MROV Chapter 2 2014
SYNTHESES AND CHARACTERIZATION OF FERROCENYL CHALCONES
Chapter 2:
Synthesis and Characterization of Ferrocenyl Chalcones from Acetylferrocene.
33
MROV Chapter 2 2014
Chapter
2.
Synthesis
and
Characterization
of
Ferrocenyl
Chalcones
from
Acetylferrocene.
2.1.
Introduction
Bis(η5-cyclopentadienyl) iron(II) is one of a special class of organometallic
compounds because of its remarkable structure and distinctive aromatic behavior. For
decades, ferrocene has been the subject of several preparative organic chemistry
syntheses due to its interesting properties and the number of derivatives that could be
obtained. For example, numerous ferrocene derivatives, or their complexes, are used
as catalysts for asymmetric synthesis of a wide number of optically active organic
compounds1. Of particular importance are ferrocene derivatives whose carbon atom
connected to the ferrocene unit with a functional group, because they mostly are
optically active, or can easily be transformed into the optically active compounds2 or
biomedical agents3. Acetylferrocene - a name which was adopted4a and will be used in
this work- has a place among them, because of the well-known high reactivity of the
carbonyl group towards many reagents. The X-ray crystal structure4b-c was published
by K. Sato, M. Katada, H. Sano, and M. Konno4b and, L. Qiwang, H. Yucai, L. Fongzhe,
and H. Jinshun4c in 1984 and 1986, respectively. The crystal data showed eclipsed
cyclopentadienyl (Cp) rings with C-C distances in Cp rings of 1.392-1.442 Å and Fe-C
distances of 2.028-2.061 Å4b. To be in agreement with the data reported by Sato et al.
and Qiwang et al., each molecular structure of acetylferrocene or chalcone will be
represented with an eclipsed Cp rings in this work.
The acylation of ferrocene has become one of the most important methods to
prepare acetylferrocenes because it was found that ferrocene is more reactive than its
phenyl analogue by about a factor of two1,6. Acetylferrocene can be synthesized by the
34
MROV Chapter 2 2014
Friedel–Crafts acylation of ferrocene with substituted ferrocenes, carboxylic acid
chlorides or acetic anhydride in the presence of anhydrous aluminum chloride as the
catalyst or phosphoric acid and anhydrides1. Also, acylation of ferrocene using ionic
liquids as catalysts and other solvents have been developed using 1-ethyl-3methylimidazolium-AlCl3 (([EMIM]I-AlCl3)x) or 1-butyl-3-methylimidazolium (BMIM)2b.
Scheme 2.1. Friedel-Crafts acylation of ferrocene6.
Ferrocenyl chalcones from acetylferrocene have been extensively studied due to
their interesting biological properties and for their use as precursor for various other
important molecules such as β-arylacryl ferrocene derivatives, which have electroactive
properties23a and ailanthoidol (chinese herbal with anti-inflammatory effects23b)
derivatives to protect the DNA23c. As established in Chapter 1, both ferrocene and
chalcones have been separately known to form a large number of derivatives which not
only shows potential biological properties but also various electrochemical and optical
properties23d.
Several syntheses of the first family of ferrocenyl chalcones (Fc-1) presented here
have been reported using different synthetic routes and approaches. However, the
base-catalyzed Claisen-Schmidt condensation continues to be the preferred reaction as
it is described in Table 2.1–2.1.1. Although this reaction can be easily performed,
Tables 2.1-2.1.1 show reported modifications that improved reaction times and yields.
As mentioned before7, the changes in methodology range from reactions in solvent free
conditions15,22, under microwave irradiation15 to ultrasound irradiation21.
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MROV Chapter 2 2014
Table 2.1. Timetable for Claisen-Schmidt condensations of ferrocenyl chalcones Fc-1
colored based on the green chemistry principles.
Year
Authors
Experimental Conditions
Base /
Solvent
19578
Temp.
o
( C)
%Yield
Special
Considerations/
Comments/ Substituent
First ferrocenyl chalcone
(-H)
H-, 2-,3-,4-NO2, 2-Cl
NaOH
r.t.
19609
Schlögl, K.
Raush, M.8b
Furdik, M et. al
NaOH
40 - 50
60
47
60-96
19639b
Biochard, J. et. al
NaOH
0-60
30-50
196510
Toma, Š.
NaOH
10-15
30-96
196811
Toma, Š.
NaOH
10-15
----a
198012
Solcăniová, E.
et. al
----a
----a
----a
199013
Shibata, K. et. al
r.t.
44-95
199414c
Villemin, D. et. al
r.t.
25
H-
199414c
Villemin, D. et. al
MW
63
200115
Liu, W. et. al
KOH,
EtOH
KOH,
S.F.
KOH,
S.F.
NaOH/
S.F.
65
----a
200216
Liu, W-L. et. al
NaOH/
S.F.
r.t. – 50
92-96
200117
Liu, W. et. al
NaOH/
S.F.
65
65
PTC – Aliquat 336
MW, 4-OCH3
Precursors of 1,5diketones
4-Cl, 3-NO2, 4-N(CH3)2
Mild conditions
H, 4-OCH3, 3-NO2,
4-N(CH3)2
Aldehyde ylide
200218
Wu, X. et. al
r.t.
----a
200319
Song, Q-B. et. Al
r.t.
96
200320
Mendez, D. et. al
KOH/
EtOH
NaOH/
EtOH
t-BuOK
r.t.
60
200321
Ji, S-J. et. al
KOH/
EtOH
r.t.
82-92
36
Two different methods
were used 4-Cl, 4-OCH3,
4-NO2
H, 4-Cl, 4–F, 4-OCH3,
4-NO2, 4-NH2, 4-N(CH3)2
H, 4-Cl, 4–F, 4-OCH3,
4-NO2, 4-NH2, 4-Cl
1
H NMR and 13C NMR
analyses
4-Cl, 3-Cl, 4–F, 4-OCH3,
3-OCH3, 4-NO2, 3-NO2,
4-Br, 3-Br, 4-N(CH3)2
H-, 4-Cl, 2-pyr.
3-pyr, 2-,3-,4-Cl, 4-F,
4-NO2
Novel Ferrocene
Biarenes 3-Br
As Villemin’s et al.
synthesis
Ultrasonication
H, 2-, 4-Cl, 4-OCH3,
4-NO2, 2-pyr
MROV Chapter 2 2014
Table 2.1.1. Timetable for Claisen-Schmidt condensations of ferrocenyl chalcones Fc1 colored based on the green chemistry principles.
Year
Authors
Experimental Conditions
Base /
Solvent
200322
Ji, S-J. et. al
200523a
Song, Q.B. et. Al
200624
Wu, X. et. al
201025
Temp.
o
( C)
%Yield
KOH or
NaOH/
S.F.
NaOH/
EtOH
KOH/
EtOH
r.t.
80-91
(KOH)
r.t.
90
r.t.
15-75
Cardona, R. et. al
NaOH/
EtOH
r.t.
61-90
201026
Parveen, H. et. al
KOH/
EtOH
r.t.
70-74
201127
Attar, S. et. al
NaOH/
EtOH
r.t.
----b
201228
Kumar, C.K. et. Al KOH/
EtOH
r.t.
----a
201229
Muller, T. et. al
KOH/
EtOH
r.t.
57-95
201230
Liu, Y-T. et. al
KOH/
EtOH
r.t.
83-91
a
b
Special
Considerations/
Comments/
Substituent
H-, 2-, 4-Cl, 4-OCH3,
4-NO2, 2-pyr
2-Br as precursors of
novel β-aryl compound
Antiplasmoidal activity
H, 2-,3-,4-Cl, 4-OCH3,
2-,3-,4-NO2, 2-,3-,4-pyr,
4-F
Electrochem.
4-Cl, 4-OCH3, 3-,4-NO2,
2-,3-,4-pyr, 4-N(CH3)2,
2-, 3-F
Precursors of
pyrimidine derivatives
H-, 4-Cl, 4-OCH3
Nematocidal activity
H-, 2-,3-Cl, 2-OCH3,
2-,3-,4-pyr
Ultrasonication,
electrochem. and
optical prop.
H-, 2-,4-Cl, 2-,4-OCH3,
3-,4-NO2, 3-,4-Br
DFT, electrochem. and
spectroscopic
H-, 4-OCH3, 4-Br
Precursors of Fc-based
Schiff bases as
antibacterial and
antifungal
H-, 4-Cl, 4-Br, 4-F,
4-OCH3, 4-NO2, 4-pyr
---- No data reported. ---- Partial information reported.
The color chart is based only in the procedure condition. It did not take in consideration the workup
procedures and is only qualitative based on Green Chemistry principles and MSDS/SDS information.
Hazard procedure.
Mild conditions.
Green procedure.
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MROV Chapter 2 2014
To the best of our knowledge K. Schlögl8 and M. Rausch8b (1957) synthesized the
first ferrocenyl chalcone from acetylferrocene with benzaldehyde using the ClaisenSchmidt condensation and after that, their spectroscopic properties were extensively
studied from 196931 throughout early 198012. During these years, the researchers were
interested in the effect of the substituents in chalcones when one benzene ring was
substituted with ferrocene.
Figure 2.1. Molecular structures of ferrocenyl chalcones: series 1 (Fc-1) and 1’ (Fc-1’)1.
It was found that the chemical shifts of Hα and Cα of the ferrocenyl chalcones are at
higher field for both series (Fc-1 and Fc-1’) than those reported for Hβ and Cβ12, similar
to the chemical shifts found for chalcones12, 32. Researches argued that this is caused
by the polarization of the C=C double bond by the carbonyl group12. Also, the chemical
shift of Cβ in both series was at higher field than those of the analogous chalcones
because of the strong electron-donating character of the ferrocenyl group. In addition,
results of the correlation of Hα and Cα chemical shifts revealed that their shielding in
series 1 (Fc-1) was more sensitive to the substituents effect than series 1’ (Fc-1’). The
resonance effects of the substituents are the predominant influence on the Hα and Cα
shieldings in Fc-1 while the inductive effects of the ferrocene are responsible for the Cα
shielding in Fc-1’.
These findings are important and useful when predicting the
behavior of the ferrocenyl chalcones according to the substituents and their position,
especially for the systems that act as ligands, with a well-defined geometry because of
its fixed intramolecular spacing, toward transition-metal ions12b. These kinds of ligands
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MROV Chapter 2 2014
are of valuable interest for the construction of heterobimetallic systems, which can
behave either as chemical sensors or as redox-active and photoactive molecular
devices12b.
In 1990’s K. Shibata13 synthesized some of the derivatives reported by J. Bioghard
using an alcoholic medium. As shown in scheme 2.2, these ferrocenyl chalcones were
precursors of ferrocenyl-R-3-cyano-2-methylpyridines, which are an important class of
heterocyclic compounds for non-linear optical materials and precursors of the nicotinic
acids and nicotinamides13 which are known to be important vitamins.
Scheme 2.2. Synthesis of ferrocenyl-R-3-cyano-2-methylpyridine4.
The synthesis of ferrocenyl chalcones reported by Shibata13 used an alcoholic
solution (15 mL) of 0.02 mol of acetylferrocene, 10% aqueous potassium hydroxide (15
mL) and 0.02 mol of the aldehyde of interest. This aldol condensation produced 1ferrocenyl-3-phenyl-2-prop-en-1-one (95%), 1-ferrocenyl-3-(2-pyridyl)-2-prop-en-1-one
(44%), and 3-(4-chlorophenyl)-1-ferrocenyl-2-prop-en-1-one (57%).
However, this
procedure utilized methanol to recrystallyze all ferrocenyl compounds. Methanol is a
highly flammable and very toxic solvent which can also contaminate soil and water.
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MROV Chapter 2 2014
In 1990 Toma et. al described the synthesis of ferrocene derivatives by the ClaisenSchmidt condensation of acetylferrocene and ferrocene carboxaldehyde using phasetransfer conditions and 18-crown-6 ether as catalyst14a. At the same time, F. Toda
described the synthesis of chalcones by an aldol condensation of cyclohexanone using
pulverized KOH in a solvent-free medium14b.
Taking advance of these early
publications, Didier Villemin (199414c) reported the first synthesis of ferrocenyl
chalcones combining both, phase-transfer and solvent-free procedures, but using
microwave irradiation14c.
Villemin reported a rapid and efficient solvent-free aldol condensation in the
presence of solid KOH under liquid phase transfer catalyst (PTC) at room temperature.
When the reactions were too slow at room temperature, they accelerated the reaction
efficiently with microwave irradiation. The reported yields fluctuated between 63% to
53% and the reaction times were 30 and 2.5 minutes for 1-ferrocenyl-3-phenyl-prop-2en-1-one and 1-ferrocenyl-3-(4-methoxyphenyl)prop-2-en-1-one, respectively. For the
4-methoxy ferrocenyl chalcones, Villemin used microwave irradiation to obtain 53% of
product in 2.5 minutes improving the previous data reported by Biochard4 of 30% yield
in several hours. However, the new approach for synthesis of 1-ferrocenyl-3-phenylprop-2-en-1-one using Aliquat 336 as catalyst in a solvent-free medium only produced
63% yield in 30 minutes which was much lower for that reported by Toma10-11 and
Schlogl8 of 84.5% and 95% in 3 and 4 hours, respectively.
Even though these results showed an improvement for the synthesis of these
derivatives due to the reduction of reaction time, the yields were not as good as the
previous data and were lower than expected with the new approach. Futhermore, this
procedure presents some drawbacks that limit their use or generalization for the
syntheses of ferrocenyl chalcones.
Among the drawbacks are the use of Starks'
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MROV Chapter 2 2014
catalyst, also known as Aliquat 336, or tricaprylmethylammonium chloride, and a
workup that includes dichloromethane (CH2Cl2), filtration on Celite, preparative thin
layer chromatography and recrystallization with diethyl ether.
Also, not all the
derivatives could be synthesized using microwave irradiation. Furthermore, although
the reaction was performed with a solvent-free approach and under microwave
irradiation, the auxiliaries used and the workup presented a disadvantage when the
concept of green chemistry is addressed. Aliquat 336 is a viscous amber liquid mainly
used for oxidations and as phase transfer catalyst (PTC)34. In addition, the use of
(CH2Cl2), the preparative chromatographic layer of silica gel (AcOEt:Cyclohexane
20:80) and the recrystallization with diethyl ether increase the chemical wastes because
none of these materials can be reused.
After these first steps to find a methodology to synthesize ferrocenyl chalcones with
good yields and shorter reaction times, other scientists reported new methods applying
the green chemistry approach. These routes reported moderate to good yields and
shorter reaction times. But the biggest limitations remain to be the excess of one of the
reagents, use of large amount of toxic solvents as CH2Cl2 and the final process going
through many steps like neutralization process, extractions, column chromatography
purification9a-b,13,14a, 14c,19,21-22 and recrystallization.
The synthetic procedures that we will summarize in this Chapter address some
green chemistry principles. The proposed route uses a stoichiometry of 1:1 of starting
materials, minimizes the uses of solvents from 45 mL to 5 mL, and eliminates the need
of workup.
Also, alternate route with an environmental-friendly approach is being
developed for the synthesis of ferrocenyl chalcones. This approach presents an easier
and less expensive route than the procedures published before9a,b,13-14c,19,21-22 obtaining
good to moderate yields in shorter reaction times.
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MROV Chapter 2 2014
2.2. Experimental
2.2.1. Glassware and instrumentation
The glassware was dried in the oven and assembled with a magnetic bar and sealed
with septum.
In cases needed, the glassware was covered to avoid compounds
decomposition by light exposure. All chemicals used were reagent grade from Sigma
Aldrich, Fisher and Alfa Aesar. All products were analyzed by 1H and
13
C NMR using a
Bruker Avance spectrometer AV-500 or DRX-300 at room temperature. The samples
were diluted in 0.7 mL of CDCl3 and the signals were calibrated with this solvent signals
at 7.26 and 77.0 ppm for 1H NMR and
13
C NMR, respectively. The crystal diffraction
data of some ferrocenyl chalcones were collected on a Bruker AXS SMART 1K CCD
area detector, with graphite monochromatic Mo K R radiation (λ) 0.71073 Å, at room
temperature using the program SMART-NT 17. The collected data was processed by
SAINT-NT. An empirical absorption correction was applied by the SADABS. Structures
were solved by direct methods and refined by full-matrix least squares methods on F2.
Infrared spectra were recorded on a Bruker Tensor 25 IR A spectrophotometer.
The
voltammograms were obtained using BAS 100W epsilon potentiostat and the UV-Vis
absorption spectra were obtained using a Perkin Elmer Lambda 35 UV-Vis
spectrophotometer.
Minimal
inhibitory
concentrations
(MICs)
were
spectrophotometrically determined using a Multiskan FC microplate reader (Fisher
Scientific) at 620 nm.
42
MROV Chapter 2 2014
2.2.2. Chemicals
1. 1-Butanol (Sigma Aldrich Co.) was used as received.
2. 2-bromobenzaldehyde (Aldrich Co.) was used as received.
3. 2-chlorobenzaldehyde (Aldrich Co.) was used as received.
4. 2-fluorobenzaldehyde (Aldrich Co.) was used as received.
5. 2-methoxybenzaldehyde (Aldrich Co.) was used as received.
6. 2-nitrobenzaldehyde (Aldrich Co.) was used as received.
7. 2-pyridnium carboxaldehyde (Aldrich Co.) was stored at 10 °C prior to use.
8. 3,4-dichlorobenzaldehyde (Aldrich Co.) was used as received.
9. 3-bromobenzaldehyde (Aldrich Co.) was used as received.
10. 3-chlorobenzaldehyde (Aldrich Co.) was used as received.
11. 3-fluorobenzaldehyde (Aldrich Co.) was used as received.
12. 3-methoxybenzaldehyde (Aldrich Co.) was used as received.
13. 3-nitrobenzaldehyde (Aldrich Co.) was used as received.
14. 3-pyridinium carboxaldehyde (Aldrich Co.) was stored at 10 °C prior to use.
15. 4-bromobenzaldehyde (Aldrich Co.) was used as received.
16. 4-chlorobenzaldehyde (Aldrich Co.) was used as received.
17. 4-dimethylaminobenzaldehyde (Aldrich Co.) was used as received.
18. 4-fluorobenzaldehyde (Aldrich Co.) was used as received.
19. 4-methoxybenzaldehyde (Aldrich Co.) was used as received.
20. 4-nitrobenzaldehyde (Aldrich Co.) was used as received.
21. 4-pyridinium carboxaldehyde (Aldrich Co.) was stored at 10 °C prior to use.
22. Acetone (ACS grade) (Sigma Aldrich Co.) was used as received.
23. Acetylferrocene (98%) (Aldrich Co.) was recrystallized using hexane.
24. ACN-d3 (99.6% D) (Sigma Aldrich Co.) was used as received.
25. Benzaldehyde (Aldrich Co.) was used as received.
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MROV Chapter 2 2014
26. Butanol (Sigma Aldrich Co.) was used as received.
27. Chloroform-d (99.8% D) (Sigma Aldrich Co.) was used as received.
28. Dichloromethane (Fisher Scientific Co.) was distilled prior to use.
29. Distilled water (17 MΩ – cm, Barnstead) was used in all experiments.
30. Ethanol (Sigma Aldrich Co. ACS grade) was used as received.
31. Ethyl acetate (Sigma Aldrich Co.) was used as received.
32. Hexane (Sigma Aldrich Co.) was used as received.
33. Magnesium sulfate (Sigma Aldrich Co.) was used as received.
34. Silica gel (Sigma Aldrich Co.) was used as received.
35. Sodium bicarbonate (Sigma Aldrich Co.) was used as received.
36. Sodium Hydroxide (Sigma Aldrich Co.) was used as received.
37. Tetrahydrofuran (Sigma Aldrich Co.) was used as received.
38. Thin layer chromatography (Whatman 250 μm Al2O3 plates) was used as received.
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MROV Chapter 2 2014
2.2.3. General Procedures
A. Syntheses and characterization of ferrocenyl chalcones from acetylferrocene 1
1. General procedure for the preparation of the acetylferrocene derivatives
In a 50 mL Erlenmeyer flask equipped with a magnetic stirring bar, 2 mmol of the
acetylferrocene was added. In another beaker, a basic solution was prepared by mixing
5 mmol of NaOH, 1 mL of water, and 1 mL of ethanol. This solution was allowed to cool
down to room temperature. In a clean and dry beaker 2 mmol of the benzaldehyde was
dissolved with 3 mL of ethanol, if the benzaldehyde is liquid. If the benzaldehyde was
solid it was dissolved in 5 mL of ethanol, and in some cases it was necessary to use a
glass rod to help dissolve the solid. The basic solution was slowly added dropwise to
the acetylferrocene solution, and stirred at 1200 revolutions per second.
After
approximately 5 minutes of stirring, the dissolved benzaldehyde was added to the
Erlenmeyer flask. The reaction was continuously stirred and monitored by TLC until
completion or no changes observed in the TLC. Some reactions were light sensitive;
therefore the exposure to it was avoided.
The solid was collected using vacuum
filtration. The crude material was recrystallized using the appropriate solvent.
2. General procedure for the preparation of the acetylferrocene derivatives using a
solvent-free approach
A mixture of acetylferrocene (2 mmol) and benzaldehyde (2 mmol) were grounded in
a 50 mL beaker and allowed to stand at 70 °C. Then, 5 mmol of NaOH previously
grounded with an agate mortar and a pestle, were slowly added. The reaction was
monitored by TLC until completion and then, enough cold water was added to remove
1
None of the procedures discussed or reported are exactly as our procedures.
45
MROV Chapter 2 2014
the excess base. The solid was collected using vacuum filtration. If the reactions were
not completed, drops of cold hexane and cold ethanol were added to remove the
starting materials. If necessary, the products were purified by recrystallization using the
appropriate solvent.
2.2.4
Results
A. Syntheses of ferrocenyl chalcones (Fc-1) from acetylferrocene using the Claisen
Schmidt aldol reaction.
Scheme 2.3. Synthesis of ferrocenyl derivatives from acetylferrocene applying ClaisenSchmidt condensation.
A total of twenty one chalcones Fc-1 were synthesized and characterized to
accomplish this objective and each of them were characterized by NMR, FT-IR and Xray crystallography when possible; all of them were found with 95% of purity or higher
(Table 2.2). The substituents chosen have different effects on the reactivity of the
carbonyl towards the aldol condensation either by their inductive effect (electrondonating or electron-withdrawing) or their position relative to the carbonyl group in the
benzene ring. Their effects will be discussed in Section 2.3. The reaction time of these
substituents varies from 25 minutes to 19 hours and their yields vary from 40 to 94
percent. The reaction was not completed in most of the derivatives synthesized except
46
MROV Chapter 2 2014
for the pyridyl derivative. This can explain why the yields are not as good as for the
pyridyl derivatives. A comparison of yields and reaction times within our data and the
data previously reported will be discussed in Section 2.3 and summarized in Section
2.6.
Among of all the compounds synthesized for this objective, four of these compounds
have not been synthesized previously; 1-ferrocenyl-3-(2-fluorophenyl)prop-2-en-1-one
(1b, 89% yield), 1-ferrocenyl-3-(3-fluorophenyl)prop-2-en-1-one (1c, 70% yield), 3-(4acetamidophenyl)-1-ferrocenyl-prop-2-en-1-one
(1u,
35%
yield),
dichlorophenyl)-1-ferrocenyl-prop-2-en-1-one (1v, 45% yield).
and
3-(3,4-
Furthermore, we
obtained the information about the overall structure by the unreported X-ray
crystallography of two derivatives: 3-(2-bromophenyl)-1-ferrocenyl-prop-2-en-1-one (1h,
Figure 2.4) and 1-ferrocenyl-3-(2-methoxyphenyl)prop-2-en-1-one (1n, Figure 2.6). The
X-ray crystal structure of 1-ferrocenyl-3-(3-nitrophenyl)prop-2-en-1-one (1l, Figure 2.5)
was published by I. Liu and co-workers in 200838b.
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MROV Chapter 2 2014
Table 2.2. Data of the ferrocenyl chalcones synthesized from acetylferrocene using the
alcoholic medium approach.
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MROV Chapter 2 2014
In general, the benzaldehydes, with substituents that are electron-withdrawing (EW)
and are in the para position, required less time to react than when they are occupying
positions ortho or meta. The pyridyl’s derivatives 1q, 1r, and 1s also react faster than
other substituents because the electron-withdrawing effect of the pyridyl rings. The
nitrophenyl derivatives behavior is the most interesting case in this Section 2.2.4
because they are more soluble in the alcoholic medium than other derivatives. This can
explain why they react more slowly when comparing the reactivity with other EWG.
Also, this methodology failed when the preparation of the ortho-nitrophenyl derivative
(1k) was attempted.
These and other findings will be discussed in Section 2.3 and supported with the
findings of the Nuclear Magnetic Resonance (NMR) and the Fourier Transform Infrared
(FT-IR) spectroscopy, summarized in the Table 2.4.
B. Syntheses of ferrocenyl chalcones from acetylferrocene using Claisen-Schmidt aldol
reaction following general procedure 2.
Some of the derivatives synthesized following the general procedure 1 were also
synthesized using the solvent-free approach in order to compare both procedures
(Table 2.3).
As we expected, using the solvent free-approach the reaction times
reduced from 30 minutes or 19 hours to no more than 30 minutes.
However, as
obtained with the syntheses in the alcoholic medium, the reaction was not completed
and the yields were not as good as expected.
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MROV Chapter 2 2014
Table 2.3. Data of the ferrocenyl chalcones synthesized from acetylferrocene using the
solvent-free approach.
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MROV Chapter 2 2014
The most significant finding of this approach was the synthesis of the orthonitrophenyl derivative (1k). As mentioned before the workup of the alcoholic medium
for these derivatives only included filtration of the solid and recrystallization and when
the reaction was stopped, no solid was recovered for Fc-1k. Also, when an extraction
was tried for Fc-1k the product decomposed. However, when solvent-free conditions
were applied for this substituent an oil-like solid was recovered as reported by Furdik9 in
1960, but with a pleasant grape odor. The compound was purified by column
chromatography obtaining only 16% of the product.
Interestingly it highlights that
Furdick could not purify the product by column chromatography, but in 2006, Wu24
achieved the synthesis using the same alcoholic methodology and obtaining a solid that
was recrystallized with ethanol.
However, it was noticed that 1k is soluble in the
alcoholic medium (procedure #1) because when attempts were made to remove the
excess of NaOH with water it completely solubilized, becoming the only derivative
synthesized in our laboratory which exhibit this property.
nitrophenyl derivative was as described in this section part C-1.
51
The workup of ortho-
MROV Chapter 2 2014
C. Characterization of ferrocenyl chalcones from acetylferrocene
1. Nuclear Magnetic Resonance: Proton (1H) and 13Carbon Spectra
Figure 2.2. 1H NMR spectrum of the new ferrocenyl chalcone 3-(3,4-dichlorophenyl)-1-ferrocenyl-prop-2-en-1-one chalcone in CDCl3
obtained from Bruker spectrometer at 500 MHz (AV-500) at room temperature. X Represents solvent impurities.
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MROV Chapter 2 2014
Figure 2.3. 13C NMR spectrum of the new ferrocenyl chalcone 3-(3,4-dichlorophenyl)-1-ferrocenyl-prop-2-en-1-one chalcone in CDCl3
obtained from Bruker spectrometer at 125 MHz (AV-500) at room temperature.
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MROV Chapter 2 2014
1.
Spectroscopic data summary.
1-ferrocenyl-3-phenylprop-2-en-1-one (1a).
1-ferrocenyl-3-phenylprop-2-en-1-one
was obtained with a 65% yield [Lit. 60%]8 as red crystals according to general
procedure # 1. Reaction time of 60 min, m. p. (133-134) °C (uncorrected) [Lit. (137140) °C]. 1H-NMR (δ in ppm, CDCl3, 500 MHz): 4.22 (5H, s), 4.62 (2H, d), 4.92 (2H, d),
7.10 (1H, d), 7.30 (2H, dd), 7.53 (1H, d), 7.69 (1H, d), 7.79 (2H, d).
13
C-NMR, (δ in
ppm, CDCl3), 69.8, 70.1, 72.9, 80.3, 123.0, 124.1, 132.8, 127.2, 130.4, 139.1, 192.5.
FT-IR {neat, σ (cm-1)}: 1647.4 (C=O), 1596.0 (C=C), 1573.5 (C=Carom.), 1376.4 (Fc).
1-ferrocenyl-3-(2-fluorophenyl)-prop-2-en-1-one
(1b).
1-ferrocenyl-3-(2-
fluorophenyl)-prop-2-en-1-one was obtained with a 89% yield as violet crystals
according to general procedure # 1. Reaction time of 60 min, m. p. (104–105) °C
(uncorrected). 1H-NMR (δ in ppm, CDCl3): 4.26 (5H, s), 4.64 (2H, d), 4.96 (2H, s), 7.42
(4H,m), 7.65 (1H, bs), 7.91 (1H,bs).
13
C-NMR, (δ in ppm, CDCl3), 69.8, 70.2, 72.9,
80.6, 116.24, 123.3, 124.5, 125.9, 130.1, 131.3, 133.8, 160.8, 162.8, 193.1. FT-IR
{neat, σ (cm-1)}: 1645.6 (C=O), 1587.6 (C=C), 1449.8 (C=Carom.), 1078.5 (C-F), 1376.4
(Fc). Anal. Calc. for C19H15FFeO: C, 68.29; H, 4.52. Found: C, 68.28; H, 4.62.
1-ferrocenyl-3-(3-fluorophenyl)-prop-2-en-1-one
(1c).
1-ferrocenyl-3-(3-
fluorophenyl)-prop-2-en-1-one was obtained with a 70% yield as vivid red crystals
according to general procedure # 1. Reaction time of 180 min, m. p. (136–137) °C
(uncorrected). 1H-NMR (δ in ppm, CDCl3): 4.22 (5H, s), 4.62 (2H, s), 4.91 (2H, s), 7.08
(2H, bd, J = 13.2 Hz), 7.40 (3H,m), 7.72 (1H, d, J = 15.3 Hz).
13
C-NMR, (δ in ppm,
CDCl3): 69.8, 70.2, 73.0, 80.4, 114.1, 116.8, 124.1, 130.5, 137.4, 139.43, 161.5, 164.7,
192.7. FT-IR {neat, σ (cm-1)} 1648.9 (C=O), 1592.5 (C=C), 1445.0 (C=Carom.), 1079.6
54
MROV Chapter 2 2014
(C-F), 1376.8 (Fc). Anal. Calc. for C19H15FFeO: C, 68.29; H, 4.52. Found: C, 68.18; H,
4.68.
1-ferrocenyl-3-(4-fluorophenyl)-prop-2-en-1-one
(1d).
1-ferrocenyl-3-(4-
fluorophenyl)-prop-2-en-1-one was obtained with a 40% yield [Lit. 49%]24 as vivid red
crystals according to general procedure # 1. Reaction time of 30 min, m. p. (145–146)
o
C (uncorrected) [Lit.148-149 °C]. 1H-NMR (δ in ppm, CDCl3 4.21 (5 H, s) , 4.59 (2 H, d,
J = 1.3 Hz), 4.91 (2 H, d, J = 1.6 Hz), 7.05 (1 H, d, J = 15.8 Hz), 7.10 - 7.13 (2 H, m),
7.62 - 7.65 (2 H, m), 7.76 (1 H, d, J = 15.8 Hz). 13C-NMR, (δ in ppm, CDCl3): 69.7, 70.1,
72.8, 80.4, 116.0, 116.1, 122.8, 130.02, 130.09, 131.44, 139.6, 162.79, 164.78, 192.7.
FT-IR {neat, σ (cm-1)}: 1650.2 (C=O), 1584.7 (C=C), 1505.1 (C=Carom.), 1077.3 (C-F),
1373.0 (Fc).
3-(2-chlorophenyl)-1-ferrocenyl-prop-2-en-1-one
(1e).
3-(2-chlorophenyl)-1-
ferrocenyl-prop-2-en-1-one was obtained with a 83% yield [Lit. 79%]9 as red crystals
according to general procedure # 1. Reaction time of 120 min, m. p. (119-120) °C
(uncorrected) [Lit. (116-118) °C]. 1H-NMR (δ in ppm, CDCl3): 4.23 (5H, s), 4.60 (2H, d),
4.91(2H, d), 7.09 (1H, d), 7.11, 7.33, 7.45, 7.73 (4H, m), 8.15 (1H, d).
13
C-NMR, (δ in
ppm, CDCl3), 80.3, 125.9, 127.0, 127.7, 130.3, 130.7, 133.6, 135.3, 136.7, 192.8. FTIR {neat, σ (cm-1)}: 1644.7 (C=O), 1586.1 (C=C), 1439.8 (C=Carom.), 1373.1 (Fc), 753.4
(C-Cl).
3-(3-chlorophenyl)-1-ferrocenyl-prop-2-en-1-one
(1f).
3-(3-chlorophenyl)-1-
ferrocenyl-prop-2-en-1-one was obtained with a 58% yield [Lit. 40%]24 as orange
crystals according to general procedure # 1. Reaction time of 180 min, m. p. (135-136)
°C (uncorrected) [Lit. (135-136) °C]. 1H-NMR (δ in ppm, CDCl3): 4.15 (5H, s), 4.55 (2H,
d), 4.90 (2H, d), 7.05 (1H, d), 7.2 - 7.8 (4H, m), 7.85 (1H, d).
55
13
C-NMR (δ in ppm,
MROV Chapter 2 2014
CDCl3): 69.7, 70.1, 72.9, 80.3, 124.1, 126.8, 130.2, 134.9, 137.0, 139.2, 127.6, 129.9,
192.5. FT-IR {neat, σ (cm-1)}: 1653.4 (C=O), 1599.2 (C=C), 1452.6 (C=Carom.), 1376.0
(Fc), 784.6 (C-Cl).
3-(4-chlorophenyl)-1-ferrocenyl-prop-2-en-1-one
(1g).
3-(4-chlorophenyl)-1-
ferrocenyl-prop-2-en-1-one was obtained with a 67% yield [Lit. 57%]13 as orange
crystals according to general procedure # 1. Reaction time of 25 min, m. p. (160-162)
°C (uncorrected) [Lit. (160-161) °C]. 1H-NMR (δ in ppm, CDCl3): 4.21 (5H, s), 4.60 (2H,
d,), 4.91 (2H, d), 7.09 (1H, d) 7.39 (2H, d), 7.58 (2H, d), 7.74 (1H, d).
13
C-NMR, (δ in
ppm, CDCl3): 69.7, 70.1, 72.9, 80.4, 123.2, 139.4, 129.2, 129.4, 133.7, 135.9, 192.7.
FT-IR {neat, σ (cm-1)}: 1649.9 (C=O), 1592.8 (C=C), 1490.5 (C=Carom.), 1377.0 (Fc),
771.7 (C-Cl).
3-(2-bromophenyl)-1-ferrocenyl-prop-2-en-1-one
(1h).
(Figure
2.4)
3-(2-
bromophenyl)-1-ferrocenyl-prop-2-en-1-one was obtained with a 69% yield [Lit. 90%]23
as violet crystals according to general procedure # 1. Reaction time of 195 min, m. p.
(125-127) °C (uncorrected). 1H-NMR (δ in ppm, CDCl3): 4.23 (5H, s), 4.64 (2H, d), 5.03
(2H, d), 7.04 (1H, d, J = 15.5 Hz), 7.24 (1H, m), 7.38 (1H, t, J = 7.5 Hz), 7.65 (2H, dd, J
13
= 7.5 Hz), 8.11 (1H,d, J = 15.5 Hz).
C-NMR, (δ in ppm, CDCl3), 69.9, 70.2, 72.9, 80.3,
125.7, 126.2, 127.7, 127.8, 130.9, 133.6, 135.5, 139.3, 192.8. FT-IR {neat, σ (cm-1)}:
1644.5 (C=O), 1587.4 (C=C), 1437.6 (C=Carom.), 1373.4 (Fc), 580.01 (C-Br).
3-(3-bromophenyl)-1-ferrocenyl-prop-2-en-1-one
(1i).
3-(3-bromophenyl)-1-
ferrocenyl-prop-2-en-1-one was obtained with a 78% yield [Lit. 96%]19 as dark red solid
according to general procedure # 1. Reaction time of 20 min, m. p. (160-162) °C
(uncorrected) [Lit. (142-144) °C].
1
H-NMR (δ in ppm, CDCl3): 4.22 (5H, s), 4.62 (2H,
d), 4.92 (2H, d), 7.03 (1H, d, J = 13.8 Hz), 7.30 (1H,d) 7.50, (2H,s) 7.64 (1H,d, J = 14.4
56
MROV Chapter 2 2014
Hz), 7.76, (1H, s).
13
C-NMR, (δ in ppm, CDCl3), 69.8, 70.1, 72.9, 80.3, 123.0, 124.1,
127.2, 130.4, 132.8, 137.3, 139.1, 192.5. FT-IR {neat, σ (cm-1)}: 1656.3 (C=O), 1585.9
(C=C), 1561.3 (C=Carom.), 617.8 (C-Br).
3-(4-bromophenyl)-1-ferrocenyl-prop-2-en-1-one
(1j).
3-(4-bromophenyl)-1-
ferrocenyl-prop-2-en-1-one was obtained with a 76% yield as orange crystals according
to general procedure # 1. Reaction time of 40 min, m. p. (172-173) °C (uncorrected).
1
H-NMR (δ in ppm, CDCl3): 4.22 (5H, s), 4.62 (2H, d), 4.92 (2H, d), 7.07 (1H, d, J = 15.6
Hz), 7.52 (4H,d, J = 5.7 Hz), 7.69, (1H, d, J = 15.6 Hz).
13
C-NMR, (δ in ppm, CDCl3),
69.7, 70.1, 72.9, 80.4, 123.4, 129.6, 132.1, 134.0, 129.4, 192.6. FT-IR {neat, σ (cm-1)}:
1650.2 (C=O), 1595.3 (C=C), 1486.8 (C=Carom.), 1376.8 (Fc), 544.2 (C-Br).
1-ferrocenyl-3-(2-nitrophenyl)prop-2-en-1-one
(1k).
1-ferrocenyl-3-(2-
nitrophenyl)prop-2-en-1-one was obtained with a 16% yield [Lit. 62%]24 as violet solid
according to general procedure # 2 at temperature between 55-60 °C. Modification to
general procedure # 2: The oily crude product was washed with cold hexane, let to dry
and then, dissolved with ethanol and filtered by gravity to remove the excess of NaOH.
The solution was rotoevaporated and the solid dissolved in ethyl acetate:hexane (1:1)
and purified by silica gel column chromatography and ethyl acetate:hexane (7:3) as
eluents. Reaction time of 10 min, m. p. (131-133) °C (uncorrected) [Lit. (132-133) °C].
1
H-NMR (δ in ppm, CDCl3, 500 MHz): 4.25 (5H, s), 4.62 (2H, t, J = 1.5, 2 Hz), 4.91(2H,
t, J = 1.5, 2 Hz), 6.97 (1H, d, J = 15 Hz), 7.55 (1H), 7.70 (2H, m) 8.13 (1H, d, J = 15.5
Hz).
13
C-NMR, (δ in ppm, CDCl3): 69.91, 70.26, 73.11, 79.82, 124.87, 128.32, 129.25,
129.89, 131.62, 133.33, 136.06, 148.66, 192.42.
57
MROV Chapter 2 2014
1-ferrocenyl-3-(3-nitrophenyl)prop-2-en-1-one (1l). (Figure 2.5) 1-ferrocenyl-3-(3nitrophenyl)prop-2-en-1-one was obtained with a 65% yield [Lit. 62%]24 as violet crystal
according to general procedure # 1. Reaction time of 60 min, m. p. (172-174) °C
(uncorrected) [Lit. (132-133) °C]. 1H-NMR (δ in ppm, CDCl3, 500 MHz):
13
C-NMR, (δ in
ppm, CDCl3): 69.72, 69.83, 70.19, 73.20, 80.16, 121.97, 124.20, 125.60, 129.7, 134.31,
137.03, 137.87, 148.79, 192.16. FT-IR {σ (cm-1)}: 1649.2 (C=O), 1591.3 (C=C), 1454.4
(NO2), 1375.5 (Fc), 840.3 (C-N).
1-ferrocenyl-3-(4-nitrophenyl)prop-2-en-1-one
(1m).
1-ferrocenyl-3-(4-
nitrophenyl)prop-2-en-1-one was obtained with a 61% yield [Lit. 54%]24 as dark-violet
crystal according to general procedure # 1. Reaction time of 195 min, m. p. (198-199)
°C (uncorrected) [Lit. 190-191) °C]. 1H-NMR (δ in ppm, CDCl3, 500 MHz): 4.23 (5 H, s),
4.65 (2 H, br. s.), 4.92 (2 H, br. s.), 7.20 (1 H, d, J = 15.8 Hz), 7.77 - 7.81 (3 H, m), 8.27
(2 H, d, J = 8.2 Hz)
13
C-NMR, (δ in ppm, CDCl3): 69.8, 70.2, 73.3, 80.2, 124.2, 126.7,
128.7, 137.7, 141.5, 148.3, 192.1. FT-IR {neat, σ (cm-1)}: 1654.4 (C=O), 1592.5 (C=C),
1516.0 (C=Carom.), 1336.8 (NO2), 1376.6 (Fc), 756.6 (C-N).
1-ferrocenyl-3-(2-methoxyphenyl)prop-2-en-1-one (1n). (Figure 2.6) 1-ferrocenyl-3(2-methoxyphenyl)prop-2-en-1-one was obtained with a 84% yield [Lit. 89%]27 as dark
violet crystals according to general procedure # 1. Reaction time of 210 min, m. p.
(148-149) °C (uncorrected) [Lit. (112-114) °C]. 1H-NMR (δ in ppm, CDCl3): 3.90 (3H, s),
4.20 (5H, s), 4.60 (2H, d), 4.90 (2H, d), 7.05 (1H, d), 6.99 (2H, b.dd), 7.25 (1H, d, J = 16
Hz), 7.40 (1H,b.s) 7.61 (1H, b.s), 8.12 (2H, d, J = 15 Hz).
13
C-NMR (δ in ppm, CDCl3):
55.5, 69.7, 70.1, 72.5, 80.9, 111.2, 123.9, 120.7, 124.7, 128.9, 131.2, 136.3, 158.7,
193.5. FT-IR {neat, σ (cm-1)}: 1642.8 (C=O), 1582.4 (C=C), 1488.5 (C=Carom.), 1241.6
(C-O-C), 1453.5 and 1377.8 (CH3), 1354.3 (Fc).
58
MROV Chapter 2 2014
1-ferrocenyl-3-(3-methoxyphenyl)prop-2-en-1-one
(1o).
1-ferrocenyl-3-(3-
methoxyphenyl)prop-2-en-1-one was obtained with a 84% yield as red-orange crystals
accordig to general procedure # 1. Reaction time of 120 min, m. p. (125-127) °C
(uncorrected). 1H-NMR (δ in ppm, CDCl3): 3.87 (3H, s), 4.22 (5H, s), 4.60 (2H, d), 4.91
(2H, d), 6.97 (1H, d), 7.16, 7.26, 7.34 (4H,m), 7.76 (1H, d).
13
C-NMR (δ in ppm, CDCl3):
55.4, 69.7, 70.1, 72.8, 80.5, 113.6, 123.3, 115.5, 120.8, 129.9, 136.6, 140.7, 159.9,
192.9. FT-IR {σ (cm-1)}: 1650.9 (C=O), 1601.7 (C=C), 1523.2 (C=Carom.), 1242.5 (C-OC), 1455.0 and 1347.4 (CH3), 1377.4 (Fc).
1-ferrocenyl-3-(4-methoxyphenyl)prop-2-en-1-one
(1p).
1-ferrocenyl-3-(4-
methoxyphenyl)prop-2-en-1-one was obtained with a 84% yield [Lit. 51%] as redorange crystals according to general procedure # 1. Reaction time of 120 min, m. p.
(152-154) °C (uncorrected) [Lit. (122-123) °C]. 1H-NMR (δ in ppm, CDCl3): 3.86 (3H, s),
4.21 (5H, s), 4.57 (2H, d), 4.91 (2H, d), 6.95 (1H, d), 7.26 (2H, d), 7.61 (2H, d), 7.76
(1H, d).
13
C-NMR, (δ in ppm, CDCl3): 55.4, 69.6, 70.0, 72.5, 80.8, 120.7, 140.6, 114.4,
127.8, 129.9, 161.3, 192.9. FT-IR {neat, σ (cm-1)}: 1646.2 (C=O), 1579.7 (C=C), 1508.6
(C=Carom.), 1239.4 (C-O-C), 1453.5 and 1374.8 (CH3).
1-ferrocenyl-3-(2-pyridyl)prop-2-en-1-one (1q). 1-ferrocenyl-3-(2-pyridylphenyl)prop2-en-1-one was obtained with a 94% yield [Lit. 90%]21 as violet crystals according to
general procedure # 1. Reaction time of 30 min, m. p. (150-152) °C (uncorrected) [Lit.
(152-153) °C]. 1H-NMR (δ in ppm, CDCl3): 4.23 (5H, s), 4.65 (2H, d), 4.97 (2H, d), 7.38
(1H, m), 7.69 (1H,dd) 7.75, (1H,m) 7.84 (1H,dd), 7.44, (1H, dd).
13
C-NMR, (δ in ppm,
CDCl3), 70.5, 70.7, 73.6, 81.9, 124.9, 125.3, 127.7, 137.7, 139.9, 150.9, 154.7, 192.5.
FT-IR {neat, σ (cm-1)}: 1650.2 (C=O), 1595.0 (C=C), 1476.6 (C=Carom.), 1374.8 (Fc),
1565.9 (C-N).
59
MROV Chapter 2 2014
1-ferrocenyl-3-(3-pyridyl)prop-2-en-1-one (1r). 1-ferrocenyl-3-(3-pyridylphenyl)prop2-en-1-one was obtained with a 72% yield [Lit. 44%]21 as violet crystals according to
general procedure # 1. Reaction time of 35 min, m. p. (171-172) °C (uncorrected) [Lit.
172 °C].
1
H-NMR (δ in ppm, CDCl3): 4.23 (5H, s), 4.64 (2H, d), 5.03 (2H, d), 7.58 (1H,
d), 7.72 (1H,d) 8.96, (1H,d) 8.23 (1H,d), 8.59, (1H, d).
13
C-NMR, (δ in ppm, CDCl3),
70.5, 70.7, 73.5, 81.8, 124.6, 126.3, 132.0, 135.3, 137.2, 150.9, 151.4, 192.0. FT-IR
{neat, σ (cm-1)}: 1650.8 (C=O), 1595.67 (C=C), 1477.1 (C=Carom.), 1375.7 (Fc), 1566.5
(C-N).
1-ferrocenyl-3-(4-pyridyl)prop-2-en-1-one (1s). 1-ferrocenyl-3-(4-pyridylphenyl)prop2-en-1-one was obtained with a 90% yield [Lit. 32%]21 as violet crystals according to
general procedure # 1. Reaction time of 35 min, m. p. (195-197) °C (uncorrected) [Lit.
196 °C].
1
H-NMR (δ in ppm, CDCl3): 4.24 (5H, s), 4.66 (2H, d), 5.03 (2H, d), 7.63 (1H,
d), 7.63 (1H,d) 7.72, (2H,d) 8.65 (2H,d), 8.65, (2H, d).
13
C-NMR, (δ in ppm, CDCl3),
70.6, 70.8, 73.8, 81.7, 122.9, 128.5, 137.8, 143.4, 151.4, 192.1. FT-IR {neat, σ (cm-1)}:
1651.9 (C=O), 1592.0 (C=C), 1374.6 (Fc), 1549.0 (C-N).
1-ferrocenyl-3-(4-N,N-dimethylaminophenyl)prop-2-en-1-one (1t). 1-ferrocenyl-3-(4N,N-dimethylaminophenyl)prop-2-en-1-one was obtained with a 87% yield [Lit. 38%]11
as orange crystals according to general procedure # 1. Reaction time of 19 h, m. p.
(141-143) °C (uncorrected) [Lit. 137 °C]. 1H-NMR (δ in ppm, CDCl3): 3.05 (3H, s), 4.25
(5H, s), 4.55 (2H, d d), 4.95 (2H, d), 6.68 (2H, d), 6.95 (1H, d, J = 14 Hz), 7.53 (2H, d),
7.75 (1H, d, J = 13.5 Hz).
13
C-NMR, (δ in ppm, CDCl3): 40.2, 69.6, 69.9, 72.2, 81.2,
118.0, 141.6, 111.9, 122.8, 130.0, 151.7, 193.0 FT-IR {neat, σ (cm-1)}: 1636.6 (C=O),
1606.5 (C=C), 1568.5 (C=Carom.), 1446.1 and 1363.3 (CH3), 1412.6 (Fc), 481.2 (C-N).
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MROV Chapter 2 2014
3-(4-acetamidophenyl)-1-ferrocenyl-prop-2-en-1-one (1u). 3-(4-acetamidophenyl)-1ferrocenyl-prop-2-en-1-one was obtained with a 35%, isolated 16% yield as dark brown
crystals according to general procedure # 2. Reaction time of 25 min, m.p. >190 °C
(uncorrected).
1
H-NMR (δ in ppm, CDCl3, 500 MHz): 2.22 (3H, s), 4.59 (2H,s), 4.91
(2H, s), 7.09 (1H, d, J = 15.6 Hz), 7.41 (1H, s), 7.61 (4H, s), 7.77 (1H, d, J = 15.6 Hz).
13
C-NMR, (δ in ppm, CDCl3): 24.7, 69.7, 69.7, 72.7, 80.7, 119.8, 122.0, 129.2, 131.0,
139.7, 140.2, 168.3, 193.0. FT-IR {neat, σ (cm-1)}: 3311.8 (NH), 1643.2 (C=O), 1681.3
(C=Oamide), 1510.0 (C=Carom.), 1446.8 (CH3), 1369.6 (Fc), 1290.0 (C-N). Anal. Calc. for
C21H19FeNO2: C, 67.58; H, 5.13. Found: C, 67.52; H, 5.21.
3-(3,4-dichlorophenyl)-1-ferrocenyl-prop-2-en-1-one (1v). 3-(3, 4-dichlorophenyl)-1ferrocenyl-prop-2-en-1-one was obtained with a 45% yield as red crystals according to
general procedure # 1. Reaction time of 60 min, m. p. (160-161) °C (uncorrected). 1HNMR (δ in ppm, CDCl3): 4.25 (5H, s), 4.60 (2H, d), 4.95 (2H, d), 7.05 (1H, d, J = 13 Hz),
7.45 (1H, d, J = 15 Hz), 7.65 – 7.72 (2H, m, J = 15.5 Hz).
13
C-NMR, (δ in ppm, CDCl3):
69.7, 70.1, 72.9, 80.6, 122.9, 140.8, 128.2, 128.9, 130.1, 135.1, 142.5, 192.9. FT-IR
{neat, σ (cm-1)}: 1654.6 (C=O), 1594.6 (C=C), 1548.1 (C=Carom.) 826.2 (C-Cl). Anal.
Calc. for C19H14Cl2FeO: C, 59.26; H, 3.66. Found: C, 59.32; H, 3.58.
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MROV Chapter 2 2014
2. X-ray crystallography of three ferrocenyl chalcones from acetylferrocene.
Figure 2.4. X-ray crystal structure of 3-(2-bromophenyl)-1-ferrocenyl-prop-2-en-1-one
(1h).
Figure 2.5.
X-ray crystal structure of 1-ferrocenyl-3-(3-nitrophenyl)-prop-2-en-1-one
(1l)38b.
Figure 2.6. X-ray crystal structure of 1-ferrocenyl-3-(2-methoxyphenyl) prop-2-en-1one (1n)38c.
Data collection: Bruker APEX2 (Bruker, 2007); cell refinement: Bruker SAINT (Bruker,
2007); data reduction: Bruker SAINT (Bruker, 2007); program(s) used to solve
structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97
62
MROV Chapter 2 2014
(Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to
prepare material for publication: SHELXTL (Sheldrick, 2008).
3. Electrochemical and UV-Vis properties of some ferrocenyl chalcones.
1.5
1.0
5
0
-5
-1
-1.5
-2
-2.5
Figure 2.7. Cyclic voltammetry (CV) with a platinum working electrode of ferrocenyl
chalcones at 1x10-3 M concentration in 0.1M TBAP/acetonitrile in a potential window
between (-500 – 1600) mV25.
The cyclic voltammetry was done with a 3-electrode electrochemical cell system with
a platinum (Pt, area = 0.0197 cm2) working electrode, Ag/AgCl (NaCl 3M) as reference
63
MROV Chapter 2 2014
and Nichrome wire as auxiliary electrode in a BAS 100W potentiostat. The working
electrode (Pt) was polished with diamond paste /metadi fluid in a microcloth and rinse
with water and air dried. Each experiment was run three times with fresh solution and
clean electrodes.
Figure 2.8. UV-Vis absorption spectra of 1x10-6 M of ferrocenyl chalcones prepared in
acetonitrile obtained from Lambda 35 spectrophotometer.25
The UV-Vis spectra were obtained in acetonitrile and Beer’s law was used to
calculate the molar absorptivity. A stock solution of 1x10-3 M of each derivative was
prepared and diluted in concentrations between (2-1000)x10-6 M. The spectra were
recorded in a Perkin Elmer (Lambda 35) spectrophotometer from 190 – 850 nm and the
cell path was 1.00 cm.
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2.3 Discussion
The first family of ferrocenyl chalcones Fc-1 synthesized by base catalyzed ClaisenSchmidt reaction were characterized by their melting points (uncorrected), FT-IR, 1H
and
13
C NMR chemical shifts (Bruker AV-500 MHz spectrometer, reported in δ (ppm),
X-ray crystallography and elemental analyses for carbon and hydrogen. The selection
of the correct reaction medium to carry out the Claisen-Schmidt condensation may
define the rate, the yield and/or the final product of the reactions. However, it is
important to mention that none of the procedures in the literature are exactly the same
as the one developed in this objective hence the results have to be analyzed by the
reaction media and their green chemistry contribution independently of the final yields.
During these experiments, two different approaches of the Claisen-Schmidt reaction,
alcoholic and solvent-free media, were performed. In both cases the main observation
was shorter reaction times when compared with the literature. Seeking for a greener
route to synthesize the ferrocenyl chalcones, the amount of ethanol and water was
reduced from 15 – 45 mL (as reported in the literature) to 5 mL which includes the basic
solution and the solvent used to dissolve the benzaldehyde. In addition, equimolar
quantities of starting materials were used. This change reduced the reaction times from
hours to minutes (Table 2.1A-2.1.1A).
This reduction of reaction times can be
explained because of the solvation of the transition state or the intermediate formed
(the enolate)35. When protic polar solvents were used, like ethanol and water, they can
coordinate with both the metal cation (Na+) and the enolate ion. The solvated enolate is
less reactive because the hydrogen - bonded enolate must be disrupted during the
condensation36. When the aldol condensation was carried out in a solvent-free medium
the reaction times were also reduced because the reaction rate increased due to the
fact that the enolate cannot be stabilized by hydrogen bond formation.
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Another important aspect that needs to be considered is the counterion used for the
enolate formation.
Some reports argue that when KOH is used, better yields are
obtained. This is probably because K+ is a soft acid, more than Na+, then the reactivity
of the enolate increase (because the oxygen is a hard base as Hard-Soft Acid-Base
theory)36. However, KOH is more hygroscopic than NaOH and more water from the
environment will be present, which may affect the reaction rate.
In addition to the effect of the media, the reaction time also depends on the
substituents and their position in the benzene ring. The electron-withdrawing group
tends to draw electron density through the benzene ring hence, the carbonyl becomes
more electropositive and reacts faster in the presence of any nucleophile when
compared with benzaldehyde; electron-donating group has the opposite effect.
Figure 2.9. Comparison of LUMO orbital energies of para-substituents and
benzaldehyde calculated by Spartan Program.
Figure 2.9. shows the relationship between the LUMO orbital calculated by the
Spartan program of some para-substituents which are ED or EW and describes that the
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derivatives which have the ED character will be less reactive than benzaldehyde and
the EW substituents are more reactive which is in agreements with the experimental
reaction time data.
The position of the substituents also affects the capacity of the carbonyl group of the
benzaldehyde to react with the ferrocene enolate (nucleophile). The ortho position
tends to reduce significantly the carbonyl reactivity due to the steric hindrance as is
shown in the Spartan models of methoxy derivatives shown in Figure 2.10 and which is
also observed in the experimental results.
(a)
(b)
Figure 2.10. Comparison of the electron density of 2-methoxybenzaldehyde (a), and 4methoxybenzaldehyde (b) obtained from Spartan program.
In this manner, it was found that the pattern of reactivity for ortho derivatives follows:
2-pyr > 2-F ≈ H > 2-Cl > 2-Br > 2-OCH3. Although models allowed us to predict and
explain these reactivity phenomena, the calculations provided by Spartan program does
not help to explain why the meta-derivatives 3-fluorophenyl (Fc-1c) and 3-chlorophenyl
(Fc-1f), which are the most EW derivatives, react slower than the ortho-derivatives.
This observation remains unanswered; however, it can be postulated that this behavior
can be related to the solubility of the chalcone in the reaction medium as is observed for
other derivatives like o-nitrophenyl chalcone.
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The o-nitrophenyl chalcone Fc-1k is the only ferrocenyl derivative known to be
soluble in water having a net charge of zero and no other nitrophenyl ferrocenyl
chalcone are soluble in water without treatment25. Probably no researcher who has
published the synthesis of this derivative has noticed this detail because their treatment
of the crude included the uses of dichloromethane for the extraction prior to column
chromatography. When the reaction was carried out in the alcoholic medium it was
assumed that the product was not obtained because a solid was expected as the other
derivatives synthesized. The solution could not be analyzed due to its insolubility in all
deuterated NMR solvents. Also, the workup steps performed only considered filtration
with cold water and ethanol and, when the extraction was tried it decomposed. Hence,
when the o-nitrobenzaldehyde condensation with acetylferrocene was attempted using
a solvent-free approach, an oil-like solid9a with a pleasant grape odor appeared.
Spartan models provided a possible explanation to the behavior of this derivative. The
molecular modeling showed that the electrostatic potential of the 2-nitrophenyl and
carbonyl group is oriented in the same direction making their electron density greater
probably due to the sum of their dipolar moments (Figure 2.11).
4-NO2Ph (Fc-1m)
3-NO2Ph (Fc-1l)
2-NO2Ph (Fc-1k)
Figure 2.11. Electrostatic potentials of nitrophenyl derivatives obtained by Spartan 04
program.
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This effect makes a great part of the molecule “hydrophilic” or correctly oriented to
easily interact with water molecules dissolving much more easily the chalcone in the
medium.
When comparing both methodologies, another key factor is that the solvent-free
reactions were carried out using a water bath at 70 °C. When the reaction was carried
out in solid-solid state at room temperature the reactions were not completed and poor
yields were obtained. It was necessary to increase the solubility of the starting material
by increasing the temperature. Also, the reaction proceeds more efficient if the starting
materials have the same melting points.
The analyses of the NMR spectroscopic data corresponding to the ferrocenyl
chalcones synthesized for this objective are in agreement with the determination of the
substituents effect’s reported by Solcăniová in chalcones, whereas one of the phenyl
groups is substituted with ferrocene. As describe by Solcăniová in 198012 the chemical
shifts of Hα and Cα of the ferrocenyl chalcones are very sensitive to the substituents
effect and act with the normal polarization of the α, ß-unsaturated carbonyl system
(Figure 2.12) showing that the resonance effects of the substituents are the
predominant influence on the Hα and Cα shielding (Table 2.4) .
Figure 2.12. Molecular structure of ferrocenyl chalcone and its polarization of the α, ßunsaturated ketone.
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MROV Chapter 2 2014
Based on the results obtained it can be added that the most important factor
contributing to the shielding of the carbonyl group is the degree of the extended
conjugation with the aromatic ring.
When the phenyl group is substituted with an
electron-withdrawing group (EWG) the α-carbon decreases its electron density making
a chain effect, lowering the resonance ability of the carbonyl group itself and shielding
it.
This effect also decreases the EW effect of the carbonyl group itself. This is more
evident with EWG which make resonance throughout the molecule. An example is the
4-NO2Ph, which showed an α-carbon displacement of δ 126.6 ppm and δ 192.1 ppm for
the carbonyl group. In contrast, the 4-N(CH3)2Ph EDG has the opposite effect with an
α-carbon displacement of δ 118.0 ppm and δ 193.0 ppm for the carbonyl group. The
ortho-derivatives with resonance effect have the same tendency but with a less
magnitude. The halogens substituents have also the same tendency as para and ortho
EWG but their effects are mainly by donation of electron density via induction more than
their effect due their electronegative character. As seen in Table 2.4 the α-carbon of 4fuorophenyl derivatives is at 122.8 ppm and the carbonyl group is at 192.7 ppm, but the
α-carbon of 4-bromophenyl is at 123.4 ppm and the carbonyl is at 192.6 ppm.
It
demonstrates that the fluorophenyl derivative produced more effective shielding in the
α-carbon than the bromophenyl derivatives.
In agreements with the literature, the
examples described show that the α-carbon is more susceptible to changes in the
polarization of the molecule however; the effect (Δδ ppm) is not as significant in the
carbonyl group. The β-carbon behaves as expected for the α,β-unsaturated ketone
which are more deshielding than the α-carbon due the effect of the conjugation.
However, a more remarkable tendency is observed in FT-IR spectroscopy.
Infrared spectroscopy can play a powerful role in the characterization of the carbonyl
because this group possesses key properties that give rise to an excellent group
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frequency. The carbonyl group has a large dipole-moment, a stretching frequency that
occurs at high values outside the fingerprint region and, their stretching band are
sensitive enough to the electronic and structural effects to allow the interpretation of the
surrounding structure41. The carbonyl and alkene bands for the twenty two derivatives
synthesized are summarized in Table 2.4.
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The possible factors that affect the manner in which the carbonyl absorbs radiation
and allow us to interpret the structure behavior are as follows:41
a. Geometric effects – Although the displacement of the oxygen atom
involves simple stretching or compressing of the C=O bond, the
displacement of the carbon atom is more complex because of the
neighbors attached. The magnitude of the additional force constant of
these neighbors is angle dependent. As the angle between the bonds
(C—CO—C) decreases, the contribution of the neighbors to the effective
C=O stretching force constant will be increased41.
b.
Electronic effects (inductive and conjugative effects) - The inductive
effect comes from a more electronegative system which slightly shifts
away the balance of the contributing resonance structures by their strong
inductive effect. The shift results in a larger effective C=O force constant
and higher frequency.
On the other hand, the direct conjugation of
carbonyl via α,β-unsaturated system will introduce new dipolar carbonyl
resonance forms that decrease the effective force constant values and,
thus, decrease the carbonyl stretching frequency41.
c. Interaction effects – Among all the interactions that we can mention, the
interaction or field effect became more remarkable in our study. The
field effect comes from the relative position of the substituent towards the
carbonyl group. If they are eclipsed, a repulsive lone-pair interaction can
occur which results in suppression of the contribution of the dipolar
carbonyl resonance form, and therefore cause an increase in the
stretching frequency41.
Based on these factors, the behavior for each group of derivatives can be explained.
As any other highly conjugated system, the carbonyl absorption band of un-substituted
ferrocenyl chalcone 1a can be found at wavenumber around 1647 cm-1. As expected
for the halogen group, the C=O band appeared at wavenumber between 2.5 to 3 units
higher than the unsubstituted ferrocenyl chalcone Fc-1a regardless of their
electronegative character (Table 2.4) especially, for the substituents in meta and para
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positions. Their effect is also additive and is observed in C=O band of the 3,4-diClPh
derivative Fc-1v, which has an additional chlorine, and appears at a wavenumber of
1654 cm-1, 4 wavenumbers more than the halogen derivatives and 7 more than 1a. The
energy in which the ortho-substituted halogen derivative absorbs radiation is affected by
the geometric effect, which is guided by the steric hindrance. Thus, if the carbonyl force
constant is angle dependent and is proportionally inverse to the frequency41 then, when
the angle of the α,β-unsaturated ketone system in ortho derivatives is higher than 120°
the stretching force constant and the wavenumber of the C=O decrease. This is in
agreement with the data obtained in which the C=O frequencies of all ortho derivatives
are between 2 to 5 wavenumbers less than the unsubstituted ferrocenyl chalcone Fc-1a
and is more dramatic with the ortho-methoxy derivative Fc-1n. The wavenumber of the
carbonyl group for the meta-substituted derivatives are higher than the phenyl
derivative by 1.5 to 9 cm-1. The meta-substituted derivative’s reduced the conjugation
of the phenyl group with the α, β unsaturated ketone.
Hence, the carbonyl group
behavior of the meta group is more likely affected by its resonance with the alkene than
the phenyl group and both, the carbonyl force constant and the wavenumber at which
the derivatives absorb radiation increase. As the methoxy group, the 4-dimethylamino
derivative (Fc-1u) has the lower C=O frequency because their strong electron-donating
capacity and the opposite effect is found by the p-nitro derivative.
The pyridyl
derivatives show the field effects because the pyridyl suppressed the dipolar
contribution of the resonance form of the phenyl and increases the carbonyl stretching
frequency.
The ability to increase the resonance forms of the molecule is related to the degree
of the extend conjugation of the system. The conjugation term appeal to the planarity of
the system and the X-ray crystallography of three ferrocenyl chalcones corroborate the
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overall planarity of the α, ß-unsaturated carbonyl system (Table 2.7A-2.8A). The angles
subtended for the atoms at the α,ß-unsaturated ketone deviated only marginally from
the ideal angle of 120° but enough to be noticed in the FT-IR spectra.
However,
significant deviations were apparent in the carbons between the double bond and the
phenyl group, an effect that can be attributed to the presence of the substituents in the
phenyl group. The three molecules exist as the most stable configuration of the (E)isomer (Figure 2.4-2.6), and all carbon atoms are sp2-hybridized.
In the ferrocene
moiety, the Cps (substituted cyclopentadienyl ring) plane and Cp (the unsubstituted
cyclopentadienyl ring) plane are almost parallel, and the carbon atoms of Cp and Cps
are in the eclipsed conformation for 2-BrPh and 3-NO2Ph38b but in gauche conformation
for the 2-OCH3Ph. The C=O bond lengths of the three derivatives correspond well with
the statistical values for a carbonyl group conjugated to a C=C double bond [1.222 Å]38
and the C=C bond lengths compares well with the values found for C=C-C=O
conjugated systems [1.340 Å]38 (Table 2.7A) .
The X-ray crystal structure of 3-(2-bromophenyl)-1-ferrocenyl-prop-2-en-1-one (1h)
showed an average C-C bond length of the substituted Cp ring of 1.423 Å and 1.395 Å
for the the unsubstituted Cp ring. The average of both Fe-C(ring) distance is 2.036 Å and
the bond length of the carbonyl and alkene groups are 1.227 Å and 1.317 Å,
respectively. The bond angles in the Cp rings average 107.7°. Also, the X-ray crystal
structure of 1-ferrocenyl-3-(3-nitrophenyl)-prop-2-en-1-one (1l) showed an average C-C
bond length of the substituted Cp ring of 1.421 Å and 1.402 Å for the unsubstituted Cp
ring. The average of both Fe-C(ring) distances is 2.044 Å and the bond length of the
carbonyl and alkene groups are 1.229 Å and 1.305 Å, respectively. The bond angles in
the Cp rings average 107.9°.
The X-ray crystal structure of 1-ferrocenyl-3-(3-
nitrophenyl)-prop-2-en-1-one (1l) is in agreement with previously reported structure38b
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but does not showed H-bonds as Liu et al. argue in their publication38b. Finally, the Xray crystal structure of 1-ferrocenyl-3-(2-methoxyphenyl) prop-2-en-1-one (1n) showed
an average C-C bond length of the substituted Cp ring of 1.418 Å and 1.403 Å for the
unsubstituted Cp ring. The average of both Fe-C(ring) distances is 2.040 Å and the bond
length of the carbonyl and alkene groups are 1.227 Å and 1.335 Å, respectively. The
bond angles in the Cp rings average 108.3°. The X-ray structure of acetylferrocene4b-c
showed C-C and Fe-C bond lengths between 1.392-1.442 Å and 2.028-2.061 Å,
respectively, which means that the new structures are in agreement with these values
and no significant changes occurs with the ferrocenyl moiety after the condensation of
the corresponding benzaldehyde.
The electrochemical behavior of some of the ferrocenyl chalcones was reported in
201025. All the compounds were chemically reversible with an anodic peak current over
catholic peak current (Ipa/Ipc) between 1.0-2.0 at 200 mV and electrochemically quasireversible, ΔEp = 72-90 mV because the ΔEp are higher than those expected for a
Nernstian value of 59 mV per electron. The number of electron transferred (n = 1 e-)
and the diffusion coefficients (Dox = 1.65 - 3.7 x 10-5 cm2/s) values were in agreement
with those published by A. Bond, T. Henderson and D. Mann et al.42 and are closely to
Dox of ferrocene (2.4 x 10-5 cm2/s). Similar work was done on ferrocene derivatives by
S. Batterjee43 and co-workers in 2003 which also showed a reversible one-electron
oxidation-reduction behavior, and the effect of the susbtituents was attributed to the
electronic properties of the compounds.
The majority of the ferrocenyl chalcones showed three bands in the UV region
(~180-450 nm) and one in the visible region (~500-550 nm) with absorption coefficients
from (1.8 x 104 to 7.5 x 104) M-1 cm-1. The most variable region was the 250-340 nm
which is related to the carbonyl group n-π* and π-π* electronic transitions. These
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variations are associated to the EDG or EWG character of the substituent in the phenyl
group whose extension to the α,β-unsaturated ketone are widely discussed before and
is also demonstrated in the values of the formal redox potential (Eo’) which varies from
+665 mV to +773 mV. The most interesting case is the 4-N,N-dimethylamino derivative
Fc-2t which shows the lower Eo’ (+665 mV) due its ED effect and absorption band near
400 nm.25 For the Fc-2t derivative three well-defined oxidations bands were observed:
one at Eo’=+665 mV attributed to ferrocene reversible behavior and, two chemically
irreversible oxidation bands with Epa =+694 and +974 mV which are assigned to the
loss of nitrogen electrons of the substituent25.
As discussed in this section, any of the procedures reported before are not exact to
the procedure presented in this work.
Although in some cases we still needed to
recrystallize the crude product, this procedure is greener even though, when some
reports used the solvent-free approach, their work up included extraction14c, 22, column
chromatography14c or recrystallyzation22. Both approaches mainly impact at least four
of the green chemistry principles proposed by Anastas: waste prevention, less
hazardous chemical synthesis, reduction of derivatives, and energy efficiency. One of
the drawbacks found in the solvent-free methodology is the manual stirring. Probably
this can be improved by changing the mechanical way to grind the solids during the
synthesis. If the reaction is completed, then only washing the crude material to remove
any organic impurity is needed hence, also avoiding the recrystallization step.
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2.4 Application
Infections by bacteria are the most threatening condition worldwide44. The toxins
produced by bacteria and fungus are some of the most deadly chemicals known and
represent an ongoing bioterrorism threat44. Although one of the most recognized
bacteria which takes prominence because of various terrorism attacks in 200145 is
Bacillus anthracis, which produce anthrax toxin protein44, other bacteria are constantly
under investigation.
According to the Centers for Disease Control and Prevention
(CDC), Bacillus cereus, Gram-negative bacteria is constantly tested because of its
great capacity to resist new antibiotic treatments46. Bacillus cereus is a type of bacteria
commonly found in food and is associated with food poisoning and anyone can be
exposed to it46. This baterium is recognized as an infrequent cause of serious nongastrointestinal infection, particularly in drug addicts, the immunosuppressed, neonates,
and postsurgical patients, especially when prosthetic implants such as ventricular
shunts are inserted47. Septicemia, meningitis, endocarditis, osteomyelitis, and surgical
and traumatic wound infections are other manifestations of severe disease stage47. B.
cereus produces beta-lactamases, unlike Bacillus anthracis, and so, it is resistant to
beta-lactam antibiotics; it is usually susceptible to treatment with clindamycin,
vancomycin, gentamicin, chloramphenicol, and erythromycin.
However, these
antibiotics have several side effects such as colitis, kidney problems, nerve damage
and decrease of the white cells47a. Due to these side effects, newer, safer and effective
drugs have to been developed and some ferrocene derivatives have been explored48-51
with positive results.
To the best of our knowledge, ferrocenyl chalcone derivatives developed in this work
have not been studied as antibiotic for B. cereus bacteria.
The 3-NO2Ph, 4-BrPh, 3-
ClPh and 4-ClPh ferrocenyl chalcones were tried to inhibit the growing of B. cereus
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colonies using the Clinical and Laboratory Standards Institute, CLSI, protocol modified
by Dr. David J. Sanabria and published in 201452. The ferrocenyl chalcones were
dissolved in 95% ethanol and serially diluted with sterile Tryptic Soy Broth (TSB).
The preliminary data showed that all compounds exhibit activity against this bacterium
in concentration between 62 μM and 125 μM (Table 2.11A). However, the study had
shown solubility problems and another assay has to be done changing the solvent from
ethanol to dimethyl sulfoxide (DMSO) to reach conclusions. DMSO dissolved most of
the ferrocenyl chalcones and is miscible with water which can improve the solubility of
the chalcone in the medium.
2.5 Conclusion
The goal of synthesizing and characterizing ferrocenyl chalcones by Claisen-Schmidt
condensation was accomplished. They were fully characterized by 1H NMR,
13
C NMR,
IR spectroscopy, and the effect of the substituent in the ferrocenyl chalcones was
established. The synthetic procedure that has been developed allowed the synthesis of
4 new compounds and two new structures that were elucidated by X-ray
crystallography.
Although none of the reported procedures were exact to the
methodology presented, when comparing to those previously reported, the one
introduced in this project is an eco-friendly procedure that improved the yields of
various derivatives. Some of these derivatives were also subjected to the determination
of their antibacterial activity. The compounds showed activity at MIC between 62 μM to
125 μM. Although these studies are preliminary, it is shown here the provided useful
information about the biological activity of ferrocene derivatives and their capacity to be
a potent class of biologically active compounds.
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37. House, J. Inorganic Chemistry 1st Ed., Academic Press/Elsevier: Amsterdam;
Boston, 2008, p.197.
38. (a) Lindeman, S.; Bozak, R.; Hicks, R.; Huseby, S. Acta Chem. Scand. 1997, 51,
966-968. (b) Liu, I.; Ye, J.; Liu, X. et al. Acta Cryst. 2008, E64, m1241. (c) Otaño Vega,
M.; Rivero, K.; Montes, I. Acta Cryst. 2014, E70, m108-109.
39. Rastogi, P.; Bassi, P J. Phys. Chem. 1964, 68 (9), 2398–2406.
40. Savchenko, P. S. Russ. J . Inorg. Chem. 1959, 4, 187-190. (b) Petrucci, R. J.
Chem. Educ. 1959, 36 (12), 603-604.
82
MROV Chapter 2 2014
41. Mayo, D.; Pike, R.; Trumper, P. Microscale Techniques for the Organic Laboratory
2nd Ed., Wiley: Ney York, p.66-142.
42. Bond, A. M.; Henderson, T. L. E.; Mann, D. R. et al. Anal. Chem. 1988, 60, 1878–
1882.
43. Batterjee, S.; Marzouk, M. I.; Aazab, M. E.; El-Hashash M. A. Appl. Organometal.
Chem. 2003, 17, 291-297.
44. http://www.cdc.gov/biomonitoring/pdf/Toxins_Fact_Sheet.pdf
Accessed
on
December, 2013.
45. http://911research.wtc7.net/post911/terror/anthrax.html Accessed on December,
2013.
46. http://www.cdc.gov Accessed on December, 2013.
47. (a)
Drobniewski,
F.
A.
Clin.
Microbiol.
Rev.
1993,
6,
324-328.
(b)
http://www.nlm.nih.gov Accessed on December, 2013.
48. Li, S.; Wang, Z.; Wei, Y. et al. Biomaterials 2013, 34, 902-911.
49. Haque, E.; Hossen, F.; Islam, S. et al. Int. J. Agri. Biol. 2006, 8, 774-777.
50. Yavuz, S.; Yildirim, H. J. Chem. 2013, 1-7.
51. Al-Bari Alim, M. A.; Hossen, F. M.; Khan, A. et al. Pak. J. Biol. Sci. 2007, 10, 24232429.
52. Sanabria-Ríos, D.; Rivera-Torres, Y.; Maldonado-Domínguez, G. et al. Chem.
Phys. Lipids 2014, in press.
83
MROV Chapter 2 2014
Appendix I. Physical properties and purification methodologies.
84
MROV Chapter 2 2014
2.7 Appendix I. Physical properties and purification methodologies.
A. Experimental and literature data.
a. Synthesis of ferrocenyl chalcones using alcoholic medium.
Table 2.1A. Data of previously reported ferrocenyl chalcones from acetylferrocene in
alcoholic medium.
G
Ph
Experimental Data
Reaction
Melting
Time
Point
(min)
(°C)
60
133-134
Yield
65
4-FPh
30
145-146
40
2-BrPh
3-BrPh
4-BrPh
2-ClPh
195
20
40
120
125-127
160-162
172-173
119-120
69
78
76
83
3-ClPh
4-ClPh
180
25
135-136
160-162
58
67
2-NO2Ph
----
----
----
3-NO2Ph
60
172-174
65
4-NO2Ph
195
198-199
61
2-pyridyl
30
150-152
94
85
Literature
Reaction
Melting
Time (min)
Point
(°C)
180
137-140
240
139-140
4.5a
139
120
141-142
30
141
20
139-141
120
137-138
10
137-138
---130-131
4.5 a
152
---148-149
150
---60-120
142-144
------a
4
116-118
25
104-105
---116-117
---135-136
---160
4.5 a
160
120
160-161
20
171-172
120
161-162
---155-156
4a
168-172
---132-133
a
4
172-173
---172-173
4a
198
---190
4.5 a
198
120
192
---190-191
120
120
----
152-153
152-153
150-152
Yield
608
609
8510
9513
6314c
9516
8321
9022
6824
8410
4924
9023
9619
----28
769
8022
6624
4024
509
8610
5713
9217
8221
5124
899b
6224
819
7624
969
509b
9610
9221
5424
4411
9021
4524
MROV Chapter 2 2014
Table 2.1.1A. Data of previously reported ferrocenyl chalcones from
acetylferrocene in alcoholic medium(cont.).
Experimental Data
G
Reaction
Melting
Time
Point
(min)
(°C)
3-pyridyl
35
171-172
Yield
72
4-pyridyl
35
195-197
90
2-OCH3Ph
3-OCH3Ph
4-OCH3Ph
210
120
120
148-149c
125-127
152-154
84
84
84
4-N(CH3)2Ph
19 h
141-143c
87
a
Literature
Reaction
Melting
Time (min)
Point
(°C)
---169
172
---190-191
---196
---------4.5a
2.5
< 10
120
---4.5a
30
112-114
---150
150
149
146-147
153-154
122-123
137
135-136
b
Yield
5524
4421
1624
3221
8927
----12
309b
3810
5314
9317
9221
5124
3811
9624
c
Reported in hours. Not pure. ----Non reported data. Melting points are uncorrected. This melting
point was taken three times. The purity of all compounds was determined by NMR.
Table 2.2A New ferrocenyl chalcones from acetylferrocene synthesized in
alcoholic medium.
G
2-FPh
a
Experimental Data
Reaction
Melting
Time
Point (°C)
(min)
60
104-105
Yield
89
3-FPh
180
136-137
87
3,4-diClPh
4-NH(COCH3)Pha
60
25
160-161
190
45
35
It decomposes above this temperature.
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MROV Chapter 2 2014
b. Syntheses of ferrocenyl chalcones form acetylferrocene using Claisen
Schmidt aldol reaction following general procedure 2.
Table 2.3A. Results of ferrocenyl chalcones which were not reported in literature using
the solvent-free apporach.
Experimental
G
Reaction time
Melting point
Yield
(min)
(°C)
(%)
2-FPh
5
104-106
42
3-FPh
5
136-137
54
4-FPh
10
145-146
50
2-OCH3Ph
5
147-149
61
3-OCH3Ph
10
125-127
63
2-BrPh
5
124-126
57
3-BrPh
5
160-162
50
5-10
156-158
17
10
131-133
16
10
190
13b
3,4-diClPh
2-NO2Ph
a
4-NH(COCH3)Ph
a
b
It decomposes above this temperature. Isolated. Melting points are uncorrected.
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MROV Chapter 2 2014
Table 2.4A. Results of ferrocenyl chalcones using solvent-free approach which were
previously reported in the literature.
Experimental data
G
Literature data
Reaction
Melting
Yield
Reaction
Melting
time (min)
point (°C)
(%)
time (min)
point (°C)
5
133-134
50
10
----
8422
20
139-141
9516
Ph
Yield (%)
2-ClPh
5
119-120
75
25
----
8422
4-ClPh
5
159-161
70
15
----
8322
4-OCH3Ph
10
152-154
56
2.5
149
5314
25
----
8322
40
146-147
9316
2-pyridyl
5
150-151a
32
7
192
9022
3-NO2Ph
15
170-171
42
20
171-172
9216
4-N(CH3)2Ph
30
140-142ª
52
30
135-136
9616
a
This melting point was taken three times. The purity of all compounds was determined by NMR. Melting
points are uncorrected.
B. Purification conditions for ferrocenyl chalcones.
Table 2.5A. Thin Layer Chromatography (TLC) conditions for ferrocenyl chalcones.
The TLC plates used for monitoring the reaction progress were silica gel in each case.
G
TLC solvents
2-FPh, 4NH(COCH3)Ph,
3-FPh, 3,4-diClPh, Ph,
2-, 3-, 4-BrPh, 2-, 3-, 4ClPh, 3, 4-NO2Ph, 2-,
3-, 4-OCH3Ph,
4-N(CH3)2Ph
4-NH(COCH3)Ph
Hexane:Ethyl Acetate (7:3)
4-FPh
Hexane:Ethyl Acetate (8:2)
2-NO2Ph
Hexane:THF (4:1)
2-, 3-, 4-pyridyl
Butanol:Hexane (2:1)
Hexane:Ethyl Acetate (2:1)
Hexane:Ethyl Acetate (7:3)
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MROV Chapter 2 2014
Table 2.6A. Recrystallization solvents for ferrocenyl chalcones.
G
Solvents
3,4-diClPh, 4-ClPh,
p-NO2Ph
2-, 3-, 4-FPh
2-, 3-pyridyl, 3-OCH3Ph
4-NH(COCH3)Ph,
3-, 4-BrPh, 2-, 3-ClPh,
2-OCH3Ph, 4-N(CH3)2Ph, 3-NO2Ph
Ph, 2-BrPh, 4-OCH3Ph
Acetone
4-pyridyl
Ethanol:H2O (1:1)
89
Acetone:H2O (1:1)
Acetone:H2O (2:1)
Ethanol
MROV Chapter 2 2014
Appendix II. X-ray crystallography data and UV-Vis and Electrochemical properties.
(The UV-Vis and electrochemical properties were acquired in collaboration with Dr. Ana
R. Guadalupe Quiñones research laboratory. The X-ray crystallography data was
acquired in collaboration with Dr. Raphael Raptis research laboratory. )
90
MROV Chapter 2 2014
A. X-ray crystallography data.
Figure 2.1A. Carbon labeling for the analyses of the ferrocenyl chalcones X-ray
crystallography (3-NO2Ph derivatives is shown as a model).
Table 2.7A. Experimental bond lengths of 2-BrPh, 3-NO2Ph and 2-OCH3Ph ferrocenyl
chalcones from X-ray crystallography obtained by Mercury Program.
Atom –
bond
C-12-C-13
(C=C)
C=O
C=C
benzene
Experimental
Length (Å) of
2-BrPh
1.318
Experimental
Length (Å) of
3-NO2Ph
1.305 (1.330)38b
Experimental
Length (Å) of
2-OCH3Ph38c
1.335
1.227
1.363 - 1.401
1.229 (1.226)38b
1.380 - 1.401
1.227
1.351 – 1.397
Table 2.8A. Experimental bond angles of 2-BrPh, 3-NO2Ph and 2-OCH3Ph ferrocenyl
chalcones from X-ray crystallography obtained by Mercury Program.
Atom - bond
C6-C11-O1
O1-C11-C12
C12-C13-C14
Experimental angle
(°) of 2-BrPh
121.30
120.87
127.08
Experimental angle
(°) of 3-NO2Ph
121.18
121.51
126.96
91
Experimental angle
(°) of 2-OCH3Ph38c
119.81
122.47
126.76
MROV Chapter 2 2014
B. Electrochemical and UV-Vis characterization.
Table 2.9A. Electrochemical parameters of ferrocenyl chalcones25.
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MROV Chapter 2 2014
Table 2.10A. Absorption coefficients for the most prominent bands of ferrocenyl chalcones25.
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MROV Chapter 2 2014
Appendix III. Anti-bacterial activity of 3-NO2Ph, 4-BrPh, 3-ClPh and 4-ClPh ferrocenyl
chalcones against B. cereus bacteria (The data were acquired in collaboration with Dr.
David J. Sanabria Ríos).
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MROV Chapter 2 2014
Procedure for the susceptibility test of 3-NO2Ph, 4-BrPh, 3-ClPh and 4-ClPh ferrocenyl
chalcones.
A modified version of the microdilution method outlined by the Clinical and
Laboratory Standards Institute (CLSI) was used52. The ferrocenyl chalcones were
dissolved in 95% ethanol, serially diluted with sterile TSB, and transferred to a flatbottomed microplate wells that were previously inoculated with 10 μL of TSB solution
containing 4-5 x 105 colony-forming units (CFU).
The wells were inspected
spectrophotometrically (620 nm) using both a positive control well (containing the
bacterial inoculated TSB but not the ferrocenyl solution) and a negative control well
(containing only TSB) for comparison. The minimum inhibitory concentration (MIC) was
considered to be the concentration at which the ferrocenyl chalcones prevented
turbidity in the well after incubation for 18-24 h at 37 °C.
Table 2.11A. Average (n=2) of the percentage of antibacterial inhibition of ferrocenyl
chalcones in Ethanol.
Derivatives 1000
4-ClPh
85.1
4-BrPh
108.0
3-ClPh
153.5
3-NO2Ph
62.0
500
250
125
74.4 32.5 87.6
41.6 159.7 70.6
22.5 13.2 25.5
55.6 48.6 29.0
MIC (μM)/%
62
31
39.4 37.2
32.3 22.9
28.5 28.0
34.0 29.9
95
15
8.3
8.8
16.1
20.3
8
4
2
6.7 10.3 9.8
12.9 6.3 12.9
26.5 13.5 21.0
24.6 26.9 11.0
MROV Chapter 3 2014
SYNTHESES AND CHARACTERIZATION OF FERROCENYL CHALCONES
Chapter 3:
Synthesis and Characterization of Ferrocenyl Chalcones from 1,1’-Diacetylferrocene
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MROV Chapter 3 2014
Chapter 3. Synthesis and Characterization of Ferrocenyl Chalcones from 1,1’Diacetylferrocene (DiAcFc).
3.1.
Introduction
Ferrocene having substitution at both cyclopentadienyl (Cp) rings compose a wide
sub-group of ferrocene architectures and are the second family of ferrocene
derivatives studied (Fc-2). Among the three structural types that can represent most
of these 1,1’-diacetylferrocenes with open-arm motif1a, the U-shape and S-shape
(Figure 3.1a and 3.1b) called our attention.
Figure 3.1. Molecular structures of 1,1’-disusbtituted ferrocene1.
The 1,1’-diacetylferrocene X-ray crystal structure was determined in 1970 by G.
Palenik1b. The crystal data revealed that the average C-C distance is 1.419 Å in the
Cp and that the rings are eclipsed. They also found that the Fe-C distances are
2.030-2.060 Å. The acetyl groups are S-shape and the carbonyl groups are pointed to
the same direction. To be in agreement to the previously reported data, in this work,
each molecular structure of 1,1’-diacetylferrocene or chalcone will be represented as
S-shape with the Cp rings eclipsed.
1,1’-Diacetylferrocenes also known as 1,1’-dienonylferrocenes2, are important
compounds because of their photographic properties3 and as precursors for
semiconducting polymers,2,3 accelerators of curing reactions in unsaturated polyesters
97
MROV Chapter 3 2014
resins4 as well as chiral ligands5,6,7. Also, 1,1’-bis-diacetylferrocene derivatives which
are water soluble (Figure 3.2) have been reported to have anti-cancer activity that is
more potent than water insoluble drugs8.
Figure 3.2. Molecular structure of water-soluble ferrocenyl derivative as anti cancer
agent8.
1,1’-bis-diacetylferrocene
Furthermore,
derivatives
were
synthesized
as
phenothiazine ferrocenyl chalcones because their extended conjugated electronic
systems make them useful as starting materials for organic conducting materials
(Scheme 3.1)9 .
Scheme
3.1.
Synthesis
of
ferrocenyl
diacetylferrocene9.
98
phenothiazine
chalcones
from
1,1’-
MROV Chapter 3 2014
1,1’-bis-ferrocenyl chalcones can also be precursors of pyrazole-type derivatives
which are known as insecticides, herbicides and antitumor agents (Scheme 3.2)10.
Scheme 3.2. Synthesis of ferrocenyl pyrazole derivative from 1,1’-bis-ferrocenyl
chalcone10.
Gul Nabi and Zai-Qun Liu reported in 201111 the radical-scavenging capacities of
the ferrocenyl and phenolic hydroxyl groups in ferrocenyl chalcone which demonstrate
their importance in medicinal chemistry. However, the biological activity of 1,1’-bisferrocenyl chalcones by themselves have not been extensively studied. Therefore, it
is propose that the 1,1’-bis-ferrocenyl chalcones will also exhibit biological activity and
will be useful for drug mimics as well as other important properties that are attributed
to acetylferrocene derivatives.
Hence, the synthesis of this type of ferrocenyl
chalcones deserves attention.
As for the acetylferrocene derivative synthesis, the aldol condensation is the main
reported reaction for the synthesis of 1,1’–bis-diacetylferrocene derivatives2.
However, the Claisen–Schmidt reaction is not as easy as it is for acetylferrocene
99
MROV Chapter 3 2014
derivatives.
In 1960 T. A. Mashburn, C. E. Cain and C. Hauser12 reported the
synthesis of the first 1,1’-bis-diacetylferrocene chalcone using the classic ClaisenSchmidt condensation.
Also, a yellow product was reported that was not
characterized at that moment because of its insolubility in solvents likes ethanol,
benzene, CCl4, THF and, DMF.
Although the researchers expected that the by-
product could be the monocondensated derivative the Infrared (IR) spectroscopy did
not supported that idea. Mashburn, Cain and Hauser12 predicted that the by-product
could be the cyclic ether (1), the ether dimer (2), the ferrocenophane (3) or the dimer 4
(Figure 3.3).
Figure 3.3.
Molecular structures of possible by-products proposed by Mashburn,
Cain and Hauser12.
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MROV Chapter 3 2014
A year later, Furdick13 and co-workers identified and confirmed that the yellow
product was a cyclic compound that could result from the internal addition of the
intermediate, but not as cyclic ether (1) or dimer (2 or 4), but as the ferrocenyl
diketone cycle (3) commonly known as ferrocenphane2 or ferrocenophane14. In 1968,
T. H. Barr15 was the first to propose that a possible mechanism for the formation of the
cyclic compound (3) is a base-catalyzed reverse aldol type condensation of the biscondensated product to form the enolate, which is followed by an internal Michael
addition to form the cyclic compound as describe by J. Winstead16 in 1972.
Scheme 3.3. Mechanism proposed by J. Winstead for the formation of
ferrocenophane Fc-316.
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MROV Chapter 3 2014
3.1.1. Bridged ferrocene
Ferrocenophanes are ferrocene derivatives in which the two Cp rings are
connected by an atomic or molecular bridge17 and they represents the third family of
compounds under investigation (Fc-3).
These compounds posses most of the
desirable properties mentioned for open-arm motif, but the rotation of the Cp are
restricted and their angles depend on the length and structure of the bridge.
The
carbon-bridged ferrocenophanes can be categorized into two major groups: the
mononuclear in which one Cp is attached to one or more bridges and, the multinuclear
in which two or more ferrocene units are linked together by one or more bridges
(Figure 3.4)17.
Figure 3.4. Molecular structures of different ferrocenophane where m denotes the
length of the bridge and n the relative location from m17.
[1]Ferrocenophane, with just one carbon in the bridge (m=1), is too strained to exist
however, it can exist if it is composed as a heteronuclear bridge18. On the other hand,
the [2]ferrocenophane was synthesized and characterized by M. Buretea and T. Tilley
in 199719, being the first scientists to introduce the ferrocenophanes as polymer
precursors. They successfully polymerized [2]ferrocenophane in the presence of the
Ring-opening
i
Metathesis
Polymerization
(ROMP)
catalyst,
Mo[N(2,6-
Pr2C6H3)](CHCMe2Ph)[OCMe(CF3)2]2(Mo), to produce poly ferrocenylene vinylene.
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MROV Chapter 3 2014
The X-ray structure of the intermediary ansa cycle revealed a “bent-sandwich”
geometry of the Cp with a very strained bridge. Also, the X-ray data revealed that the
squares planes intersect at an angle of 23°19. This value reflects moderate ring strain
which has to be less in ferrocenophanes with longer bridges (Scheme 3.4)19.
Scheme 3.4. Synthesis of poly ferrocenylene vinylene from 1,1’-ferrocene
carboxaldehyde by a McMurry coupling and ROMP catalyst19.
The [3] and [4]ferrocenophanes can be formed by an internal Friedel-Crafts
cyclization, as a product of the Dieckmann condensation or by the basic or acid
Claisen-Schmidt condensation and Michael addition2,12-16,19. As [2]ferrocenophane,
these compounds are suitable candidates for polymerization because of the promise
of the polymer conjugation to conduct electricity18.
The [5]ferrocenophanes (Fc-3) is the most versatile cycle and many of the attention
has been directed to its formation and the variation in the size and the composition of
the cycles16,20-22. These cycles are more flexible than the other examples with shorter
bridges and are the only ferrocenophanes that can be used as monomers for
nonconjugated conducting polymers (Scheme 3.5).
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MROV Chapter 3 2014
Scheme 3.5. Synthesis of polyferrocenophane from 3-phenyl[5]ferrocenophane using
AIBN as radical initiator23.
Although [5]ferrocenophanes (Fc-3) can be synthesized by the same routes of the
smaller ferrocenophanes, the basic Claisen-Schmidt is preferred. In 1981 L. Tataru24
again treated the classic Claisen-Schmidt synthesis of the bis-ferrocenyl chalcone
(Scheme 3.1, 1) at 0 °C as a precursor of ferrocene polymers without the cyclic byproduct raising the curiosity of S. Toma because the monochalcone (Scheme 3.3, 2)
have not been isolated in none of the previous reports. Toma25 acetylated the
ferrocenyl chalcone and investigated the kinetics of the cyclization of 1-acetyl-1’-(xcinnamoyl)ferrocenes (Scheme 3.3, 2) to establish the factors that promotes the
cyclization. S. Toma found that the sensitivity of the Michael addition to the polar
effects of the substituents increased with the increment of the electron-donating
properties of a group, activating the multiple bond25. S. Toma also found that the
cyclization depends on steric factors which determine the capacity of rotation and the
arrangement in the transition state26.
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MROV Chapter 3 2014
3.1.2. Resurge of the 1,1’-bis-ferrocenyl chalcone
At the end of the 20th century the synthesis of 1,1’–bis-diacetylferrocene derivatives
re-emerged because of the possibility of these compounds to be electroactive and
fluorescent27.
B. Delavaux-Nicot27 and A. Tárraga28 reported the synthesis of the
1,1’–bis-azoferrocenyl derivative27 and the 1,1’–bis-aza or azacrownferrocenyl
derivative28 with their respective cycles using a mixture of NaOH and ethanol (10%)
and a stoichiometry of 1:1 to 1:4 of the starting materials which always gave a ratio of
2:3 (di:cyclic) of both products18. Trying to better understand this system, W. Liu et
al.2 reported in 2001 the condensation of 1,1’-diacetylferrocene with aromatic
aldehydes without the formation of the ferrocenophane (3) in a solvent-free medium,
but with the formation of the mono-chalcone compound (2). W. Liu et al. prepared a
series of compounds varying the amount of benzaldehyde (1:1 to 1:6), temperature
(r.t. to 40-70 °C) and medium (ethanol or solvent-free). They found that when the ratio
of DiAcFc/CHO is 1:1, in solvent-free medium, the principal product is DiAcFc and the
di-chalcone product (1) which is also the main product produced along with an
increase of benzaldehyde (CHO)2. However, Liu et al. established that reactions in
the presence of 5% aqueous–ethanolic sodium hydroxide produced both compounds,
the di-chalcone (1) product and the yellow cyclic product (3) which is the major
product2. Also, from their data its deduced that when the temperature increases in the
presence of solvent, the cyclic product (3) increases regardless the amount of
benzaldehyde added. Although the findings of W. Liu et al. are quite convincing, S.
Pedotti14 et al. reported the microwave-assisted synthesis of di-chalcone (1), monochalcone (2) and ferrocenophane (3) products changing the amounts of base,
solvents, and temperatures. Pedotti established that the way leading to the formation
of 1 is limited, independently from the stoichiometry of the benzaldehyde used and
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MROV Chapter 3 2014
that no matter which medium is used (ethanol:water, dioxane or solvent-free) or the
amount of benzaldehyde added the ferrocenophane 3 is always produced (but in
presence of polar solvents its ratio increases)14. Also, Pedotti et al. established that if
the amount of the base decreases in solvent-free medium, the mono-chalcone 2 is the
major product, but is reduced if more benzaldehyde is added14.
As is summarized in Table 3.1, the ideal conditions to avoid the cyclic product and
only synthesize the 1,1’-bis-ferrocenyl chalcone have not been clearly established
except by the fact that the use of more equivalents of the benzaldehyde than the
ketone reduces the possibility of the cycle formation. Also, a set of conditions or
patterns cannot be established with the reported information for the question of why
the cycle is produced. Since our interest was primarily concerned with the greener
synthesis
of
1,1’-bis-ferrocenyl
chalcones,
the
condensation
between
1,1’-
diacetylferrocene and the corresponding benzaldehyde in aqueous and solvent-free
media were re-investigated. However, the formation of ferrocenophanes in this work
also deserves attention and are hence, discussed in this chapter.
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MROV Chapter 3 2014
Table 3.1. Timetable for Claisen-Schmidt condensations of 1,1’-bis-ferrocenyl
chalcone (Fc-2).
Year
1960
12
Author
A. Mashburn /
Hauser
Experimental
conditions
Equivalents
DiAcFc:CHOPh
Products and ratio
NaOH: ethanol 5%,
r.t.
NaOH: ethanol 5%,
r.t. to 0 °C
1:1
Di-chalcone and cyclic
product (1:2)
Di-chalcone and cyclic
product (3:1) Substituent:
H
Di-chalcone and cyclic
product
Substituents: H;
piperonal; 2-Cl; 2-,3-,4NO2; furfural
Di-chalcone and cyclic
product (3:1)
Substituent: H
Di-chalcone product.
Only for furyl substituent.
1:6
1961
13
M. Furdick, et al.
NaOH: ethanol,
40-50 °C
1:2
1972
16
J. Winstead
NaOH:ethanol 5%,
r.t. to 0 °C
1:6
1981
24
L. Tataru, et al.
NaOH:ethanol,
0 °C
1999
27
NaOH:Etanol 10%,
20 °C
1:2
2001
2
B.DelavauxNicot,
et al.
W-Y. Liu, et al.
Solvent-free, r.t.
Solvent-free, r.t.
Solvent-free, 70 °C
Solvent-free,
40-70 °C
Ethanol:water,
15 °C
Ethanol:water, r.t.
Ethanol:water, r.t.
1:1
1:4
1:1
1:2-1:3
2008
14
S. Pedotti, et al.
1:2 (furfurol)
MW, 50W, 30 min
Solvent-free
Solvent-free
Ethanol:water
Ethanol:water
Ethanol:water
Ethanol:water,
NaOH (xs)
107
Di-chalcone and cyclic
product (1:1.3)
Substituent: 4-N(CH3)2
Mono-chalcone
Di-chalcone
Mono:Di:cycle(3:1:0)
Mono:Di:cycle(traces:9:0)
1:1
Di:cycle (1:11)
1:2
1:4
Di:cycle (1:3)
Di:cycle (3:1)
Substituent: H, 2-Furyl,
4-Cl, 3-,4-OCH3, 3-NO2,
4-N(CH3)2
Mono:di:cycle
(8:1:4)
(3:1:2)
(1:0:5)
(1:1:18)
(1:1:11)
(2:1:19)
Substituent: H, 4-Cl,
2-MePh, 4-MePh,
4-N(CH3)2, β-Naphtyl,
4-pyr, Fc
1:1
1:2
1:1
1:2
1:4
1:1
MROV Chapter 3 2014
3.2.
Experimental
3.2.1. Glassware and instrumentation
The glassware, metal spatula, mortar and pestle were dried in the oven. In cases
needed, the dried glassware were assembled with a magnetic bar, sealed with septum
and covered to avoid decomposition by light exposure.
All chemicals used were
reagent grade from Sigma Aldrich, Fisher and Alfa Aesar with high purity. All the
products were analyzed by 1H and
13
C NMR using a Bruker Avance spectrometer AV-
500 or DRX-300 at room temperature. The samples (30 mg) were diluted in 0.7 mL of
CDCl3 and the signals calibrated by this solvent signals at δ 7.26 and δ 77.0 ppm for
1
H NMR and
13
C NMR, respectively. The melting points were measured with a Melt-
Temp II Laboratory devices apparatus and were uncorrected. The crystal diffraction
data of some 1,1’-bis-ferrocenyl chalcones were collected on a Bruker AXS SMART
1K CCD area detector, with graphite monochromatic Mo K R radiation (λ) 0.71073 Å,
at room temperature using the program SMART-NT 17.
processed by SAINT-NT.
The collected data was
An empirical absorption correction was applied by the
SADABS. Structures were solved by direct methods and refined by full-matrix least
squares methods on F2. Infrared spectra were recorded on a Bruker Tensor 25 IR A
spectrophotometer. The molecular modeling was performed using Spartan 04 and
Gaussian 03 programs.
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MROV Chapter 3 2014
3.2.2. Chemicals
1. 1,1’-Diacetylferrocene (95%) (Aldrich Co.) was recrystallized using hexane.
2. 2-bromobenzaldehyde (Aldrich Co.) was used as received.
3. 2-fluorbenzaldehyde (Aldrich Co.) was used as received.
4. 2-methoxybenzaldehyde (Aldrich Co.) was used as received.
5. 2-pyridnium carboxaldehyde (Aldrich Co.) was stored at 10 °C prior to use.
6. 4-bromobenzaldehyde (Aldrich Co.) was used as received.
7. 4-fluorobenzaldehyde (Aldrich Co.) was used as received.
8. 4-methoxybenzaldehyde (Aldrich Co.) was used as received.
9. 4-pyridinium carboxaldehyde (Aldrich Co.) was stored at 10 °C prior to use.
10. Acetone (ACS grade) (Sigma Aldrich Co.) was used as received.
11. Butanol (Sigma Aldrich Co.) was used as received.
12. Chloroform-d (99.8% D) (Sigma Aldrich Co.) was used as received.
13. Dichloromethane (Fisher Scientific Co.) was distilled prior to use.
14. Distilled water (17 MΩ – cm, Barnstead) was used in all experiments.
15. Ethanol (Sigma Aldrich Co. ACS grade) was used as received.
16. Ethyl acetate (Sigma Aldrich Co.) was used as received.
17. Hexane (Sigma Aldrich Co.) was used as received.
18. Silica gel (Sigma Aldrich Co.) was used as received.
19. Sodium Hydroxide (Sigma Aldrich Co.) was used as received.
20. Tetrahydrofuran (Sigma Aldrich Co.) was used as received.
21. Thin layer chromatography (Whatman 250 μm Al2O3 plates) was used as received.
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MROV Chapter 3 2014
3.2.3. General Procedures
A. Syntheses and characterization of ferrocenyl chalcones from 1,1’diacetylferrocene
1. General procedure 1 for the preparation of the 1,1-diacetylferrocene
derivatives using a solvent free approach.
A mixture of 1,1’-diacetylferrocene (1 mmol) and the appropriate benzaldehyde
were ground in a 50 mL beaker and allowed to stand at 70 °C. Then, 5 mmol of
NaOH previously grounded with an agate mortar and a pestle, were slowly added.
When the reaction was completed, enough cold water is added to remove the excess
of base. The solid was collected using vacuum filtration. If the reactions are not
completed cold hexane and/or cold ethanol are added to remove the starting
materials; in some cases cyclopentyl methyl ether (CPME) is also added.
If
necessary, the products are purified by recrystallization using the appropriate solvent.
2. General procedure 2 for the preparation of the 1,1’-diacetylferrocene
derivatives using the alcoholic medium.
In a 50 mL Erlenmeyer flask with a magnetic stirring bar, 1 mmol of the 1,1’diacetylferrocene compound was added. In another beaker, a basic solution was
prepared by mixing 5 mmol of NaOH, 1 mL of water, and 1 mL of ethanol. This
solution was allowed to cool down to room temperature. In a clean and dry beaker the
benzaldehyde (the amount of benzaldehyde depends on the substituent) was
dissolved with 3 mL of ethanol, if the benzaldehyde is liquid. If the benzaldehyde was
solid it was dissolved in 5 mL of ethanol, and in some cases it was necessary to use a
glass rod to help the solid dissolve. The basic solution was added dropwise to the
DiAcFc solution, and stirred at 1200 revolutions per second. After approximately 5
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MROV Chapter 3 2014
minutes of stirring, the dissolved benzaldehyde was slowly transferred to the
Erlenmeyer flask. The reaction was continuously stirred and monitored by silica gel
TLC and hexane:ethyl acetate (3:2) as solvents until completion. Some reactions are
light sensitive hence; the exposure to light was avoided. The solid was collected
using vacuum filtration and treated as indicated in general procedure # 1.
3.2.4. Results
A. Syntheses of ferrocenyl chalcones form 1,1’-diacetylferrocene using ClaisenSchmidt reaction.
Scheme 3.6.
Synthesis of ferrocenyl derivatives from 1,1’-diacetylferrocene
applying Claisen-Schmidt condensation.
A total of eight 1,1’-bis-ferrocenyl chalcones were attempted to synthesize and
characterize using the solvent-free Claisen-Schmidt condensation to accomplish this
aim. However, only 4 of them were pure or were isolated from the staring materials
and by-product. The reaction time of these substituents varied from 5 minutes to 15
minutes and the yield varied from 37 to 82 percent (Table 3.2 and 3.3). Among all of
the
compounds
synthesized
for
this
aim,
only
1,1’-bis-ferrocenyl-3-(4-
metoxyphenyl)prop-2-en-1-one was previously reported. However, it was obtained
the unreported X-ray crystal structure of this derivative as well as for the 1,1’- bisferrocenyl-3-(2-pyridyl)prop-2-en-1-one derivative.
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MROV Chapter 3 2014
As general observation, when the reaction was carried out in solvent-free medium
(general procedure 1) the substituents in para position exhibit a mixture of 1,1’-bisferrocenyl chalcone and ferrocenophane which cannot be isolated. Also, as an early
publications argued, to manipulate the final product more equivalents of the
benzaldehyde was needed but it was unsuccessful for the para-substituted
derivatives. The substituents that are in ortho position mainly produce the 1,1’-bisferrocenyl chalcone implying that a substituent position effect could exists, which is
important to determinate or predict the final product (Table 3.2).
Table 3.2. Results of 1,1’-bis-ferrocenyl chalcones using solvent-free approach.
The 2-pyridyl (Fc-2c), 2-fluorophenyl (Fc-2a) and 2-methoxyphenyl (Fc-2d)
produced the bis-ferrocenyl chalcones by using a 1:1 ratio of 1,1’-diacetylferrocene to
benzaldehyde. This is not the case of the 2-bromophenyl derivative (Fc-2b) which
regardless of the equivalent used, the ferrocenophane was always obtained. On the
other hand, to seek the 1,1’-bis-ferrocenyl chalcones with the substituents at the para
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MROV Chapter 3 2014
position, more benzaldehyde equivalents were used.
However, although the di-
chalcone was obtained, the by-product was always present (Table 3.3).
These
findings did not coincided with the Liu and co-workers report of 20012, which
established that with more equivalents of the benzaldehyde present in the solvent-free
reaction, the cyclic compound disappeared. The 4-methoxyphenyl derivative (Fc-2h)
was isolated once by “hand picks” or manually separated using a microscope and a
tweezers and recrystallized several times. Via this way, a single crystal was obtained
to elucidate the structure and obtain the NMR information. However, this procedure is
not reproducible for this or any other substituents.
Table 3.3. Results of the condensation of the p-substituted benzaldehyde and 1,1’diacetylferrocene using the solvent-free media.
To study if the medium had an effect as it was argued in early publications, the
same substituents were tried using an alcoholic medium (Table 3.4). In these cases,
it was found that almost all of them showed the signals characteristics of
ferrocenophane and the 1,1’-bis-ferrocenyl chalcone but the ratio of these products
varied depending on the substituents position. These results imply that the reaction
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MROV Chapter 3 2014
medium also affect the final product and is also an important factor as is the position
of the substituent. In the alcoholic medium, the 2-pyridyl substituent only produced
the ferrocenophane regardless of the amount of benzaldehyde used.
Table 3.4. Results of the condensation of 1,1’-diacetylferrocene and benzaldehyde
using the classic alcoholic medium.
All compounds were characterized by NMR, FT-IR and X-ray crystallography when
possible and the derivatives isolated were found ranging in 63% to 90% purity.
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MROV Chapter 3 2014
B. Characterization of Bis-ferrocenyl chalcones from 1,1’-diacetylferrocene
1. Nuclear Magnetic Resonance: Proton (1H) and 13Carbon (13C)
Part
Figure 3.5. 1H NMR of 1,1’-bis-ferrocenyl-3-(4-methoxyphenyl)prop-2-en-1-one in CDCl3 obtained from a Bruker spectrometer at 500
MHz (AV-500) at room temperature and following the general procedure #1. (X) Represents impurities.
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MROV Chapter 3 2014
Figure 3.6. 13C NMR of 1,1’-bis-ferrocenyl-3-(4-methoxyphenyl)prop-2-en-1-one in CDCl3 obtained from a Bruker spectrometer at 125
MHz (AV-500) at room temperature and following the general procedure #1.
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MROV Chapter 3 2014
2.
Infrared Spectrospcopy
90%
80%
70%
50%
40%
-CH3
C=O
C=Carom
C=C
Transmittance %
60%
30%
C-O
20%
10%
0%
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber cm-1
Figure 3.7. Infrared spectrum of 1,1’-bis-ferrocenyl-3-(4-methoxyphenyl)prop-2-en-1-one from region of (500 – 4000)cm-1.
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MROV Chapter 3 2014
3. Spectroscopic data summary
1,1’-bis-ferrocenyl-3-(2-fluorophenyl)prop-2-en-1-one (2a).
1,1’-bis-ferrocenyl-3-
(2-fluorophenyl)prop-2-en-1-one was obtained with a 82% yield as orange crystals
according to general procedure # 1. The crude was washed with drops of cold CPME
to remove the starting materials and no further purification was needed. Reaction
time of 5-6 min, melting point: (146-148) °C.
1
H-NMR (δ in ppm, CDCl3, 500 MHz):
4.62 (br. s., 2H), 4.91 - 4.97 (m, 2H), 7.03 - 7.10 (m, 1H) 7.11 - 7.19 (m, 2H), 7.34 (d,
J=4.41 Hz, 1H), 7.62 (br. s., 1H), 7.87 (d, J=15.45 Hz, 1H).
13
C-NMR, (δ in ppm,
CDCl3) 71.4, 74.3, 81.8, 116.2, 122.8, 124.4, 125.0, 129.8, 131.6, 134.7, 160.7, 192.1.
FT-IR {neat v(cm-1) }: 1650.2 (C=O), 1593.7 (C=C), 1453.5 (C=C)arom., 1229.5 (C-O),
1078.6 (C-F). The compound was found in 76% pure determined by 1H NMR.
1,1’-bis-3-(2-bromophenyl)ferrocenyl-prop-2-en-1-one
(2b).
1,1’-bis-3-(2-
bromophenyl)ferrocenyl-prop-2-en-1-one was obtained with a 37% yield as red solid
according to general procedure # 1. Purification: Silica gel column chromatography
with hexane:ethyl acetate (7:3) as eluent. Reaction time of 15 min, melting point: it
decomposes above 135 °C. 1H-NMR (δ in ppm, CDCl3, 500 MHz): 4.52 - 4.66 (m, 4H)
4.85 - 4.98 (m, 4H), 6.96 (d, J=15.45 Hz, 1H), 7.13 (br. s., 1H), 7.17 - 7.23 (m, 1H),
7.34 (br. s., 1H), 7.58 (d, J=7.57 Hz, 1H), 7.62 (d, J=7.57 Hz, 1H), 7.73 (d, J=7.88 Hz,
1H), 8.10 (d, J=15.76 Hz, 1H). Traces of ferrocenophane were present.
13
C-NMR, (δ
in ppm, CDCl3) 71.5, 74.2, 81.7, 125.4, 125.8, 127.7, 127.9, 131.1, 133.4, 140.4,
191.8. The compound was found in 63% pure determined by 1H NMR.
1,1’-bis-ferrocenyl-3-(2-pyridyl)prop-2-en-1-one
(2c).
1,1’-bis-ferrocenyl-3-(2-
pyridyl)prop-2-en-1-one was obtained with a 56% yield as vivid violet crystals
according to general procedure # 1. Recrystallization solvent is CH2Cl2 at 10 oC.
Reaction time of 2-5 min, melting point 244 °C. 1H-NMR (δ in ppm, CDCl3, 500 MHz):
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MROV Chapter 3 2014
4.61 - 4.68 (m, 2H), 5.02 - 5.09 (m, 2H), 7.27 - 7.34 (m, 1H), 7.45 - 7.52 (m, 1H), 7.59
- 7.64 (m, 1H), 7.69 - 7.80 (m, 2H), 8.66 (d, J=4.71 Hz, 1H).
13
C-NMR, (δ in ppm,
CDCl3) 71.5, 74.9, 81.7, 124.3, 125.3, 126.1, 136.9, 140.1, 150.0, 153.2, 192.4. FT-IR
{neat v(cm-1) }: 1651.1 (C=O), 1596.4 (C=C), 1566.7 (C-N), 1081.4 (C-O).
The
compound was found in 88% pure determined by 1H NMR.
1,1’-bis-ferrocenyl-3-(2-methoxyphenyl)prop-2-en-1-one (2d).
1,1’-bis-ferrocenyl-
3-(2-methoxyphenyl)prop-2-en-1-one was obtained with a 45-57% yield as pale red
solid according to general procedure # 1. Purification: the crude is washed with drops
of cold CPME and recrystallized with chloroform:hexane. Reaction time of 9-10 min,
melting point (152-155) °C.
1
H-NMR (δ in ppm, CDCl3, 500 MHz): 3.89 (br. s., 3H),
4.47 - 4.68 (m, 2H), 4.94 (br. s., 2H), 6.75 - 7.02 (m, 3H), 7.33 (br. s., 1H), 7.60 (br.
s.,1H), 8.11 (br. s., 1H).
13
C-NMR, (δ in ppm, CDCl3) 55.4, 71.3, 74.2, 82.1, 111.2,
120.7, 123.4, 123.9, 129.2, 131.4, 137.4, 158.8, 192.8. FT-IR {neat v(cm-1)}: 1650.3
(C=O), 1587.6 (C=C), 1488.8 (C=C)arom., 1460.4, 1379.8 (-CH3), 1242.6 (C-O-C),
1028.4 (C-O). The compound was found in 90% pure determined by 1H NMR.
1,1’-bis-ferrocenyl-3-(4-methoxyphenyl)prop-2-en-1-one (2h).
1,1’-bis-ferrocenyl-
3-(4-methoxyphenyl)prop-2-en-1-one was obtained with a 17% yield as orange
crystals according to general procedure # 1. The crude solid is washed with drops of
cold CPME to remove the starting materials. The compound was recrystallized with
methyl ethyl ether. The yellow and red solids were carefully separated and rerecrystallized. Both compounds were analyzed and the X-ray and NMR confirm the
presence of both product. Reaction time of 10 min
1
H-NMR (δ in ppm, CDCl3, 500
MHz): 3.84 (s, 3H) 4.59 (s, 2H) 4.91 (s, 2H) 6.83 (d, J=8.83 Hz, 1H) 6.94 (d, J=15.45
Hz, 1H) 7.51 (d, J=8.83Hz, 2H) 7.74 (d, J=15.45 Hz, 2H).
13
C-NMR, (δ in ppm, CDCl3)
55.3, 71.4, 73.9, 82.2, 114.3, 120.2, 127.5, 130.1, 141.8, 161.5, 192.2. FT-IR {neat
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MROV Chapter 3 2014
v(cm-1) }: 1646.8 (C=O), 1586.2(C=C), 1508.7 (C=C)arom., 1236.0 (C-O-C), 1028.2 (CO), 1451.6, 1375.6 (-CH3).
4. X-Ray crystallography of two ferrocenyl chalcones from 1,1’diacetylferrocene.
Arm B
Arm A
Figure 3.8. X-ray crystal structure of 1,1’-bis-ferrocenyl-3-(2-pyridyl)prop2-en-1-one
(Fc-2c).
Figure 3.9. X-ray crystal structure of 1,1’-bis-ferrocenyl-3-(4-methoxyphenyl)prop-2en-1-one (Fc-2n). Also shown the recrystallization solvent: 2-methyl-2-butanone.
Data collection: Bruker APEX2 (Bruker, 2007); cell refinement: Bruker SAINT (Bruker,
2007); data reduction: Bruker SAINT (Bruker, 2007); program(s) used to solve
structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure:
SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008);
software used to prepare material for publication: SHELXTL (Sheldrick, 2008).
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MROV Chapter 3 2014
C. Characterization of [5]ferrocenophanes from 1,1’-diacetylferrocene
1. Nuclear Magnetic Resonance: Proton (1H) and 13Carbon (13C)
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. (X)Represent solvent impurities.
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MROV Chapter 3 2014
Figure 3.11. 13C NMR of [5]ferrocenophone-3-(2-pyridyl)-1,5-dione (3a) in CDCl3 obtained from a Bruker spectrometer at 125 MHz
(AV-500) at room temperature following the general procedure #2.
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MROV Chapter 3 2014
2. Spectroscopic data summary
3-(2-bromophenyl)-[5]ferrocenophone-1,5-dione
(3h).
3-(2-bromophenyl)-
[5]ferrocenophone-1,5-dione was obtained in a 62-78% yield as yellow solid according
to general procedure # 2.
Reaction time 60 min, melting point 222 °C.
Recrystallization solvent is methyl ethyl ketone (MeEtK).
1
H-NMR (δ in ppm, CDCl3,
500 MHz) 2.95 (br. s., 5H), 4.57 (s, 2H), 4.64 (br. s., 2H), 4.77 (t, J=10.88 Hz, 1H),
4.89 (d, J=0.95 Hz, 2H), 4.96 (br. s.,2H), 7.14 (t, J=8.04 Hz, 2H), 7.32 - 7.37 (m, 1H),
7.63 (d, J=7.88 Hz, 1H).
13
C-NMR, (δ in ppm, CDCl3) 20.6, 65.1, 71.5, 73.5, 74.3,
81.7, 127.9, 128.9, 129.1, 131.1, 132.6, 133.5, 140.4, 191.8. FT -IR {neat v(cm-1) }:
1662.0 (C=O), 1461.5 (-CH2-), 1435.0 (C=C)arom, 549.4 (C-Br).
Anal. Calc. for
C21H17BrFeO2: C, 57.70; H, 3.92. Found: C, 56.35; H, 3.79.
[5]ferrocenophone-3-(2-pyridyl)-1,5-dione (3q).
[5]ferrocenophone-3-(2-pyridyl)-
1,5-dione was obtained in a 30-80% yield as yellow solid according to general
procedure # 2. Reaction time 50 min, melting point 190 °C. Recrystallization solvent
is THF:Hexane. 1H-NMR (δ in ppm, CDCl3, 500 MHz) 2.49 (d, J=11.98 Hz, 1H), 3.10 3.21 (m, 1H), 4.35 - 4.46 (m, 1H), 4.55 - 4.63 (m, 1H), 4.88 (s, 1H), 4.98 (s, 1H), 7.19
(dd, J=7.41, 4.89 Hz, 1H), 7.40 (d, J=7.88 Hz, 1H), 7.68 (td, J=7.72, 1.58 Hz, 1H),
8.58 (d, J=3.78 Hz, 1H).
13
C-NMR, (δ in ppm, CDCl3) 44.9, 47.7, 69.0, 72.1, 73.6,
74.3, 82.0, 121.9, 122.3, 137.0, 149.2, 163.4, 198.8. FT -IR {neat v(cm-1)}: 1653.3
(C=O), 1590.5 (C=C)arom., 1549.9 (C-N), 1458.3 (-CH2-), 583.4 (CHpyr bend).
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3.3.
Discussion
The synthesis of the second family of ferrocenyl chalcones Fc-2 by the base
catalyzed Claisen-Schmidt reaction was more complex than the same reaction for the
first family Fc-1 because of the possibility of by-products or competing mechanisms.
In addition, if other parameters such as the reaction medium are added, the synthesis
and subsequent analysis becomes even more complicated.
As mentioned before, when the derivatives are synthesized using the solvent-free
approach, the main product is the expected bis-ferrocenyl chalcones. S. Toma25-26
reported “that the sensitivity of the Michael addition to the polar effects of the
substituents increases with the increase of the electron-accepting properties of a
group, activating the multiple bond (alkene). Also, the cyclization depends on the
steric factors which determine the capacity of rotation and the arrangement in the
transition state”. The free rotation capacity of the Cp rings was well established by D.
Semenow and J. Roberts in 195737a and, M. Rosenblum and R. Woodward in 195837b.
Both research groups established that the preferred conformation of the acetyl group
will be the S-shape or gauche conformation and this conformation can be affected by
steric or electronic factors.
Based on these statements some questions arise about the results obtained in this
work. Why a pattern comparing the nature of the substituents like electronegativity
and steric factor could not be found? Why by changing the reaction medium not all the
compounds exhibited the same trend for by-product formation?
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MROV Chapter 3 2014
As proposed by Winstead16 after the first condensation, the enolates can take two
routes as shown in the Figure 3.12: (a) keep the S conformation of 1,1’diacetylferrocene and attack another benzaldehyde or (b) adopt the U-conformation to
promote an attack as an intramolecular Michael addition to the alkene of the first arm
of the chalcone. However, to do this, the Cp ring has to rotate.
Figure 3.12. Possible mechanisms of attack of the enolate formed after the first
condensation.
It is clear that this rotation has to be guided by forces, either by the medium or by
the molecule itself but according to our results the electronegativity or their electrondonating or-accepting capacity of the substituent is not the main factor as established
by Toma. According to Toma the activation of the alkene by an electron-donating
substituent can acelerate the cyclation of the chalcones, but it was determined here
that no matter how ED or EW is the substituent if it is in para position, the cyclic
product is obtained.
However, the ratio of the di-chalcone formation to
ferrocenophane decreases when more benzaldehyde is added (Table 3.3) as is
established in the literature.
When the substituents are in ortho position as 2-
fluorophenyl (Fc-2a), 2-pyridyl (Fc-2c) and 2-methoxyphenyl (Fc-2d) derivatives, their
behavior can be explained by the steric factor which is more remarkable in Fc-2d.
However, the atomic radio of the bromo substituent in 2-bromophenyl derivative (Fc-
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MROV Chapter 3 2014
2b) is bigger than fluor (190 pm vs. 150 pm) hence, the steric factor influences but
cannot be used to generate a reactivity pattern.
Also, what was reported before was confirmed that if the reaction proceeds in the
alcoholic medium most of the derivatives have ferrocenophane (Table 3.4).
The
exceptions are 2-fluorophenyl (Fc-2a) and 2-methoxyphenyl (Fc-2d) which produced
the bis-ferrocenyl chalcones meanwhile the 2-pyridyl (Fc-2c) derivative produced
ferrocenophane regardless of the amount of benzaldehyde added.
The behavior of the 2-pyridyl derivative (Fc-2c) in alcoholic medium cannot be
explained using the steric factor concept because the product of its reaction should be
as the solvent-free medium, the bis-ferrocenyl chalcone.
Among the possible
explanations for the formation of the bis-ferrocenyl chalcones it is suggest a
neighboring group participation (NGP)29 or anchimeric effect of the nitrogen as is
represented in Scheme 3.7.
Scheme 3.7. Proposed mechanism for the anchimeric assistances of Nitrogen in the
2-pyridyl derivative synthesis.
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MROV Chapter 3 2014
Even thought there is sufficient information in the literature that allows us to propose
this nonclassic intermediate30-33, also an internal SN2 reaction can occur which will
produce the ferrocenophane. Therefore, it is proposed a stable transition state which
allows the rotation of the Cp ring making easier the internal attack.
In order to explain the formation of the ferrocenophane of 2-pyridyl derivative by
virtue of the transition state in the alcoholic medium, we refer to the theory proposed
in Chapter 2. As argued “the solvated enolate is less reactive because the hydrogen bonded enolate must be disrupted during the condensation”. Taking this argument as
starting point, a stable transition state is postulated in which the Michael addition is
more probable. If this transition state is possible, it can explain why the
ferrocenophane increases in the alcoholic medium than in solvent-free as it was
experimentally observed.
Figure 3.13. Proposed transition state for the ferrocenophane derivative of 2-pyridyl in
alcoholic-aqueous medium.
Although we postulated some arguments that can be used to design routes to
obtain the bis-ferrocenyl chalcones, the question of why the ferrocenophane is
produced remains unanswered.
Attempting to answer this question, a molecular
modeling of the intermediary 1’-acetyl-1-ferrocenyl-3-(#-G)prop-2-en-1-one (monocondensated intermediate) was performed, whereas G is the substituent and # is its
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position and their enolates, in alcoholic-aqueous medium using Spartan 04 and
Gaussian 03. The molecular modeling predicts the position of the acetyl group as the
intermediary, relative to the chalcone arm and calculates the HOMO and LUMO
energies (eV) of each derivative (Table 3.5). With these models it is possible to
suggest which compounds are more close to cyclization or to the condensate with a
new benzaldehyde in the alcoholic-aqueous medium.
Table 3.5. Molecular modeling information of the HOMO-LUMO energy gap for the
mono-substituted intermediate and the enolate of the alcoholic reaction obtained using
Spartan 04 and Gaussian 03.
Following the mechanism proposed by Barr et al.15 and Winsted et al.16 where an
internal Michael addition leads to the cyclization product, we looked at the distance
between the α-carbon of the ketone and the β-carbon of the α,β-unsaturated of the
chalcone (Figure 3.14) was first given. Compounds 4-BrPh, 4-OCH3Ph, 2-OCH3Ph
and 4-pyridyl had a distance that varied from 6.113 Å to 7.500 Å, while 2-pyridyl
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chalcone shows a smaller distance of 4.877 Å.
The closer distance of 2-pyridyl
chalcone can explains why the intramolecular Michael addition is favored in this
system which is in accordance with the experimental data. However, the derivative 4bromophenyl (Fc-2e) has the less favorable conformation to cycle with a distance of
7.50 Å, which not coincides with our findings. Also, the molecular modeling and the
data did not coincided because the models predicted that the acetyl of the 4methoxyderivative Fc-2h was very far from the chalcones arm and it produced a
mixture of products in both media.
The bis-ferrocenyl chalcone was produced in
higher ratio in the solvent-free medium.
2-pyridyl
4-pyridyl
2-OCH3
4-OCH3
4-Br
Figure 3.14. Distance between the acetyl group and the β-carbon of the α,βunsaturated ketone for intramolecular Michael addition on 4-BrPh, 4-OCH3Ph, 2OCH3Ph, 4-pyr and 2-pyr derivatives1.
1
Data obtained from Spartan 04 and Gaussian 03 Programs. Steps as follow: Monte Carlo,
Semi empiric computation and finally, DFT Bl3YP/6-316*. The molecular modeling analyses
were done in collaboration with Dr. Gerardo Torres from UPR-Rio Piedras.
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Although there are some coincidences found, there are not enough to predict and
explain the formation of the ferrocenophane hence, the HOMO-LUMO gap energy
differences (Table 3.5) of the mono-substituted intermediate and the enolate were
investigated.
These energy differences finally put the products in a pattern of
reactivity that matched the experimental results.
For this analysis the mono-
substituted intermediate was preferred as a pre-transition state.
It was found that the energy difference for the pre-transition state of 2-pyridyl
derivative is only 1.96 eV, compared to the other compounds where the ΔE goes from
2.33 to 3.96 eV (Figure 3.15). The pattern was maintained when the enolate was
formed. It is also, demonstrated that the ΔE of the 2-methoxyphenyl derivative is 3.96
eV and is the higher energy when the enolate is formed. It is known38-39 the greater
the ΔE between the HOMO and the LUMO within the molecule, the more difficult is
the intramolecular attack because the energy differences of the corresponding
molecular orbital.
o-OCH3
o-OCH3
Figure 3.15 Molecular modeling of the HOMO-LUMO gap energy difference of the
mono-substituted intermediates obtaining from Spartan 04 and Gaussian 03.
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An ED substituent can lower the energy gap diferences39 and the EW groups can
increases but a direct influence of the substituent on the energy gap differences
cannot be assumed because a pattern could not be established. Therefore it can only
be establish that:
a) Ortho derivatives preferred the formation of bis-ferrocenyl chalcones regardless
of the media.
b) The ferrocenophane is more likely to form in the alcoholic medium because of
the transition state stabilization.
c) The molecular modeling of the HOMO-LUMO energy gap is a helpful tool to
determine the final product and the reactivity is guided by the electrostatic
interaction within the molecule itself.
d) The solvent-free reaction proceeds efficiently at 70 °C to obtain the bisferrocenyl chalcones.
The analyses of the NMR spectroscopic data (Table 3.1A) of the bis-ferrocenyl
chalcones synthesized for this objective are in harmony with the data found in Chapter
2.
Nevertheless, the α-hydrogen of the α,β-unsaturated ketone are a little more
shielded than the same chalcones of the Fc-1 family. Also, only one C=O band in the
IR spectra which confirmed the symmetric structure of the derivatives. However, the
C=O was found and the alkene bands are at higher wavenumber than the same
substituents of the acetylferrocene family Fc-1 by 4 to 7 units. This could be a result of
the electronic effect of the crystalline structure which is more complex for these
derivatives.
In agreement with the literature14, the NMR analyses of the ferrocenophane
showed a split of the proton signals of the ferrocene moiety displaying three separate
signals, two accounting for two protons each one on the bridged Cp rings and one for
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the other four protons. Also, two triplets for Ha and Hb in the methylene groups and a
broad doublet for the methinic proton on the bridge appeared hence, an asymmetric
conformation of the molecule could be inferred.
The most interesting finding of this ferrocenyl family is the crystal structure of two
derivatives, 2-pyridyl (Fc-2c, Figure 3.8) and 4-methoxyphenyl (Fc-2n, Figure 3.9).
The X-ray structures of both compounds showed an S-shape conformation with and
both alkenes in trans-configuration. The average angles and the bond lengths of the
Cp rings (Tables 3.2A and 3.3A) are in agreement with the X-ray crystal structure of
1,1’-diacetylferrocene suggesting no-effects of the substituents in the ferrocenyl
moiety, an exception being the configuration of the Cp rings which are eclipsed and
staggered, respectively. This staggered configuration of the Cp rings can be due to
the bulky property of the methoxy group which can make sufficient disorder in the
crystal structure to rotate the Cp rings to a more stable configuration 1a. Also, this
explains why the carbonyl groups are pointed in opposite direction. These findings
are remarkable because similar structures of highly conjugated chalcones were found
in U-shape structure due to the π-bonds interaction of the sp2 system35. However, it is
known that the structure can be influenced by the temperature and solvent which is
used during the recystallization36, implying that under other conditions or in the same
solution the final structure could be either S- or U-shaped.
Finally,
the discrepancies with the theory about
the formation of
the
ferrocenophane were rounded off and new approaches, such as molecular models to
answer the questions that arise during the implementation of this project and were not
found in the literature. A greener procedure, which allowed synthesis of the products
was used via the Claisen-Schmidt solvent-free reaction. Some of the products were
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synthesized without further purification with good to moderate yields. However, it is
concluded that this project has a lot of branches that can grow and contribute to the
knowledge of this molecular system. There are still more analyses to be performed. In
the meantime, some of them are in progress, including UV-Vis spectroscopy and
cyclic voltammetry (CV) as well as the bioassays to explore them as potentially active
drugs against cancer and Alzheimer diseases are in progress.
3.4.
Conclusions
The goal of synthesizing and characterizing ferrocenyl chalcones by ClaisenSchmidt condensation was achieved. The products isolated were fully characterized
by 1H NMR,
13
C NMR, IR spectroscopy, and the effect of the substituent and media in
the bis-ferrocenyl chalcones were well established. The synthetic procedure that has
been developed allowed the synthesis of four new compounds and two new X-ray
structures.
The synthetic route developed reduced the energy requirements because long
reflux time was not required. Also, the use of the solvents in the reaction media was
eliminated and, in some cases, the equivalents of the starting materials were reduced.
Although the recrystallization and the column chromatography is not a very green
process there were the best methodology found to purify some products.
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3.5.
References
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4. Kalenda, P. Eur. Polym. J. 1995, 31, 1099-1102.
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17. Hopf, H.; Gleiter, H., Ed. Modern Cyclophane Chemistry; Wiley-VCH: Germany,
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18. Smith, S. Bridged Aromatic Compounds; Academic Press: New York, NY, 1964.
19. Buretea, M. A.; Tilley, T. D. Organometal.1997, 16, 1507-1510.
20. Rinehart, K.; Curby, R.; Gustafson, D. et al. J. Am. Chem. Soc.1962, 84, 3263–
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21. Furdick, M.; Toma, S.;Suchy, J. Chemické Zevesti 1962, 16, 449-457.
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23. Arimoto, F. S.; Haven A. C. J. Am. Chem. Soc.1955, 77, 6295-6297.
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25. Toma, S.; Gaplovsky, A.; Federic, J. Collect. Czech. Chem. Commun. 1982, 47,
1991-2003.
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27. Delavaux-Nicot, B.; Frey-Forgues, S. Eur. J. Inorg. Chem. 1999, 1821-1825.
28. Tárranga, A.; Molina, P.; López, J. L. Tetrahedron Lett. 2000, 41, 2479-2482.
29. Smith, M.; March, J. March’s Advanced Organic Chemistry; 6th Ed.: New York,
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30. Cram, D. J. J. Am. Chem. Soc. 1949, 71, 3863-3870.
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35. Lee, S-K.; Noh, Y-S.; Son, K-I.; Noh, D-Y. Inorg. Chem. Comm. 2010, 13, 1343–
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37. (a) Semenow, D.; Roberts, J. J. Am. Chem. Soc. 1957, 79, 2741-2742. (b) M.
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Appendix IV
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3.6. Appendix
A. Tendencies in NMR and FT-IR spectroscopies.
Figure 3.1A. General molecular structure of ortho-1,1’-bis-ferrocenyl chalcones.
Table 3.1A. Bis-ferrocenyl chalcones δ tendencies in 13C NMR and σ in FT-IR for
ortho- position derivatives.
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B. X-ray crystallography data
Arm A
Arm B
Figure 3.2A. Carbon labeling for the analyses of the ferrocenyl chalcones X-ray
crystal structure.
Table 3.2A. Experimental bond lengths of 2-pyridyl and 4-OCH3Ph bis-ferrocenyl
chalcones from X-ray crystallography obtained by Mercury Program.
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Table 3.3A. Experimental bond angles of 2-pyridyl and 4-OCH3Ph bis-ferrocenyl
chalcones from X-ray crystallography obtained by Mercury Program.
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