Introduction:
Tartaric acid has been an efficient and valuable bifunctional chiral auxiliary for the
synthesis of bilayers, due to the reason that all tartaric acid derivatives are inexpensive and readily
available. Optically active N-alkyl tartaric amides which are quite robust in the aqueous media can be
used to form structurally controlled amphiphiles and when aligned with the phospholipids, it acts as a
tunnel like path for transport within the bilayer. These bilayers are in turn used for the fabrication of
vesicles and membranes that has practical applications, like time controlled delivery of drug[1],gene
delivery[2], magnetic materials[3]and ultrasound diagnostic[4].
When using (2R,3R)-monooctylammonium tartrate 1 salt as a precursor for the synthesis of optically
active (2R,3R)-N-alkyl tartaric monoamide 2 under acidic or basic conditions above 100 oC often results in
the inversion, leading to the formation of (2R,3R)-N-alkyl tartaric cyclicimides 2 in major amount and
meso (2S,3R)-N-alkyl tartaric cyclicimide products 3 in minor quantities . So we were interested in
studying the mechanistic aspects responsible for the formation of meso N-alkyl tartaric cyclicimide 3.
Thus considering the presence of α-hydroxy and α-methine hydrogen in (2R,3R)-monooctylammonium
tartrate 1, must have played a vital role in altering the rate and the formation of meso (2S,3R)-N-alkyl
tartaric cyclicimide 3 and (2R,3R)-N-alkyl tartaric cyclicimides 2 of the reaction .
Results and Discussion:
During the synthesis of these optically active tartamides from their corresponding (2R,3R)monooctylammonium tartrate salt 1 was pyrolyzed at 160 oC for 16 hours, we observed the formation of
(2R,3R)-N-octylmonoamide 2 in minor amount, which then cyclises to form (2R,3R)-N-octylcyclicimide 4
as major product and meso (2S,3R)-N- octylcyclicimide 4a in minor product and accompanied with
(2R,3R)-N,N-dioctyltartamides 3 were found together as byproducts in the reaction mixture. The
structural assignments of the products were supported by the results of an independent synthesis of
tatramide derivatives. HPLC data
Scheme1. Synthesis of tartaric acid amides from (2R,3R)-monooctylammonium tartrate salt 1.
Synthesis of tatramides:
In order to ensure the presence of meso- tartramides, HPLC analysis for the
reaction mixture of tartramides had to be performed. References of the respective tartramides were
prepared separately the procedure stated above. We here report a short method for the synthesis of
(2S,3R)-N- octylcyclicimide 4a that combines the elements of this reactions. The N-Octylmaleimide was
accomplished starting from Maleimide 5 reacting with 1-Octanol by the Mitsunobu procedure reported
by Walker[5] (Scheme 2). Compound 6 was used to synthesis 4a by following the oxidation procedure
reported in the literature[6]. As shown in Scheme 2, 4a could also conventionally hydrolysed to 2a in 95%
yield. Compound 4a was also used to synthesis (2R,3S )-N,N-dioctyltartamides 3a by reacting it with nOctylamine in methanol to obtain 92% yield.
Scheme2. Synthesis of meso-tartramide derivatives
Optical-tartramide derivatives were prepared according to the reported literature procedure[7]. NAlkylation of 7 was accomplished by reacting it with 1-Iodooctane in the presence of tBuOK (Sheme 3).
Compound 8 was used to synthesis optically active tartramides .To avoid the use of excess alkylamine
and formation of N-alkylacetamide thropught the reaction with the acetoxy groups, selective deprtection
of 14 was first carried out in ethanol with acetyl chloride[8] to give (2R,3R)-N-octylcyclicimide 4.
Compound 2 was prepared by hydrolyzing 4 in 95% yield. Compound 4 was also used to synthesis
(2R,3R)-N,N-dioctyltartamides 3.
Scheme3: Synthesis of optical-tartramide derivatives
The reaction of (2R,3R)-monooctylammonium tartrate salt 1, refluxed in xylene may proceeds via the
formation of (2R,3R)-N-octylmonoamide 2 through direct amide formation, with (2R,3R)-Noctylmonoamide 2 being formed from thus the stereochemistry of the molecule remains intact , it
undergoes two simultaneous pathway starting with I) the formed (2R,3R)-N-octylmonoamide 2 cyclises
to form the (2R,3R)-N-octylcyclicimide 4. The presence of n-Octylamine in the reaction mixture may
promote inversion in one of the carbon atoms of (2R,3R)-N-octylmonoamide 2 leading to the cyclize
products (2R,3R)-N-octylcyclicimide 4 in major cncentration and the (2R,3S)-N-octylcyclicimide 4a in
minor concentration.
Scheme 4: Plausible mechanistic pathways
To validate the former idea the reaction mixture was subjected to kinetic analyses using NMR
spectroscopy. NMR spectrum was recorded for the reaction mixture that were taken fifteen minutes
once and dried before recording the NMR spectrum.
Mechanistic consideration:
Comprehensive mechanistic studies for the formation of tartamides from tartaric acids when
reacted with amines were virtually absent in the literature. In a preceding article published from our
group it has been proved that the formation of 4a may proceed via ketene intermediate[7] in tartrates.
In this paper we present a hypothetical mechanistic pathway for the formation of mesotartramides. Mechanistically the presence of all the stereoisomers in this reaction mixture may have
originated from different pathways, leading to the formation of optically active tartramides and their
corresponding meso- tartramide analogue’s. The formation of tartramides stereoisomers may have
proceeded via three plausible pathways
I) Direct amide formation
II) Carboanion intermediate
III) Ketene intermediate.
Scheme 5. Plausible mechanistic pathways for the formation of tartramides stereoisomers.
The formation of isomers in the reaction mixture (Scheme1) may be influenced by the presence of nOctylammonium salt, being in equilibrium with free n-Octylamine and the carboxylic acid group in the
tartaric acid. Thus n-Octylamine can perform its function either as a base or a nucleophile leading to the
formation of isomers in three plausible mechanistic pathways. n-Octylamine being a nucleophile attacks
the carbonyl group, ensuing the formation of the amide through direct formation of the amide with a
molecule of water (Scheme 4).
But when n-Octylamine acts as a base, it would rather abstract a α- proton and will further be
responsible for the cleavage of a water molecule from the system simultaneously, resulting in an
competitive mechanistic pathway leading to the formation of meso(4a) product through ketene
intermediate. In order to achieve α- proton abstraction, Octylamine may be oriented in close proximity
between the hydroxy and the carboxylic acid with the tartaric acid through hydrogen bonding,
positioned in Burgi-Dunitz trajectory[9]. Thus n-Octylamine abstracts α- proton with simultaneous
cleavage of water, resulting in the formation of a ketene intermediate, thus the attack of n-Octylamine
to the ketene will generate the amide group.
Formation of the ketene leads to the loss of chiral information associated with the α- carbon because
the Octylamine may attack either side of the ketene moiety, leading to the formation (R,R)4 isomer in
minor amounts when compared to the R,S (2a,3a,4a) counterparts.
In addition to the ketene intermediate, the presence of n-Octylamine as a base may also trigger the
formation of an enolate intermediate, this would arise when the abstraction of the α-hydrogen by the nOctylamine takes place, however the elimination of the water molecule may not proceed as if in the
ketene intermediate but instead of the n-Octylamine present in the system tends to act as a base
abstracting the α protons leading to the formation of enolate, which may exist in the form of
asymmetric ion pair with n-Octylammonium salt as the counter ion in Xylenes[10].
To test this theory we opted to carry out tagging studies with deuterium labeled tartaric acid which may
provide the information for the formation of 4a and the mechanistic paths through which they prevail.
Therefore the abstraction of α-hydrogen by n-Octylamine may proceeds either by ketene or enolate
intermediate will alter the hybridization of the α-carbon, consequently abstracting a proton from the
solution. The presence of ketene or enolate intermediate will lead to the exchange of deuterium with
hydrogens.
Scheme6
In order to carry out the tagging studies Duetrium incorporated tartaric acid was synthesized
using the following procedure[11] Diethyl acetylenedicarboxylate 9 was reduced to Deu-Diethyl maleate
10 and
Deu-Diethyl fumarate 11 by passing Deutrium in the presence of Lindlar ‘s catalyst at 25 oC for
eight hours. The mixtures 10 and 11 were refluxed with Iodine for two hours to form Deu-Diethyl
fumarate 11 using the procedure[11]. Deu-Diethyl fumarate 11 was cis-Dihydroxylated using the
procedure[6] with Hydrogen Peroxide in acetone, with Manganese(II) perchlorate hydrate as catalyst to
form Deu-Diethyl tartrate 12. Deu-Diethyl tartrate 12 was hydrolyzed to produce Deu-tartaric acid 13.
Synthesis of Deutrated tartaric acid.
The deuterium incorporated monooctylammonium tartrate salt 14 was pyrolyzed at 160 oC for 16 hours
in Xylenes. The reaction mixture was subjected to kinetic analysis using NMR spectroscopy at regular
time intervals. Upon dissolution of the monooctylammonium tartrate salt 14 in Xylenes the distinct
integral of the α protons of 2,3,4,4a seems to show up in the H1 NMR, due to the exchange of deuterium
with protons present in the system. The integrals of the α protons constantly increase with time, this
evidence confirms the existence of our proposed mechanism (scheme6).
Figure 2
The reaction mixture was also subjected to Electrospray Mass studies in the negative mode, prior to the
submission of the samples, all the samples were subjected to acid treatment by stirring them in 60%
methanol in water to replace the acidic deuterium with hydrogens. Then the sample were subjected
Electrospray Mass studies in the negative mode, the peak of the intact ion was found at m/z 241 and 242
confirms the presence of mono deutrated N-octylcyclicimide 16 and N-octylcyclicimide 15. In additional
to these cyclicimide(15,16), the molecular ion peaks at m/z 241 and 242 confirms the presence of N,Ndioctyltartamides 17 and Deu-N,N-dioctyltartamides 18.
The presence of deuterium substituted analogues in the reaction mixture signifies the
presence of direct Amide formation mechnastic pathway which is fast enough to take place without the
deuterium exchange with removal of one molecule of water to form the amide refrence.
Mechanistically the presence of meso (2S,3R)-N- octylcyclicimide 4a in minor amounts in
the reaction mixture might result either from an Enolate or Ketene intermediate. When taking Enolate
ion mechanistic pathway into consideration, the exchange of deuterium’s with hydrogens may not
always lead to racemization. The reaction taking place in xylenes, being a aprotic nonpolar solvent with
low dielectric constant favors the monooctylammonium tartrate salt 14 to exist in tight ion pairs. This ion
pair favors the abstraction of the α proton from the Tartaric acid by n-Octylamine, resulting in the
formation n-Octylammoniun ion which might still stays in the close proximity to the tartarate as
asymmetric ion pair 19. Since the solvation of the ion pair in xylenes is low, the deuterium might get
exchanged with hydrogen from the n-Octylammoniun ion or from the solution. Thus the retention in
configuration can be observed when the abstraction of deuterium and incorporation of hydrogen takes
place from the same face of the Asymmetric ion pair. On the contrary, when the hydrogen incorporation
takes place in the opposite face it might lead to the inversion resulting in meso-Tartaric acid 21.
As an illustration L-tartaic acid 22 was pyrolysied in the presence of 2,2,6,6-Tetramethylpiperidine
23 in xylenes for 13 hours. 2,2,6,6-Tetramethylpiperidine 23 (Pka 11.07 ) was the base of choice in this
reaction because it’s pka was almost similar to the n-Octylamine (pka- 10.65)[12]. After 13 hours a crude
sample was obtained from the reaction mixture and it was subjected to HPLC analysis using chiral
column. Thus analysis of crude sample confirmed the presence of two diastereiomeric tartaric aicd’s. By
comparison with authentic samples they were identified to be D-tartaric and L-tartaic acid. NEED to fill
HPLC data
It could therefore be concluded that deuterium exchange would be possible with
predominant retention, implying the possibility for the existence of ketene as one of the intermediate
repon
The reaction of Tartaric acid 1a with 2,2,6,6-Tetramethylpiperdine in Xylenes for 13 hours
Neighboring group participation:
The presence of product’s (2,3,4,4a) in the reaction mixture from the pyrolysis of(2R,3R)monooctylammonium tartrate salt, must have come from three mechanistic pathways (Scheme5) and is
evident from the previous experiments. Among them direct amide mechanism is predominant leading to
the formation of the products (2,3,4) as products with retained configuration. The direct amide
mechnastic pathway is predominant when compared to the other two because the α hydroxyl group
being an neighboring group to carboxyl group in the tartaric acid moiety might have assisted the
incoming n-Octylamine to form the (2R,3R)-N-octylmonoamide 2 .Thus neighboring α hydroxyl group is
said to be lending anchimeric assistance. Due to the presence of hydroxyl anchimeric assistance, it leads
to increased rate of formation of (2R,3R)-N-octylmonoamide 2.
In order to confirm the above assumption we carried out reactions with monooctylammonium maliate
salt 26. To obtain reference materials, monooctylammonium maliate salt 26 was synthesized from Malic
acid 24 by reacting it with n-Octylamine, monooctylammonium maliate salt 25 pyrolyzed at 160 oC for 16
hours in xylenes to obtain N-octylmalic cyclicimide 26. N-octylmalic cyclicimide 26 was hydrolysed to 2hydroxy-4-(octylamino)-4-oxobutanoic acid 27. N,N-dioctylmaliamides was synthesized from 26 by
adding n-Octylamine in methanol and stirring it for three hours
In order to find the effect of α
hydroxyl group in tartaric acid moiety 3-hydroxy-4-(octylamino)-4-oxobutanoic acid 31 was synthesized
starting from Malic acid 24 by protecting it with 2,2-Dimethoxypropane in the presence of p-TsOH to
synthesize 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid 30[13] . Malic acid was protected to ensure
the reaction to produce one required positional isomer 31 by reacting 30 with n-Octylamine in THF at RT
to obtain 31 in good yield.
Monooctylammonium maliate salt 1 was pyrolyzed at 160 oC for 16 hours, the reaction mixture was
subjected to kinetic analyses using NMR spectroscopy. NMR spectrum was recorded for samples which
were taken at regular intervals from the reaction mixture. From this analysis we observed the formation
of
3-hydroxy-4-(octylamino)-4-oxobutanoic acid 31 in major quantity where else 2-hydroxy-4-
(octylamino)-4-oxobutanoic acid 27 in minor amounts , both these positional isomers 27 and 31 cyclises
to form N-octylmalic cyclicimide 26 as major product and N,N-dioctylmaliamides 28 was found together
as byproducts in the reaction mixture. The structural assignments of the products were supported by the
results of an independent synthesis of maliamide derivatives.
In conclusion the α hydroxyl group in the tartaric acid moiety, may increase the electrophilic character
of the carboxylic acid group through hydrogen bond alters the rate of the reaction and Reference thus
assist the nucleophilic amine to attack the carboxylic group to form the (2R,3R)-N-octylmonoamide 2.
Does the α hydroxyl group in tartaric acid increases the rate of (2R,3R)-N-octylmonoamide 2
formation? To verify the possible Succiniamides derivatives were synthesized starting from Succinic
anhydride 32 was reacted with n-Octylamine in dixoane at 80
o
C for 30 min to obtain N-
octylmonosuccinamide 32. Refluxing N-octylmonosuccinamide 32 in Xylenes at 140 oC for thirteen hours
resulted in N- octylcyclicisuccinimide 33. N,N-dioctysuccinamides was synthesized starting from 33 by
refluxing n-Octylamine in ethanol.
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