, respectively.
141-164
Table 5.1. Results for the synthesis of Monocurcumin (Fc-5a) and Curcumin
analogue (Fc-5b).
Table 5.2. Minimal inhibitory concentration (MIC) (μg/mL) of the ferrocenyl
chalcone and the antibiotics Methicllin and Ciproflaxcin.
165-204
Appendix VI
Table 5.1A. Results for the cyclic voltammetry of glassy carbon electrode in
1.0 x10 -3 M of 1-ferrocenyl-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one
and 0.1 M TBAP/ACN as function of scan rate.
200-204
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List of Schemes
Pages
Chapter 1. Introduction: Introduction, Specific Aims and Overview.
Scheme 1.1. Synthesis of ferrocenyl chalcone reported on the literature by
Villemin et al.
Scheme 1.2. Synthesis of ferrocenyl chalcone reported on the literature
with a green workup.
13-32
21
Acetylferrocene.
33-95
22
Scheme 2.1. Fridel-Crafts acylation of ferrocene.
35
Scheme 2.2 Synthesis of ferrocenyl-R-3-cyano-2-methylpyridine.
39
Scheme 2.3. Synthesis of ferrocenyl derivatives from acetylferrocene
applying Claisen Schmidt aldol condensation.
46
Chapter 3. Synthesis and Characterization of Bis-ferrocenyl Chalcones
from 1,1’-diacetylferrocene.
Scheme 3.1. Synthesis of ferrocenyl phenothiazine chalcones.
Scheme 3.2. Synthesis of ferrocenyl pyrazole derivative.
Scheme 3.3. Mechanism proposed by J. Winstead for the formation of
ferrocenophane.
Scheme 3.4. Synthesis of poly ferrocenylene vinylene from 1,1’-ferrocene
carboxaldehyde by a McMurry coupling and ROMP catalyst.
Scheme 3.5. Synthesis of polyferrocenophane from 3phenyl[5]ferrocenophane using AIBN as radical initiator.
Scheme 3.6. Synthesis of ferrocenyl derivatives from 1,1’diacetylferrocene applying Claisen-Schmidt condensation.
Scheme 3.7. Proposed mechanism for the anchimeric assistances of
Nitrogen in the 2-pyridyl derivative synthesis.
97-140
98
99
101
103
104
111
126
chalcones.
Scheme 4.1. Synthetic pathway of the transformation of non-symmetric
derivative.
Scheme 4.2. Fridel-Crafts acetylation of 1-ferrocenyl-3-(3-fluorophenyl)prop-2-en-1-one (Fc-1b).
Scheme 4.3. Synthesis of Fc-4a from Fc-4 chalcone using the iodoform
reaction.
Scheme 4.4. Proposed synthesis of Fc-4b chalcone form Fc-4.
141-164
Chapter 5 Synthesis and Characterization of Curcumin Derivatives
Scheme 5.1. Synthesis of 1-ferrocenyl-3-(4-hydroxy-3-methoxyphenyl)
prop-2-en-1-one and 1,1’-bis-ferrocenyl-3-(4-hydroxy-3methoxyphenyl)prop-2-en-1-one using benzoic acid and pyrrolidine.
165-204
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MROV 2014
Appendix
Scheme 5.1A. Mechanism for the synthesis of the enamine formation from
vanillin and pyrrolidine.
Scheme 5.2A. Mechanism for the synthesis of the ferrocenyl chalcone
from acetylferrocene
10
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Abstract
Bioorganometallic chemistry was revolutionized with the inclusion of the ferrocene
moiety in well-known organic molecules.
Ferrocene derivatives have gained
importance due to their excellent stability in aqueous, aerobic media, the easy
accessibility to a large variety of derivatives, and ideal electrochemical properties.
Tamoxifen is one example in which one aromatic ring was replaced with a ferrocene
leading to a more active species, ferrocifen. Ferrocenyl chalcones are a family of 1,3diphenyl-2-propen-1-one in which one phenyl group is replaced with the ferrocene
moiety. In this research the synthesis and characterization of five families of ferrocenyl
chalcones is discussed: mono-, symmetric-substituted, cyclic, and nonsymmetric
ferrocenyl chalcones in addition to the synthesis, characterization and preliminary antibacterial activity of Curcumin analogues. A total of eleven new derivatives were
synthesized. Each compound was characterized by NMR spectroscopy, FT-IR, melting
point determination, elemental analyses, CV, and UV-Vis spectroscopy. In addition,
four new X-ray crystal structures are presented.
The mono- and symmetric-substituted ferrocenyl chalcones have been synthesized
via the classical base-catalyzed Claisen–Schmidt condensation reaction in ethanol
solvent and solvent-free media. The first family of ferrocenyl chalcones was the monosubstituted derivatives and is discussed in Chapter 2. A total of twenty two of these
chalcones, four of them new derivatives, were synthesized with yields ranging between
40–94% after recrystallization. Also, two new X-ray crystal structures were elucidated.
The second family, the symmetric-substituted chalcones, is discussed in Chapter 3.
For this family, four new derivatives were synthesized and characterized with 37-82%
yields and four other derivatives were attempted. Moreover, two new X-ray crystal
structures of these derivatives were also elucidated. A third family, the ferrocenophane,
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which is a cyclic derivative, were also synthesized and characterized. The fourth family
is the non-symmetric ferrocenyl chalcones. One new derivative was synthesized in
60% yield via the Fridel-Crafts acylation of a ferrocenyl chalcone. In addition, attempts
to synthesize two other nonsymmetrical ferrocenyl derivatives are discussed in Chapter
4. Finally, the synthesis and characterization of curcumin analogues is presented. A
new ferrocenyl chalcone, 1-ferrocenyl-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one,
which we commonly name as Monocurcumin, was synthesized in 27% yield after
column chromatography by a pyrrolidine-catalyzed reaction. Preliminary studies on its
susceptibility against B. cereus, S. sapro, S. aureus, K. pneumonia, E. coli and, P.
aeruginosa bacteria are presented. This derivative showed a MIC of 1.95 μM against
Gram-positive B. cereus, S. sapro, S. aureus and Gram-negative K. pneumonia
bacteria.
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SYNTHESES AND CHARACTERIZATION OF FERROCENYL CHALCONES
Chapter 1:
Introduction, Specific Aims and Overview
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Chapter 1. Introduction, Specific Aims and Overview.
1.1.
Ferrocene
The discovery of ferrocene by P. Pauson and his graduate student, T. Kealy in 19511
revolutionized science. Ferrocene, as is commonly named, is bis(η5-cyclopentadienyl)
iron(II) (Figure 1.1),
was accidentally discovered
when Kealy and Pauson
unsuccessfully attempted a reductive coupling of the Grignard reagent cyclopentadienyl
magnesium bromide in the presence of ferric chloride1. At
the same time, in 1952, Miller2 reported the same product,
this
time
obtained
through
the
direct
reaction
of
cyclopentadiene and iron in the presence of aluminum,
potassium or molybdenum oxides at 300 °C. After the publication of Miller’s report, he
sent a note to Pauson1b, mentioning that they had synthesized the compound about 3
years before its publication. However, it was quite possible that ferrocene was not
produced during the first attempt. Both groups reported the compound as an orange
crystal, stable in the presence of air and water, with melting point at 173 °C, a
sublimate, very soluble in organic solvents but, insoluble in water1,2.
The unique
structure of ferrocene proposed by Pauson1 consisted of two cyclopentadienyl rings
covalently attached to a central atom of iron. However, the sigma bond could not be
stable and the curiosity of many scientists rapidly grew.
The
correct
structure
of
bis(η5-cyclopentadienyl)
iron(II),
showed
as
two
cyclopentadienyl rings (Cp) and a Fe2+ center arranged in a sandwich-like structure,
was presented in two independent publications: one by E.O. Fischer and W. Pfab1b,2b,
and the other by G. Wilkinson, M. Rosenblum, M.C. Whiting, and R.B. Woodward 1b,2b.
Both groups made physical measurements that strongly supported the ‘sandwich-like’
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structure but it was not enough to fully characterize it1b.
Fischer relied chiefly on
preliminary X-ray data indicating that the molecule is centrosymmetric, while the
Wilkinson’s group cited the single C–H frequency in the IR and its diamagnetism1b.
Woodward found that the two cyclopentadienes were aromatic and their similarities with
benzene-like aromatic compounds led the post-doctoral student, Mark Whiting, to name
it as ferrocene1b. The X-Ray structure showed two staggered Cp rings with an intercyclopentadienyl ring space of 3.32 Å2b-c and the distance between the iron—carbon
bond is 2.064 Å2b-c (in an angle of ~107°). At room temperature, ferrocene can be
oxidized to the blue-green ferricinium cation, [(C5H5)2Fe]+
2b-c, 4c
. However, despite that
the Cp rings are in staggered conformation the Cp rings can adopt a staggered or
eclipse conformation depending their substitution4d-4f.
2.1.
General applications
This compound undergoes many characteristic reactions of aromatic compounds
and it can be mono and bis functionalized. The versatility of synthetic pathways for
ferrocene derivatives is reflected in the complex molecular architectures that have been
achieved, including ferrocene dendrimers and polymers3.
Ferrocene’s redox
properties3,4 have found applications in the field of electroanalysis4, catalysis4, anticancer therapy4, anti-plasmoidal4, anti-bacterial4, materials science (e.g., as ion
sensors, polymeric materials and DNA intercalators)4b, as an additive in fuels4a, and as
donors in energy transfer processes4.
3.1.
Biomedical applications
Ferrocene derivatives have been used as anti-cancer drugs for the inhibition of
Topoisomerases IIα and β4b.
Both isoforms exhibit similar catalytic activity in the
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relaxation of supercoiled DNA. In normal cells, the activity of Topoisomerase IIα is
highly regulated, but this is not the case when present at high levels in rapidly
proliferating cancerous cells4b.
Furthermore, substitution of phenyl by ferrocene in
traditional drugs (Figures 1.2 and 1.3) has prove to induce a greater cytotoxic effect on
human-cell lines derived from lung, endometrial, and breast cancer cells5a. This
substitution in bioactive compounds induces large changes in molecular properties,
such as the solubility, hydrophobicity, and lipophilicity6.
Solubility, lipophilicity, hydrophobicity, and redox properties are important factors to
consider when designing new ferrocene-based drugs. Recently, reports of ferrocene
derivatives of anti-malaria drugs6 (Figures 1.4a and 1.4b), have been published6a-b with
a significant anti-plasmoidal activity (Figure 1.4c). In addition, ferrocene derivatives
have been studied as chemotherapeutic agents7,8. Common therapeutic agents usually
have poor aqueous solubility, produce intensive damage to the linings of the intestines
(which leads to the loss of appetite), cause severe nausea, vomiting, and have high
toxicity towards the kidneys and bone marrow.
carcinogens themselves5,7b.
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Moreover, they are moderate
MROV Chapter 1 2014
One of the main problems is the inability of these drugs to differentiate between the
healthy and disease cell, which is known as the “targeting problem”.
The poor
selectivity of these drugs is the most fundamental barrier when a drug is delivered to
the target.
The defense mechanism of the body, the reticuloendothelial system,
recognizes the drug as foreign in order to remove it as fast as possible. This quick
excretion rate8b causes the concentration of drugs to fluctuate in the body, and hence,
leads to unpredictable therapeutic activity7.
An additional point to consider when
developing and administering anti-cancer drugs is the development of drug resistance
after prolonged use5,7.
New methods of drug delivery are being developed and
combinatory therapy is being investigated with the hope of finding synergistic effects 7-9.
Consequently, to improve the treatment of cancer, current research trends focus on
developing new and better chemotherapeutic agents having fewer side effects7a,9.
However, even though some researchers suggest that ferrocene and its derivatives
possessed potential pharmacological applications, it has limited bioavailability in vivo
probably due to their low polarity7b.
On the other hand, due to the properties of
ferrocene and it derivatives our laboratory, as other researchers7,8, postulates that
ferrocene derivatives with organic groups similar to well-known drugs may enhance
their bioavailability and increase anti-oxidant effectiveness7b.
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1.4.
Ferrocenyl derivatives
1.4.1. Chalcones
Chalcones are a family of two aromatic groups connected by an enone linkage (Ar–
COCH=CH–Ar’)10.
Chalcones are precursors of flavonoids11 and exhibit various
biological activities such as anti-cancer12, anti-inflammatory12, nitric oxide regulation12,
and anti-hyperglycemic agents12. Traditionally, they are synthesized via the Claisen–
Schmidt condensation carried out in basic or acidic media under homogeneous
conditions12 and functionalization in their core is facile to achieve. Examples of the
biological activities of chalcones such as9-13 anti-bacterial13bi-iii, anti-malarial13bi-iii, antioxidant13bi-iii, anti-tumor13bi-iii, and anti-HIV13bi-iii can be found in numerous publications2-13
(Figures 1.5a-d).
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1.4.2. Ferrocenyl Chalcones
According to the literature ferrocene derivatives that have an α,β – unsaturated
ketone system have been named as ferrocenylenones9,10c(ii), β-(#-G)acrylferrocene14a
where # is the position of the substituent G, ferrocenyldienones14b, ferrocenyl ethane14c
and, cinnamoyl ferrocene14d. In this research we will refer to these compounds as
ferrocenyl chalcones7a. Ferrocenyl chalcones belong to a chalcone family in which one
or both aromatic groups are substituted by
the ferrocenyl unit. Ferrocene derivatives’
prominent features14e are their excellent
stability in aqueous and aerobic media, the
easy accessibility of a large variety of
derivatives, and favorable electrochemical
properties5b. Ferrocenyl chalcone derivatives are important compounds because of their
many applications, which include optical
devices15, redox mediators for enzyme
sensors16,
biofuel cells17,
metal-containing
synthesis of
oligonucleotides18
as
Topoisomerase IIβ inhibitors19, for the
electrochemical detection of DNA or RNA20, for the synthesis of ferrocenyl amino
acids21, and as anti-tumor agents22. Moreover, some ferrocene derivatives have also
shown biological activity like larvicidial23a and anti-bacterial properties23b.
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1.5.
Syntheses
1.5.1. Classic Aldol reaction (Claisen-Schmidt) and the solvent-free approach
The synthesis of ferrocenyl chalcones can be performed by a variety of methods, but
the alcoholic and homogenous Claisen-Schmidt reaction is the preferred reaction for
the synthesis of ferrocenyl chalcones.14c,24
The first aldol reaction reported by
Schlögl25b in 1957 used an excess of the benzaldehyde, ethanol, and base to obtain a
60% yield of the pure product after recrystallization. Biochard25c (1963) reported the
Claisen-Schmidt syntheses of new derivatives by changing the temperature of the
reaction and equimolar quantities of the starting materials. Toma25d-e (1965 and 1968)
expanded the series of substituents and combined the procedures of Schlögl and
Biochard, by using excess of starting material and changes in temperature to obtain
products in low to moderate yields.
These reactions seem to have limitations as
multiple workup steps9,13c(ii),14c-d,25 were required and the use of reagents in excess; that
have been improved with the passing of years. This improvement came about because
the increased interest in greener and economic routes for the synthesis of commercial
products.
Green Chemistry is the design of chemical products and processes that are
environmentally benign relative to pre-existing processes30. Twelve principles rule this
concept: prevention, atom economy, less hazardous chemical synthesis, designing
safer chemicals, design for energy efficiency, use of renewable feedstocks, reduce
derivatives, catalysis, degradation design, real-time analysis for pollution prevention
and, inherently safer chemistry for accident prevention30.
To reduce the cost of the synthetic procedures, Villemin et al9. (Scheme 1.1)
reported in 1994, the synthesis of ferrocenyl chalcones from acetylferrocene using
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MROV Chapter 1 2014
powdered KOH as base without solvent in the presence of the phase transfer catalyst
(PTC) Aliquat 336. Because the impacts of the solvent-free approach in the synthesis
of ferrocenyl chalcones, other methodologies that include greener approaches have
been developed.
Scheme 1.1. Synthesis of ferrocenyl chalcone reported on the literature by Villemin, et al.9
The field of solvent-free organic synthesis covers all branches of organic chemistry.
It includes stoichiometric solid–solid reactions and gas–solid reactions without common
auxiliaries, yielding the expected pure products by avoiding solvent-consuming
purification steps26. It also includes some stoichiometric reactions that occur without
auxiliaries and with quantitative yield due to direct crystallization of the product26.
Although these reactions are by far the best choices for application of solvent-free
chemistry, the advantages of avoiding solvents should not be restricted to them.
Solvent-free conversions could be profitably applied even when unfavorable crystal
packing and low melting points impede solid-state reaction and do not provide 100%
yield of the product26.
Solvent-free organic reactions have been established as much more efficient and
faster reactions than the traditional use of solvents, since solid-state reactions are
infinitely high-concentrated27. In some cases auxiliaries such as catalysts or solid
supports may be required. Solid supports and microwave heating, instead of cooling or
conventional heating, are frequently used in solvent-free reaction steps26.
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Pursuant to solvent free and solid state approaches, Villemin’s reaction is
advantageous when compared with the synthetic procedures described before and
summarized in Table 2.1.-2.1.1 (Chapter 2) because the microwave irradiation reduces
the reaction time but not necessarily enhanced the yield. Moreover, the procedure
used Aliquat 336 which is hazardous, causes severe skin burns, eye damage and is
very toxic to aquatic life with long lasting effects. Furthermore, the workup procedure for
this reaction includes multiple workup steps such as neutralization, extraction with
CH2Cl2 or ether, filtration and finally, recrystallization9.
As Villemin et al., other scientists reported aldol reactions carried out in solvent-free
conditions,9,13c(ii),25,29a-c under microwave irradiation9 and ultrasound13c(i) irradiation
reporting moderate to good yields and shorter reaction times. Nevertheless, some of
these methods still show synthetic limitations such as the use of large amount of toxic
solvents and the multiple workup steps generating chemical waste harmful for the
environment, being also is economically un-favored (Scheme 1.2).
Scheme 1.2. Synthesis of ferrocenyl chalcone reported on the literature13c(ii) with a
green workup.
Greener workups changing solvents, and reducing or eliminating workup steps are
also reported but as we argued before, their syntheses are not as green as their
reported workup procedures9,13c(ii),14c,28,29 and vice versa.
With the current increase of interest in performing chemical transformations in
efficient, economic and environmentally friendly reactions we aim to apply this solvent22
MROV Chapter 1 2014
free methodology to the synthesis of ferrocenyl chalcones. Specifically, among the
twelve, we target three principles of green chemistry30a: (i) reduce or eliminate the use
or production of hazardous substances that involve risks to health and to the
environment, (ii) preventing waste production is better than treating it or cleaning it up
after it has been created, and (iii) wherever practicable, synthetic methods should be
designed to use and generate substances that possess little or no toxicity to human
health and the environment.
1.6. Objective of the project
This project focused on the synthesis and characterization of ferrocenyl chalcones
employing the Claisen-Schmidt condensation. The main goal of this research work was
to prepare a series of ferrocenyl chalcones from acetyl- and/or 1,1’-diacetylferrocene
that can exhibit biological activity. The rationale is that the ferrocenyl chalcones core
will show characteristic properties that will be useful in the preparation of anti-bacterial
compounds and drugs for cancer and Alzheimer diseases. According to earlier reports,
similar compounds to those that we propose, demonstrated biological activity against
these diseases.
Therefore, based on previous examples, we postulate that these
ferrocenyl chalcones will have better body recognition and activity against cancer and
Alzheimer’s disease compared to traditional drugs13b(ii) as well as anti-bacterial
properties.
Furthermore, different substituents in the ferrocenyl chalcone core can increase their
potential applications and will expand the synthetic possibilities30b-f of these derivatives.
Moreover, this work is also focused in developing a synthetic procedure that reduces or
eliminates the use of organic solvents applying the green chemistry principles above
described.
The elimination of the hazardous materials in synthetic processes is
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MROV Chapter 1 2014
important especially in the chemical industry and in academia. The importance of the
solvent-free approach to organic synthesis will be discussed in the next sections.
1.7.
Hypothesis, specific aims and overview
A general and improved methodology for the synthesis of mono, symmetric
disubstituted and non-symmetric substituted chalcones can expand their synthetic
applications. We anticipate that the availability of the compounds would continue to
spread research interest due their medicinal properties. The long term goal is to test
that the families of ferrocenyl chalcones that we synthesized will have better body
recognition and potential biological activity (eg: anti-bacterial, cancer and Alzheimer's
diseases) compared to traditional drugs. We believe that this synthetic method would
afford ferrocenyl chalcones with higher yields and grater purity. Also, it will allow the
synthesis of new derivatives that can expand their biological properties. In order to
prove this hypothesis, we pursued the following objectives:
I. To synthesize and characterize ferrocenyl chalcones from acetylferrocene.
As discussed before, ferrocenyl compounds
have been extensively studied and it is gaining
research importance in medicinal chemistry
because of its unique properties and stability.
These
compounds
exhibit
special
characteristics due to lipophilicity and electronic effects and other interesting
properties of the ferrocene ring associated with the chalcone framework. Hence, the
first Objective is elaborated in Chapter 2.
Chapter 2 elaborates the synthesis of
ferrocenyl chalcones including the Claisen–Schmidt reaction using acetylferrocene as
the starting reagent. The synthetic procedures that have been developed and a
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MROV Chapter 1 2014
comparison with those previously reported, their improvements and limitations are also
discussed. In addition, the characterization of these derivatives using 1H NMR,
13
C
NMR, IR spectroscopy, and the effects of the substituents on the ferrocenyl chalcones
properties and X-ray crystallographies are analyzed. Finally, the electrochemistry of
some derivatives was studied in Dr. Guadalupe’s research laboratory and is briefly
presented in Chapter 2 and Chapter 5.
II. To synthesize and characterize symmetric ferrocenyl derivatives from 1,1’–
diacetylferrocene. The synthesis of
1,1’-diacetylferrocene derivatives was
challenging,
but
an
interesting
objective, and is elaborated in the
Chapter 3. Their importance is due to
their photographic properties31, their significance as precursors for semiconducting
polymers14c, anti-oxidant activity32, and radical-scavenging properties33.
Their
application ranges from ligands in asymmetric catalysis to the development of new
pharmaceutical drugs used against malaria34. The synthesis of this series of symmetric
derivatives is not as easy as the methodology developed for acetylferrocene
derivatives. The synthesis of
these derivatives is complicated because an
intramolecular Michael-type attack can occur and a cyclic by- product can be obtained.
This is a problem especially in the purification process. Unfortunately, this can convert
a greener synthesis in a multiple workup procedure obtaining moderated to low yields.
Chapter 3 discusses these limitations, the characterization, and the crystal structure
of some derivatives. Finally, by using molecular modeling the formation of the cyclic
product was accomplished.
25
MROV Chapter 1 2014
III. To synthesize and characterize non-symmetric ferrocenyl derivatives. Chapter
4 presents the synthesis and characterization
of nonsymmetrical ferrocenyl chalcones. The
nonsymmetrical derivatives will expand the
synthetic
and
biological
applications
converting them in multifunctional derivatives.
The vinyl group will be incorporated in the other cyclopentadiene (Cp) ring because is a
versatile functional group that can promote polymerization or the interconversion to
other functional groups, expanding the synthetic opportunities for new derivatives. The
nonsymmetrical derivative synthesized and the other derivatives proposed as part of
this research have not been reported yet.
Chapter 5 discusses the syntheses of
Curcumin (Figure 1.13) analogues. The
compounds synthesized are structurally
similar
to
Curcumin
but
the
α,β-
unsaturated ketones are linked to the
ferrocene moiety (Figure 1.14) instead of
the -CH2- group (C-1). Curcumin is
a natural chalcone that can prevent
inflammatory,
cardiovascular,
neurodegenerative,
pulmonary,
metabolic, autoimmune and neoplastic diseases, and even inhibit cancer35. Also, recent
experiments revealed anti-bacterial effects of curcumin against standard bacterial
strains in high concentrations36.
26
MROV Chapter 1 2014
Information found in the literature encouraged us to investigate the challenging
synthesis of the new ferrocene Curcumin analogues.
The syntheses of Curcumin
analogues have been published37,38,39 including substituent with ferrocene38 (Figure
1.14) but we aim to improve the methodology applying a greener approach. It is
expected significant differences in its chemical and biological properties as occurred
with hydroxyferrocifen derivative in estrogen receptors on breast cancer cell lines MDAMB-231 and MCF75b,8a also, as occurred with the ferrocenyl hydrazone derivatives
against to E. coli, S. aureus, K. pneumonia, and P. aeruginosa bacteria23b.
To summarize, the following chapters will discuss the syntheses of five families of
ferrocenyl chalcones from acetylferrocene (Fc-1, Fc-4) and 1,1’-diacetylferrocene (Fc2, Fc-3, curcumin analogue) focusing on a synthetic procedure that reduced or
eliminated the use of organic solvents applying the green chemistry principles. This
allows the improvement of the final yields and reaction times as well as, the
development of new derivatives in an easy and environmental-friendly way. The wide
range of biological activities of ferrocene derivatives has made them popular synthetic
targets.
Throughout this work a greener and optimized methodology for the synthesis of
some ferrocenyl derivatives, eleven of them new derivatives are present; also, four new
crystal structures are elucidated. In addition, the electrochemical and antibacterial
properties are studied in collaboration with other researchers. This work is intended to
take us a step further to explore the development of more potent medicines for the
treatment of potentially mortal bacteria, cancer and Alzheimer’s diseases.
27
MROV Chapter 1 2014
1.8.
1
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