Comparative study of the N-isobutyl-(2E,6Z)-dodecadienamide chemical and electrochemical syntheses

Article abstract of DOI:10.1039/b815745f

In order to show the advantages and limitations of organic electrosynthesis in the total synthesis of a natural product, one of the promising green chemistry techniques in organic chemistry, the synthesis of N-isobutyl-(2E,6Z)- dodecadienamide (3) was undertaken. Chemical and electrochemical routes that use the same intermediates were used to carry out the syntheses. Four reactions were compared from a green chemistry point of view in the synthesis of 3: (a) alcohol to aldehyde oxidation, (b) the Horner-Emmons reaction, (c) carboxylic acid amidation with triphenylphosphonium ions and (d) the Wittig reaction. All the electrolyses were carried out in non-divided cells at a constant current. The electrochemical method in the oxidation reaction of alcohols and the carboxylic acid amidation gave better yields (95% and 67%, respectively) than the corresponding chemical reactions. The Horner-Emmons reaction gave the same yields in both techniques (80-85%); however, the electrochemical method was more environmentally friendly, due to the fact that the base used was electrogenerated, avoiding corrosive and sensitive base manipulation. Finally, the electrochemical Wittig reaction was unsuccessful in the different experimental conditions attempted, and only the chemical method produced the target product. This study demonstrated that organic electrochemistry can be a reliable method for the synthesis of important intermediates, but not all electrochemical reactions can compete with the already well-established methods of organic chemistry.

Full text of DOI:10.1039/b815745f

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www.rsc.org/greenchem | Green Chemistry
Comparative study of the N-isobutyl-(2E,6Z)-dodecadienamide chemical
and electrochemical syntheses†
Agust´ın Palma, Jorge Ca´rdenas and Bernardo A. Frontana-Uribe*
Received 9th September 2008, Accepted 19th November 2008
First published as an Advance Article on the web 11th December 2008
DOI: 10.1039/b815745f
In order to show the advantages and limitations of organic electrosynthesis in the total synthesis
of a natural product, one of the promising green chemistry techniques in organic chemistry, the
synthesis of N-isobutyl-(2E,6Z)-dodecadienamide (3) was undertaken. Chemical and
electrochemical routes that use the same intermediates were used to carry out the syntheses. Four
reactions were compared from a green chemistry point of view in the synthesis of 3: (a) alcohol to
aldehyde oxidation, (b) the Horner–Emmons reaction, (c) carboxylic acid amidation with
triphenylphosphonium ions and (d) the Wittig reaction. All the electrolyses were carried out in
non-divided cells at a constant current. The electrochemical method in the oxidation reaction of
alcohols and the carboxylic acid amidation gave better yields (95% and 67%, respectively) than the
corresponding chemical reactions. The Horner–Emmons reaction gave the same yields in both
techniques (80–85%); however, the electrochemical method was more environmentally friendly,
due to the fact that the base used was electrogenerated, avoiding corrosive and sensitive base
manipulation. Finally, the electrochemical Wittig reaction was unsuccessful in the different
experimental conditions attempted, and only the chemical method produced the target product.
This study demonstrated that organic electrochemistry can be a reliable method for the synthesis
of important intermediates, but not all electrochemical reactions can compete with the already
well-established methods of organic chemistry.
Introduction
Unsaturated N-isobutylamides such as spilanthol 1 and
a-sanshoo¨l
2 are natural products found in plants of
Echinacea,1 Salmea,2 Spilanthes,3 and Asarum species4 from
the Compositae, Piperaceae, and Rutaceae families.5 These
compounds have anaesthetic,6,7 anti-inflammatory,8 potent
mosquito larvicidal,9 cannabinoid type-2 (CB2) receptor
antagonistic,10 insecticidal,3,11 and antihelmitic12 properties. Low
stability of the natural unsaturated N-isobutyl-amides has been
reported;13 therefore, derivatives were required that are better
suited to the environmental conditions. In addition, in order to
carry out further studies of the biological activity, it is necessary
to obtain these products in larger quantities than those isolated
from natural sources. N-isobutyl-(2E,6Z)-dodecadienamide 3
was chemically prepared in our laboratories several years ago.14
Our preliminary studies using the Artemia salina biological
test15 showed that this compound was more stable than natural
products 1 and 2, and 74 times more active. Compound 3 has
also been prepared by hydrogenation of natural unsaturated
N-isobutylamides and it has been applied to flavor mixtures due
to its organoleptic properties.16
Fig. 1 N-isobutyl-amides with biological activity.
Organic chemistry generally uses specific methods for the
synthesis of natural products such as enzymatic, photochemical
and organometallic catalytic processes.17 One of the methods
that has not been widely used in organic chemistry is organic
electrosynthesis, and it is rare to find a report that describes
electrochemical steps in a total synthesis.18 Synthetic organic
electrochemistry nowadays offers many electrochemical versions
for almost all types of classical chemical reactions.19 The
use of organic electrochemistry opens a non-traditional way
of synthesizing molecules19a,19b,20 and has important charac-
teristics that make it attractive for synthetic green chemistry
applications.21 In organic electrosynthesis the electron becomes
a reactant, thus, its use opens the possibility of replacing toxic
Instituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico,
Ciudad Universitaria, Coyoaca´n, 04510, DF, Mexico City, Me´xico.
E-mail: bafrontu@servidor.unam.mx; Fax: +52 55 56162203;
Tel: +52 55 56224507
† Electronic supplementary information (ESI) available: 1H, 13C spectra
of the prepared compounds. See DOI: 10.1039/b815745f
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Scheme 1 Retrosynthetic analysis of compound 3. C: chemical reaction, E: electrochemical reaction.
redox reagents, using catalytic quantities of expensive redox
mediators via electroregenerating reactions, electrogenerating
in situ stoichiometric amounts of dangerous reagents, using
ionic liquids which are the conducting media and solvents in
electrochemistry, and opens the possibility of following the
reactions by electroanalytical techniques. These features are in
agreement with some of the basic principles of green chemistry.
Therefore, in this contribution the synthetic route previously
used14 for the synthesis of compound 3 was optimized and
compared from the green chemistry point of view, using both
electrochemical (E) and chemical (C) synthetic routes. The
retrosynthetic pathway depicted in Scheme 1 was followed for
the synthesis of this compound. In this strategy, the most
important intermediates can be obtained by organic electro-
chemistry and by classical organic chemistry reactions, a fact
that allowed us to compare both methodologies. Four reactions
were evaluated during the synthesis of 3: (a) alcohol to aldehyde
oxidation, (b) the Horner–Emmons reaction, (c) carboxylic acid
amidation with triphenylphosphonium ions and (d) the Wittig
reaction.
difficult. In addition, the use of chromium salt requires a special
treatment for the residual wastewaters due to its toxicity.
Direct electrochemical oxidation of alcohols requires a very
high positive potential and the reaction is not selective.28
Therefore, an indirect electrochemical reaction allowed us to
carry out the oxidation at lower potential values, with a higher
rate of reaction and higher selectivity.29 This methodology
requires a regenerable redox catalyst (mediator) that is used to
transport electrons between the electrode and the compound to
be oxidized. The selective electrochemical oxidation of alcohols
to aldehydes was carried out by means of the electrocat-
alytic reaction with radical 2,2,6,6-tetramethyl-piperidin-1-oxyl
(TEMPO) as a redox catalyst (1% mol) by a double mediator
electrochemical reaction (Scheme 3).30,31
In this reaction the primary oxidant, a halogen, was obtained
by electrochemically oxidizing chloride or bromide ions, which
are regenerated during the reaction. When chlorine was used
(Table 1, entries 1–3), aldehyde production was very low and,
even in the presence of a mixture of bromide and chloride
ions or at higher temperatures, the yield did not substantially
increase.32 Better results were obtained when bromine was used
as the primary oxidant (Table 1, entries 4–9). At 25 ◦C, the
yield of the isolated aldehyde was lower; thus, all the other
reactions were carried out at 0 ◦C. Three TEMPO derivatives
were studied demonstrating that TEMPO and TEMPO-4-OBz
were the better mediators for the reaction. Due to the higher cost
of TEMPO-4-OBz, TEMPO was selected as the mediator in the
macroelectrolysis. When the alcohol was added to the electrolysis
cell at the beginning of the reaction, aldehyde 5a was produced
in high yields (94%). The ester (6) was observed as a secondary
product, and its quantity depended on the alcohol used. Thus,
when 4a was electrolyzed only traces of 6a were observed;
when 4b was used, 28% of ester was produced. Consequently,
it was decided to add the alcohol in three portions during the
electrolysis of 4b, observing an improvement in the production
of aldehyde 5b reaching a 95% yield (Table 1, entry 9). An
additional advantage of the electrochemical method is its self-
indicator end of reaction property; the reaction became orange
due to the presence of bromine when the alcohol was almost
totally consumed. The fact that the reaction was carried out in
a biphasic system led to easier isolation of the final products,
since they accumulated in the organic layer. Nevertheless, it is
not possible to use electron-rich aromatic rings or unsaturated
alcohols since they suffer halogenation during the oxidation.33
Results and discussion
Oxidation of alcohols (4) to aldehydes (5)
The first intermediate required in the synthesis of compound
3 is the 4-chlorobutaldehyde (5a); hexanal (5b) was used later
in the synthesis route. Both aldehydes were obtained from
the oxidation of their corresponding alcohols (4a and 4b).
Among the classical methodologies for this oxidation (PCC,22
DMSO/(COCl)2,23 Dess–Martin,24 TPAP25), the reaction with
PCC26 was chosen for the chemical comparison because nowa-
days it is frequently used.27 The reaction of PCC with alcohols 4a
and 4b gave the corresponding aldehydes in 55% and 57% yields,
respectively (Scheme 2). The work-up of this reaction requires
a high quantity of anhydrous ether and the final mixture is a
very viscous brown tar, which made isolation of the aldehydes
Scheme 2 Chemical oxidation of alcohols 4a and 4b using PCC reagent.
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Table 1 Indirect electrooxidation of alcohols 4a and 4b using the TEMPO double mediator systema
Primary oxidant
Products (%)b
Exp.
Alcohol
X-TEMPO
Temperature/◦C
NaCl/M
KBr/M
4
5
6
1
2
3
4
5
6
7
8
9
4-Chlorobutanol (4a)
X = H
0
0
25
0
25
0
0
0.85
0.85
0.85
0
0
0
0
0
0
0.0
87
80
94
6
75
100
7
13
20
6
94
10
—
93
67
95
Td
4a
X = H
0.01
0.01
1.46
1.46
1.46
1.46
1.46
1.46
Td
Td
Td
4a
X = H
4a
X = H
4a
X = H
15
—
0
28
5
4a
X = 4-Oxo
X = 4-OBz
X = H
4a
1-Hexanol (4b)
0
0
5
4bc
X = H
Td
a Carried out using 10 mmol of alcohols 4, 0.1 mmol of TEMPO (1% mol) derivatives in CH2Cl2 (50 mL) and aqueous solution (100 mL) of the
halogen salt. The pH was adjusted to 8.6 by saturation with NaHCO3. The reaction was stopped after the passage of 2.3 F mol-1 at a current density
of 70 mA cm-2 using a carbon anode (12 cm2) and a Ti cathode (12 cm2). b Determined from the reaction mixture by 1H NMR. c The alcohol was
added in three parts during the reaction. d Traces.
Scheme 3 General mechanism of the indirect electrooxidation of alcohols using the TEMPO(+)/TEMPO(∑) and Br2/Br(-) double mediator biphasic
system.
When the yields obtained for the selective oxidation of
alcohols to aldehydes are compared using the chemical (55–
57%) and the electrochemical (94–95%) methods, the latter one
is more advantageous. From an environmental and safety point
of view, the electrochemical method is superior, because the use
of toxic metals (CrVI) is avoided, catalytic quantities of mediator
are used, the bromine used in the reaction is stoichiometrically
electrogenerated and is never manipulated and, finally, hydrogen
is generated as the final product together with the aldehyde.
Practical advantages such as selective oxidation to aldehydes,
the use of distilled solvents in biphasic aqueous-organic media
instead of pure dry solvents, the easiness of separation of the
products of reaction (concentrated in the organic layer), self-
monitoring of the end of reaction and shorter reaction times
make the electrocatalytic method a truly attractive alternative.
Synthesis of the ethyl-6-chloro-2(E)-hexenoate (9) via a
Horner–Emmons reaction
The second reaction to be compared was the production of
the a,b-(E)-unsaturated ester (9) using the Horner–Emmons
reaction,34 a variant of the classical Wittig methodology,35 which
uses an aldehyde and the triethyl phosphonoacetate carbanion
(8). The chemical version was attempted with NaH, which is a
base typically used in this reaction, and the previously obtained
4-chlorobutanal (5a) (Scheme 4).36
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Scheme 4 Chemical synthesis of compound 9 using a Horner–Emmons reaction.
The chemical reaction produced a yield (81%), which is in
agreement with the data reported in literature.36 As a limitation,
during the course of the reaction the mineral oil used for the
stabilization and conservation of NaH turned very viscous,
impeding the magnetic stirring of the reaction. Because NaH
is very sensitive fresh base is always required. The corrosive
properties of this compound also impose special manipulation
precautions such as an inert atmosphere and dry solvents.
The electrochemical Horner–Emmons reaction was carried
out using the galvanostatic non-divided cell with a sacrificial
anode methodology for the electrogeneration of triethyl phos-
phonoacetate carbanion (8).37 This method does not use a strong
base, since the cathode plays the role of base when it reduces
to hydrogen the acidic protons of triethyl phosphonoacetate
(Scheme 5). The electrochemical cell filled with the electrolytic
solution (Et4NBF4, 0.03 M dissolved in DMF) was fitted with
concentric electrodes using a Pt electrode as the cathode and an
Mg rod as the anode. Aldehyde and triethyl phosphonoacetate
were added at the beginning of the electrolysis. The Mg2+ ions
produced at the anode stabilized the carbanion, a fact that
permits the reaction to be carried out at lower reduction po-
tentials decreasing the energy required for the transformation.37
Moreover, by using a non-divided cell and a sacrificial electrode,
we were able to use a lower quantity of the supporting electrolyte;
the ionic species electrogenerated during the reaction favors the
conductivity of the medium.
hexenoate 9 was obtained in 84% yield. The reaction was stere-
ospecific because the Z isomer was never detected by 1H NMR
in the reaction mixture. The chemical and electrochemical yields
were practically the same but the electrochemical methodology
is safer since it eliminates the use and manipulation of a strong,
corrosive, and sensitive base. The use of a galvanostatic non-
divided cell assures simplicity, a fact that is appreciated by
the organic chemist. Reports in the literature mention that the
Horner–Emmons reaction carried out in a divided cell38 typically
has a 60% yield; therefore, the reaction in a non-separated cell
fitted with a sacrificial anode, as used in this study, is more
efficient. When acetonitrile was used as solvent or aluminium as
the sacrificial anode, the reaction did not work efficiently.
Synthesis of the N-isobutyl-6-chloro-(2E)-hexenamide (12)
Saponification of ester 9 with LiOH/THF39 and further acid-
ification yielded 88% of carboxylic acid 10. The amidation of
carboxylic acid 10 requires its activation, which was carried out
using the acyloxytriphenylphosphonium ion 11 (PV), generated
chemically and electrochemically by oxidizing triphenylphos-
phine (PIII). In the chemical version Fro¨yen’s methodology was
used.40 The reaction consisted of oxidizing Ph3P with N-bromo-
or N-chlorosuccinimide (NBS or NCS) in the presence of the
carboxylic acid producing 11 in situ.41 Later on, the amine
was gradually added until two equivalents were reached. This
chemical synthesis of 12 gave us, after several attempts, an
optimized yield of 27% (Scheme 6). Other final products of the
reaction were: oxidant (NBS) and the corresponding reduced
product, triphenylphosphine, its oxide, and the remaining start-
ing material. This mixture is complicated to purify and requires
Aldehyde 5a was added at the beginning of the electrolysis in
order to favor its reaction with the triethyl phosphonoacetate
carbanion as soon as the latter is formed. During electrolysis,
small bubbles could be observed on the cathode surface. After
reaction work-up and column separation ethyl-6-chloro-2(E)-
Scheme 5 Proposed mechanism for the electrosynthesis of a,b-(E)-unsaturated ester 9. Pt cathode, +1e-, charge = 1 F mol-1, current density =
2 mA cm-2, 0.03 M Et4NBF4 in DMF; Mg rod as sacrificial anode in undivided cell.
Scheme 6 Chemical amidation of 10 using Fro¨yen’s methodology.
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large quantities of solvent for the column chromatography
separation.
liberated during the amidation process, maintaining a neutral
media during the process.45
The electrochemical process takes advantage of the redox
properties or the organophosphorus compounds which can be
exploited in electrosynthesis.42 Thus, phosphonium ions can be
electrogenerated directly at the anode and activate carboxylic
acids generating their derivatives in a redox-substitution reac-
tion. In this reaction, the typical behavior of triphenylphos-
phine as a nucleophile is changed to an electrophile by an
electrochemical umpolung process, which is very useful in
electrosynthetic procedures.20a Triphenylphosphine showed an
anodic peak at 1.3 V vs. Ag/AgCl43 that increased its current
value with the addition of aliquots of carboxylic acid 10
(Fig. 2). This increment in current is provoked by the fast
consumption of the cation-radical of the triphenylphosphine
by the nucleophilic attack of the carboxylic acid generating 11,
a reaction that favors the electrochemical step.44 In this way,
the possibility of producing the acyloxytriphenylphosphonium
ion 11 by oxidation of triphenylphosphine in the presence of 11
was demonstrated. Isobutylamine and carboxylic acid 10 were
electrochemically inactive in the experimental conditions used.
The macroelectrolysis was carried out in a galvanostatic non-
divided cell using platinum electrodes in CH2Cl2 using 2,6-
lutidinium perchlorate (LutClO4) as a supporting electrolyte.
At the anode the triphenylphosphine is oxidized, whereas at the
cathode, the supporting electrolyte is reduced to hydrogen and
the corresponding base (Scheme 7). This base traps the protons
After several electrolyses (Table 2), the best conditions were
32 ◦C (CH2Cl2 boils at 34 ◦C in Mexico City), low current
density values (1.31 mA cm-2), and the addition of the amine
in three portions during the electrolysis (Table 2, entry 5). In
this way, the electrochemical reaction yield (67%) was 2.5 times
the yield obtained by means of a chemical reaction. Since the
anode replaces the oxidizing agent, the separation of the reaction
mixture is easier to carry out. A minor inconvenience of the
electrochemical reaction is the use of LutClO4, which is not
commercial but can be very easily prepared and purified (see the
Experimental).
Table 2 Electrochemical amidation of 6-chloro-2(E)-hexenoic acid
(10) using as electrogenerated acyloxytriphenylphosphonium iona
Current density/
Exp. Temperature/◦C mA cm-2
Amine added
Yield (%)b
5
1
2
3
4
5
20
32
32
32
32
1.31
1.31
1.31
2.28
1.31
At the beginning
At the beginning 24
At the end
At the end
In three parts
32
37
67
a Platinum anode (13.7 cm2), platinum cathode (24.4 cm2), charge
consumed: 2.4 F mol-1 of acid (7) 1 mM, Ph3P 2 mM, iBuNH2 4 mM,
supporting electrolyte: LutClO4 (2 mM) in CH2Cl2 (35 mL). b Yield
corresponding to isolated product.
Fig. 2 Cyclic voltammetry using a Pt disk (1 mm diam.) as a working electrode, a Pt wire as an auxiliary electrode and Ag/AgCl as a reference
electrode at 50 mV s-1. (a) Supporting electrolyte, LutClO4 0.1M in CH2Cl2; (b) triphenylphosphine, 5 mM; (c) as (b) plus 6-chloro-2(E)-hexenoic
acid (10) 5 mM; (d) as (b) plus 6-chloro-2(E)-hexenoic acid (10) 10 mM.
Scheme 7 Proposed mechanism for amide electrosynthesis via an electrogenerated acyloxytriphenylphosphonium ion.
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Scheme 8 Preparation of the Wittig salt 14.
Scheme 9 Synthesis of compound 3 using a Wittig reaction.
Preparation of N-isobutyl-(2E, 6Z)-dodecadienamide (3) via a
Wittig reaction
With compound 12 in hand a Wittig reaction was attempted
to generate target compound 3. In order to perform the
reaction, the corresponding Wittig salt of compound 12 was
produced substituting the chlorine atom with an iodine atom
using the Finkelstein method.46 This generated compound 13
quantitatively (Scheme 8), and it was used without purification.
Later on, the reaction of 13 with Ph3P in benzene produced 81%
of the Wittig salt 14.
The stereoselective Wittig reaction35 of 14 with hexanal (5b),
obtained in a previous step, was the fourth reaction compared
during the synthetic route of the target compound 3. The Z
alkene is required in the final product because the biological
activity depends on the stereochemistry of this double bond.5,47
This stereochemistry is favored when the reaction mixture is
free of the salts generated during the ylide production.48 The
chemical reaction was performed using sodium amide as the
strong base in THF, generating the phosphorous ylide (15)
(Scheme 9). Efficient mixing of the reaction was needed to
generate the ylide, therefore the reaction was carried out inside
an essay tube closed with a septum and was ultrasonically stirred.
Once ylide was formed and the salts were separated, it was
reacted at -78 ◦C with the hexanal diluted in THF. After work-
up, compound 3 was obtained in a 60% yield and 13C NMR
showed a ratio Z/E 91 : 9 for the C-6 double bond.
The electrochemical Wittig reaction requires electrogenera-
tion of the corresponding ylide 15. Two different approaches
were attempted: (a) a direct electroreduction of the protons next
to the phosphonium group and (b) the use of an electrogenerated
base (EGB). The cyclic voltammetry of salt 14 demonstrated the
possibility of using the first approach (Fig. 3). Salt 14 showed
a reduction peak on Pt electrode at -1.95 V vs. Ag/AgCl in
a system containing ACN/Bu4NBr 0.1 M. This peak could
be attributed to the reduction of the protons next to the
phosphonium group. Hexanal in the same analysis media did
Fig. 3 Cyclic voltammetry of the Wittig salt 14 (6 mM) in Bu4NBr 0.1
M/ACN, WE: Pt, AE: Pt, RE: Ag/AgCl, v = 100 mV s-1.
not show any cathodic signal. When hexanal was added to the
solution containing salt 14, a slight increment in the current of 14
was observed. With this analytical background the preparative
direct reduction of 14 was carried out using the same electrolyte
in the presence of hexanal with a divided cell and a platinum
cathode. The electrochemical reaction produced a mixture of
compounds and the NMR analysis of the major components
showed products corresponding to the cleavage of the P–C
bond and Ph3P (Scheme 10).49 After the negative results of the
direct reduction, we decided to use the second approach, which
involved the electrogeneration of a base at the cathode.
Scheme 10 Cathodic behavior of salt 14 using direct electroreduction
and electrogenerated base.
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The use of electrogenerated bases has been widely discussed
in the electrosynthetic literature50 and the most common pro-
bases used in Wittig reactions were essayed in our experiments.
Azobenzene,51 trityl,52 and hexamethyldisilazane53 were used as
pro-bases using the described experimental procedures in an
electrolysis divided cell. Using one equivalent or an excess of
pro-base and one equivalent of salt 14, in all our attempts we
never observed the typical intense red color of the ylide 15 and
the starting material was recovered without change. Stronger
bases such as acetonitrilate (ACN-) can be electrogenerated,54
but they require higher reduction potential values that pro-
voke the direct reduction of 14 promoting the C–P bond
cleavage.
In this synthetic step, only the chemical Wittig reaction
was able to produce the final compound 3 in a 60% yield.
Despite the fact that cyclic voltammetry showed that salt 14
was electroreducible, the induced reaction was not useful for the
ylide synthesis and the same result was obtained when an EGB
was used.
reduced pressure. CH2Cl2 was dried with CaH2 at reflux for
3 h and distilled. Et4NBF4 was dried at night in an Alberhaldren
apparatus before use. LutClO4, was prepared by adding 70%
HClO4 (164 g) dropwise to 2,6-lutidine (110 g) at 0 ◦C. The
crystals were filtered, recrystallized from AcOEt–EtOH, dried
under reduced pressure at room temperature, and stored in a
desiccator. Prior to its use LutClO4 was dried in an Alberhadren
apparatus. Other supporting electrolytes were obtained from
commercial sources and were dried under reduced pressure at
100 ◦C in the same apparatus.
Melting points were determined on a Fisher-Johns apparatus.
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were mea-
sured with a Varian Unity (300 MHz) spectrometer. Chemical
shifts (d) are given in ppm relative to tetramethylsilane in CDCl3;
J values are given in Hz. The following abbreviations are used: s,
singlet; d, doublet; q, quartet; dd, doublet of doublets; t, triplet;
m, multiplet; bs, broad signal. MS were recorded on a JEOL
JMS-AX 505HA spectrometer by electron impact (EI). UV
spectra were recorded in a Shimadzu U-160 spectrophotometer.
Infrared spectra were recorded in film technique using a Nicolet
Magna 750 spectrophotometer. The cyclic voltammetry and
the preparative electrolysis were performed with EG & G
PAR potentiostat Model 273A. The cyclic voltammetry was
performed on a vitreous carbon disk electrode (3 mm diameter)
using an Ag/AgCl reference electrode and a platinum wire as
a counter-electrode. Platinum cylindrical gauze and titanium
plate were used as cathodes in the preparative electrolysis, while
magnesium rod, platinum cylindrical gauze and carbon plate
were used as anodes. Thin layer chromatography (TLC) was
performed on aluminium sheets precoated with silica gel (Merck
Silica gel 60 F254). Column chromatography was performed on
silica gel (Macherey-Nagel 230–400 mesh).
Conclusions
In this work the synthesis of N-isobutyl-(2E,6Z)-
dodecadienamide 3 was carried out both by a chemical and an
electrochemical methodology, comparing the different green
chemistry aspects of four reactions: (a) alcohol oxidation to
aldehydes (PCC vs. TEMPO), (b) the Horner–Emmons reaction,
(c) carboxylic acid amidation with triphenylphosphonium ions
and (d) the Wittig reaction (Scheme 11). The electrochemical
route did not work for the Wittig reaction. The overall yield
of amide 12 (the first three steps of the synthesis) is 10% by
the chemical route and 46% by the electrochemical pathway.
Until here, the electrosynthetic pathway is clearly superior to
the chemical one not only in terms of performance (yield) but
also in being more environmentally friendly. It is also important
to remark that in a total synthesis scheme, electrosynthetic
methods are complementary to currently used chemical
methods since not all the electrochemical reactions are efficient.
Thus, combining the best electrochemical/chemical reactions a
global yield of 22% can be reached, instead of a very low 5%
by the chemical route. A synthetic organic chemist can easily
carry out the electrochemical reactions used in the synthetic
route, due to the fact that they are carried out at a constant
current and in a non-divided cell. Thus, no sophisticated
equipment was required, the major obstacle perceived by
chemists when the methodology is selected. A convenient
choice of the synthetic methodology using the best chemical
or electrochemical methodologies, can improve substantially
the total synthesis yield of organic compounds, keeping a green
chemistry philosophy along the synthetic route.
Chemical oxidation of alcohols 4a and b to aldehydes
In a round bottom-flask fitted with a reflux condenser PCC
(89.6 g, 0.415 mol) and anhydrous CH2Cl2 (450 mL) were added.
The alcohol 4 (0.277 mol) dissolved in anhydrous CH2Cl2 was
slowly added. The mixture was magnetically stirred during 2.5 h
at room temperature. Later, anhydrous diethylether (500 mL)
was added to the reaction mixture. Black insoluble residue was
washed with more anhydrous diethylether. The organic solution
R
was passed through a short florisilꢀ column followed by removal
of solvent at reduced pressure. The aldehyde was purified by
distillation at reduced pressure.
4-Chlorobutyraldehyde (5a). Colorless oil, bp. 77 ◦C (38 mm
1
Hg) 16 g, 55%. IR (film, n/cm-1): 2710, CHO; 1715, CO. H
NMR: 2.10 (q, 2H, CH2CH2CH2, J = 6.9), 2.67 (td, 2H,
CH2CHO, J = 6.9, 0.9), 3.6 (t, 2H, CH2Cl, J = 6.3), 9.8 (t,
1H, CHO, J = 0.9). EI-MS m/z (rel. int. %): [M + 2]+ 92(4),
[M]+ 90(12), 55(53), 42(81), 31(100).
Experimental
General
Hexanal (5b). colorless oil, bp. 63–65 ◦C (60 mm Hg) 15.2 g,
1
Unless otherwise noted, all starting materials were obtained
from commercial suppliers and used without purification. THF
was stirred in sodium for 2 h in an ultrasonic bath and distilled.
DMF was dried over phosphorus pentoxide and distilled at
57%. IR (film, n/cm-1): 2700, CHO; 1736, CO. H NMR: 0.9
(t, 3H, CH3, J = 6.9), 1.66–1.31 (m, 6H, 3CH2), 2.42 (td, 2H,
CH2CHO, J = 7.5, 2.0), 9.77 (t, 1H, CHO, J = 2.0). EI-MS m/z
(rel. int. %): [M]+ 100(1), 77(20), 56(83), 44(100), 41(72).
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Scheme 11 Summary of the electrochemical (left) and chemical (right) routes used for the synthesis of N-isobutyl-(2E, 6Z)-dodecadienamide 3.
290 | Green Chem., 2009, 11, 283–293
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Electrooxidation of alcohols 4a and b to aldehydes
diethylether (3 ¥ 25 mL). The organic fraction was washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated
by means of a rotatory evaporator. The product was purified by
column chromatography (hexane–EtOAc, 95 : 5). The product
was obtained as colorless oil (0.45 g, 84%).
Alcohol (10 mmol) and 2,2,6,6-tetramethylpiperidine-1-oxyl
(15.6 mg, 0.1 mmol) were dissolved in CH2Cl2 (50 mL) in an
electrolysis vessel. To this solution was added aqueous NaCl or
NaBr (100 mL) saturated with NaHCO3. Into the upper layer
(aqueous) of the resulting biphasic mixture the electrodes were
immersed in a parallel disposition: a centered carbon electrode
(6 cm2) was used as anode and two titanium electrodes (6 cm2)
behaved as the cathodes. The mixture was electrolyzed under
a constant current of 70 mA cm-2 with a moderate stirring.
The electrolysis was stopped when 2.3 F mol-1 of electricity
were passed and organic phase was separated from aqueous
phase using a separation funnel. The organic layer was purified
with successive washes with 10% HCl (20 mL) containing NaI
(0.25 g), 10% sodium thiosulfate (20 mL) and brine (20 mL).
After that, the CH2Cl2 layer was dried with Na2SO4 and
concentrated under reduced pressure. The residue was analyzed
Preparation of 6-chloro-(2E)-hexenoic acid (10)
To a solution of ester 9 (2.72 g, 15.45 mmol) dissolved in THF
(20 mL) was added a solution of LiOH·H2O in water (10 mL,
0.71 g, 17 mmol). The resulting mixture was stirred at room
temperature for 22 h. THF was evaporated, and then to the
residue was added 10% NaHCO3 solution (3 mL). The aqueous
phase was washed with CH2Cl2 (2 ¥ 15 mL), acidulated with
10% HCl until pH 4 and extracted with CH2Cl2 (2 ¥ 15 mL).
The organic extracts were put together, washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated by means
of a vacuum rotatory evaporator. The residue was purified by
crystallization from◦hexane to give 10 (2.02 g, 88%) as white
crystals (mp 36–37 C). IR (KBr, n/cm-1): 2966 broad, O–H;
1
by H NMR in order to quantify the aldehyde. The product
was purified by distillation at reduced pressure in a Kugelrohr.
4-Chlorobutaldehyde (5a) 0.96 g, 94%; hexanal (5b) 0.91 g, 95%.
1697, C O; 1655, C C. UV lmax/nm (EtOH): 207.2. 1H NMR:
1.96 (q, 2H, H-5, J = 6.9), 2.42 (c, 2H, H-4 J = 6.9), 3.56 (t, 2H,
H-6, J = 6.3), 5.9 (dt, 1H, H-2, J = 15.6, 1.5), 7.06 (dt, 1H, H-3,
J = 15.6, 6.9). 13C NMR: 29.3, 30.5, 43.8, 121.8, 149.9, 171.8.
EI-MS, m/z (rel. int. %): [M + 2]+ 150 (4.5) [M]+ 148, 99 (100).
=
=
Chemical synthesis of ethyl-6-chloro-2-E-hexenoate (9)
In a dry N2 purged round flask, NaH was added (60% dispersion
in mineral oil, 0.483 g, 11.96 mmol) in dry THF (15 mL).
Triethylphosphonoacetate 7 (2.7 g, 11.96 mmol) dissolved in
dry THF (5 mL) was added dropwise at 0 ◦C. This addition was
carried out over 30 min and later the mixture was stirred for
1.5 h at the same temperature. After this time, a solution of 5a
(1.27 g, 11.96 mmol) in dry THF (5 mL) was added dropwise at
0 ◦C. The reaction mixture was allowed to slowly warm to room
temperature and was stirred for 2 h at this temperature. The
solvent was evaporated and the resulting residue was diluted with
water (20 mL) and extracted with diethyl ether (3 ¥ 20 mL). The
combined organic extracts were dried; evaporated and resulting
oil was purified by column chromatography (hexane-EtOAc
95 : 5) to give 9 as oil (2.11 g, 81%). IR (film, n/cm-1): 1720,
Chemical synthesis of N-isobutyl-6-chloro-(2E)-hexenamide (12)
To a stirred solution of triphenylphosphine (0.67 g, 2.55 mmol)
and acid 10 (0.37 g, 2.5 mmol) in anhydrous CH2Cl2 (4 mL) at
◦
0 C, was added N-bromosuccinimide (NBS, 0.5 g, 2.8 mmol)
in one portion. The mixture was stirred for 20 min letting
it slowly reach room temperature. Isobutylamine (0.52 mL,
5.25 mmol) in anhydrous CH2Cl2 (4 mL) was added dropwise.
The reaction mixture was stirred for 1 h at room temperature in
inert atmosphere (N2). Next, to the mixture was added CH2Cl2
(20 mL) and it was washed in an extraction funnel with water
(15 mL), 10% HCl (15 mL), saturated NaHCO3 (15 mL), and
finally with brine (15 mL). The organic layer was dried with
anhydrous Na2SO4 and evaporated at reduced pressure. The
crude product was purified by column chromatography (hexane–
AcOEt, 4 : 2) and crystallized from diethylether–hexane to give
12 (0.137 g, 27%) as white solid (mp 56–57 ◦C). IR (KBr, n/cm-1):
C O; 1656, C C. UV lmax/nm (e/L mol-1 cm-1) (MeOH): 209
(246). 1H NMR: 1.26 (t, 3H, CH3, J = 7.2), 1.80–1.96 (m, 2H,
CH2), 2.30–2.40 (m, 2H, allylic-CH2), 3.52 (t, 2H, CH2Cl, J =
6.4), 4.16 (q, 2H, OCH2, J = 7.2), 5.84 (d, 1H, CHCO, J = 15.6),
=
=
6.89 (dt, 1H, CH2CH CH, J = 15.6, 6.9). 13C NMR: 14.2, 29.1,
=
=
=
30.6, 43.9, 60.2, 122.4, 146.8, 166.0. EI-MS, m/z (rel. int. %):
[M + 2]+ 178 (17), [M]+ 176 (45), 150 (11), 148 (38), 131 (100),
99 (62), 67 (26), 55 (20), 41 (26), 33 (34), 29 (17).
3297, NH; 3084, H–C C; 2800–2990 C–H; 1668, CH CH; 1625,
1
CO. UV lmax/nm (EtOH): 210.4. H NMR: 0.93 (d, 6H, CH3,
J = 6.6 Hz), 1.88–1.74 (m, 1H, CH), 1.93 (q, 2H, CH2 CH2CH2,
=
J = 7.8 Hz), 2.35 (c, 2H, CH2CH CH, J = 7.2 Hz), 3.15 (t, 2H,
CH2N, J = 6.9), 3.55 (t, 2H, CH2Cl, J = 6.6 Hz), 5.58 (s, broad,
Electrochemical synthesis of ethyl-6-chloro-2-E-hexenoate (9)
=
1H, NH), 5.84 (dt, 1H, CH CHCO, J = 15.3, 1.5 Hz), 6.80 (dt,
Into a previously N2 purged (5 min) one-compartment cell,
equipped with a concentric cylindrical Pt gauze as cathode
(15 cm2) and the magnesium rod as anode (12 cm2), a so-
lution containing anhydrous DMF (30 mL), the aldehyde 5a
(0.2 mol L-1), Et4NBF4 (0.03 mol L-1) and triethyphosphonoac-
etate 7 (0.1 mol L-1) were added. The mixture was magnetically
stirred under nitrogen and electrolyzed with 1 F mol-1 of electric-
ity at constant current (2 mA cm-2), the solution was maintained
in the electrolysis cell for 0.5 h at room temperature under
inert atmosphere. Lately, saturated NH4Cl solution (50 mL) was
added to the mixture reaction and extracted repeatedly with
1H, CH–CH C, J= 15.3, 6.9 Hz). 13C NMR: 20.07, 28.5, 28.9,
=
30.85, 44.0, 46.8, 124.8, 142.3, 165.6. EI-MS, m/z (rel. int. %):
[M + 2]+ 205 (6.5), [M]+ 203 (19.3), 190 (3.3), 188 (10), 162 (4),
150 (5.6), 148 (17.1), 133 (33), 131 (100), 60 (12.1).
Electrochemical synthesis of N-isobutyl-6-chloro-(2E)-
hexenamide (12)
A solution of triphenylphosphine (0.524 g, 2 mmol), acid 10
i
(0.15 g, 1 mmol), BuNH2 (0.15 mL, 1.5 mmol, added in three
parts during the electrolysis) and LutClO4 (0.41 g, 2 mmol)
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in dry deoxygenated (N2) CH2Cl2 (35 mL) was placed in the
electrolysis cell equipped with a two concentric cylindrical
Pt gauze electrodes (15 cm2 and 10 cm2). The mixture was
electrolyzed at 32 ◦C under N2 atmosphere and at 1.31 mA cm-2
until 2.4 F mol-1 with respect to the acid 10 had passed. The
solution was washed with 10% HCl (15 mL), brine (15 mL),
10% NaHCO3 (15 mL) and finally with brine (15 mL). The
organic layer was dried with anhydrous Na2SO4 and evaporated
at reduced pressure. The crude product was purified by column
chromatography (hexane–EtOAc, 4 : 2) and crystallized from
diethylether–hexane to give 12 as a white solid (0.136 g, 67%).
diethylether were carried out. The combined organic layers
were dried over anhydrous Na2SO4, filtered and concentrated
by means of a vacuum rotatory evaporator. The residue was
purified by column chromatography (hexane–AcOEt, 4 : 1) to
give 3 as yellow oil (307 mg, 60%). IR (film, n/cm-1): 3288,
=
NH; 3082, 309, H–C C; 2850–2960, CH3, CH2, CHO; 1670,
1
=
C C; 1632, CO. UV lmax./nm: 212.5. H NMR: 0.88–0.93 (m,
9H, 3CH3), 1.4–1.6 (m, 6H, CH3CH2CH2CH2), 1.8 (m, 1H, CH,
=
J = 6.9 Hz), 2.0 (c, 2H, CH2CH2CH CH, J = 6.6 Hz), 2.1–
=
=
2.3 (m, 4H, CH CHCH2CH2CH CH), 3.1 (t, 2H,NHCH2CH2,
=
J = 6.6 Hz), 5.3–5.5 (m, 2H, CH CH, Z isomer), 5.85 (dt,
=
1H, CH CHCO, J = 15.3, 1.2 Hz), 6.09 (s, NH), 6.81 (dt, 1H,
CH2CH=CHCO, J = 15.3, 6.3 Hz). 13C NMR: 13.9, 20.0, 22.4,
25.9, 27.1, 28.4, 29.1, 31.3, 32.1, 46.8, 123.9, 127.9, 131.0, 143.5,
166.1. EI-MS, m/z (rel. int. %): 251 (32) [M]+, 179 (59), 141 (100),
69 (85), 55 (57), 41 (44). HRMS FAB+ m/z requires C16H30NO
[M - H]+ 252.2327, found 252.2324.
Synthesis of Wittig salt (14)
A mixture of anhydrous NaI (previously dried in the rotary
evaporator under house vacuum for 2 h at 80 ◦C, 32 g,
213 mmol), anhydrous acetone (250 mL) and chloro compound
12 was heated to reflux for 18 h. The reaction mixture was cooled
and the precipitate was filtered out. The solid residue was washed
with acetone and the acetone washes were put together with the
filtrate. This solution was evaporated in the rotary evaporator
under reduced pressure. The organic mixture was dissolved in
ethyl acetate and was washed with brine and sodium thiosulfate
solution (5%) to decolorize. The organic layer was dried over
anhydrous Na2SO4, filtered and concentrated by means of a
vacuum rotatory evaporator. This crude product 13 was used
without purification in the next step.
Acknowledgements
The authors acknowledge Messrs. Roc´ıo Patin˜o, He´ctor R´ıos,
Isabel Cha´vez, Javier Pe´rez, Luis Velasco, Elizabeth Huerta
´
and Mar´ıa de los Angeles Pen˜a for the analytical technical
assistance. We thank Dr Manuel Salmo´n for lending part of
the electrochemical equipment. Miss Gabriela Salcedo carried
out the English style correction. This investigation was partially
supported by a CONACYT-Me´xico research project No 57856.
A. P. thanks CONACYT for his PhD scholarship.
In a 250 mL round-bottom flask equipped with reflux
condenser was dissolved triphenylphosphine (25.7 g, 98.2 mmol)
in benzene (75 mL). Compound 13 was added to the solution
and was heated to reflux for 24 h. After this time, the reaction
was cooled down at 10 ◦C and the Wittig salt was separated
by filtration. The solid was washed with hexane and then
recrystallized from ethanol–EtOAc◦producing 14 (43.6 g, 81%
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