Nucleophilic reactivities of Schiff base derivatives of amino acids

Article abstract of DOI:10.1016/j.tet.2018.11.075

Treatment of α-imino esters derived from glycine esters and benzophenone or benzaldehydes with potassium tert butoxide in DMSO gave persistent solutions of carbanions at 20 °C. The kinetics of their reactions with quinone methides and benzylidene malonates (reference electrophiles) have been followed photometrically under pseudo-first order conditions. The reactions followed second-order rate laws. Since addition of 18-crown-6 ether did not affect the reaction rates, the measured rate constants correspond to the reactions of the non-paired carbanions. Plots of the second-order rate constants against the electrophilicity parameters E of the electrophiles are linear, which allowed us to derive the nucleophile-specific parameters N and s_N, according to the linear Gibbs energy relationship lg k₂(20 °C) = s_N(N + E). The Ph₂C = N- and PhCH = N- groups act as very weak electron acceptors with the consequence that Ph₂C = N-CH^–-CO₂R and PhCH = N-CH^–-CO₂R have a similar nucleophilicity as Ph-CH^–-CO₂Et, the anion of ethyl phenylacetate.

Full text of DOI:10.1016/j.tet.2018.11.075

Accepted Manuscript
Nucleophilic reactivities of Schiff base derivatives of amino acids
Daria S. Timofeeva, Armin R. Ofial, Herbert Mayr
PII:
S0040-4020(18)31465-0
https://doi.org/10.1016/j.tet.2018.11.075
TET 29986
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 August 2018
Revised Date: 29 November 2018
Accepted Date: 30 November 2018
Please cite this article as: Timofeeva DS, Ofial AR, Mayr H, Nucleophilic reactivities of Schiff base
derivatives of amino acids, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2018.11.075.
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ACCEPTED MANUSCRIPT
Nucleophilic Reactivities of Schiff Base Derivatives of Amino Acids
Daria S. Timofeeva, Armin R. Ofial, Herbert Mayr*
Graphical Abstract
lg k2(20 °C) = sN(N + E)
Ph
Ph
Ph
N
CO2Et Ph
CO2Et Ph
N
CO2Et
Ph
N
CN
N
(Nucleophilicity)
in DMSO
27
28
29
30
1

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Nucleophilic Reactivities of Schiff Base Derivatives of Amino Acids
Daria S. Timofeeva, Armin R. Ofial, Herbert Mayr*
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstraße 5-13, 81377 München (Germany)
E-mail: herbert.mayr@cup.lmu.de
Dedicated to Professor Léon Ghosez in recognition of his great contributions to chemistry
Abstract
Treatment of α-imino esters derived from glycine esters and benzophenone or benzaldehydes
with potassium tert.butoxide in DMSO gave persistent solutions of carbanions at 20 °C. The
kinetics of their reactions with quinone methides and benzylidene malonates (reference
electrophiles) have been followed photometrically under pseudo-first order conditions. The
reactions followed second-order rate laws. Since addition of 18-crown-6 ether did not affect
the reaction rates, the measured rate constants correspond to the reactions of the non-paired
carbanions. Plots of the second-order rate constants against the electrophilicity parameters E
of the electrophiles are linear, which allowed us to derive the nucleophile-specific parameters
N and sN, according to the linear Gibbs energy relationship lg k2(20°C) = sN(N + E). The
Ph2C=N- and PhCH=N- groups act as very weak electron acceptors with the consequence that
Ph2C=N-CH–-CO2R and PhCH=N-CH–-CO2R have a similar nucleophilicity as Ph-CH–-
CO2Et, the anion of ethyl phenylacetate.
Keywords: α-amino acids / carbanions / nucleophilicity / kinetics / linear free-energy
relationships / Michael addition
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1. Introduction
α-Imino esters have become frequently used building blocks for synthesizing racemic and
optically active α-amino acids and derivatives, which are of great importance in
pharmaceutical, biological and synthetic chemistry.1 The benzophenone-derived imines of
glycine alkyl esters were introduced by O’Donnell in 1978,2 and in the last 30 years these
substrates have been used for the synthesis of α-amino acids via a wide variety of synthetic
routes, including phase transfer catalyzed alkylations3-5, Michael,6-11 aldol,12,13 and Mannich14-
17 reactions (Scheme 1).
Scheme 1. Amino acids from benzophenone imines of glycine esters.
During the last decades our research group has developed comprehensive nucleophilicity and
electrophilicity scales, which afford a direct comparison of the reactivities of different classes
of compounds.18 We have shown that the rates of the reactions of π-, n- and σ-nucleophiles
with Csp2-centered electrophiles can be described by the linear Gibbs energy relationship (1),
where k2 (20 °C) [L mol-1 s-1] is a second-order rate constant, N and sN are solvent-dependent
nucleophile-specific parameters and E is an electrophile-specific parameter.19
lg k2(20°C) = sN(N + E)
(1)
This method has already been employed to determine the reactivity of various carbanions,20
including nitronate anions,20b alkoxycarbonyl-,20f cyano-,19b,20d phosphoryl-,20e and sulfonyl-
stabilized20g carbanions and revealed that pKa values of the conjugate acids do not serve as
reliable measure of relative reactivities.20b,c,d,f
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Scheme 2. UV-Vis absorption maxima and pKaH values in DMSO of Schiff base derivatives
of amino acids investigated in this work. Counterion K+. a From Ref. 21.
We now report on the kinetics of the reactions of the potassium salts of different glycine- and
alanine-derived imino esters 1a-e and imino acetonitrile 1f (Scheme 2) with the Michael
acceptors 2a-e (reference electrophiles, Table 1) in DMSO solution. The resulting second-
order rate constants will then be used to determine the nucleophilicities of the title compounds
according to Eq. (1).
Table 1. Quinone methides and benzylidene malonates as reference electrophiles employed in
this work.
b
Electrophile
Ea
λmax
–18.06 283
–17.90 521
2a
2b
–17.67 302
–17.29 486
2c
2d
–16.11 393
2e
a From Refs. 19b, 22. b In DMSO solution, given in nm.
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2. Results and Discussions
2.1. Products of the Reactions of the Carbanions 1 with Reference Electrophiles 2
In order to examine the course of the reactions studied kinetically, we have characterized the
products of representative combinations of the carbanions 1 with benzylidene malonate 2c or
quinone methide 2d.
Scheme 3. Reactions of tert-butyl imino ester 1b-H with the reference electrophiles 2c and 2d
in DMSO at 20 °C. a Determined from 1H NMR spectra of the crude product.
The benzophenone-derived tert-butyl glycine imino ester anion 1b (1.1 equiv.), which was
generated from 1b-H by treatment with KOtBu in DMSO, reacted with the reference
electrophiles 2c and 2d to afford the adducts 3bc and 3bd, respectively, as a mixture of two
diastereomers after aqueous work up (Scheme 3). The products were isolated in moderate
yields after purification by column chromatography and characterized by mass spectrometry
and 1H and 13C NMR spectroscopy. Analogous products have recently been reported by Deng
and coworkers via enantioselective copper-catalyzed additions of glycine Schiff bases to
para-quinone methides.11 The conjugate additions of glycine imino esters to arylidene
malonates catalyzed by AgOAc/ThioClick Ferrosphos complexes have been reported to give
the corresponding adducts in good yields with high enantioselectivities.10
As shown in Scheme 4, the imino acetonitrile anion 1f was obtained by deprotonation of the
corresponding CH acid with 1.05 equivalents of KOtBu. Addition to the quinone methide 2b,
followed by aqueous workup, gave the product 3fb in 82% yield as mixture of two
diastereoisomers.
Scheme 4. Reaction of imino acetonitrile 1f-H with the quinone methide 2b in DMSO at 20
°C. a Determined from the 1H NMR spectrum of the crude product.
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When 1.1 equivalents of the potassium salt of 1e-H, derived from alanine ester and
benzaldehyde, was combined with quinone methide 2d, only a small degree of conversion
was observed, probably due to the reversibility of these reactions. When this reaction was
carried out with 5 equivalents of 1e, a higher degree of conversion of 2d was observed.
However, as the corresponding adduct 3ed could not be separated from the crude reaction
mixture, it was hydrolyzed to provide 12 % of the amino ester 4ed (dr 2:3) after column
chromatography (Scheme 5).
Scheme 5. Reaction of 1e-H with the quinone methide 2d in DMSO at 20 °C.
A fair yield of 4cb was obtained when 2b was combined with 2 equivalents of 1c-H and 1
equivalent of KOtBu and the resulting imino ester 3cb was hydrolyzed with 2 M HCl
(Scheme 6).
Scheme 6. Reaction of 1c-H with the quinone methide 2b in DMSO at 20 °C.
2.2. Kinetic Investigations
The reactions of the 2-aza-allyl anions 1a-f with the quinone methides 2b,d,e and the
benzylidene malonates 2a and 2c were performed in DMSO solution at 20 °C and monitored
by UV-vis spectroscopy at or close to the absorption maxima of the electrophiles 2 (Table 1)
using stopped-flow techniques. The potassium salts (1a-f)-K were not isolated because of
their low stability but were generated in solution by deprotonation of the corresponding CH
acids (1a-f)-H with KOtBu (typically 1.05 equivalents) in DMSO directly before the kinetic
experiments. In order to simplify the evaluation of the kinetic experiments, the nucleophiles
1a-f were employed in large excess (≥ 10 equiv.) over the electrophiles 2. Therefore, the
concentrations of 1 can be considered almost constant throughout the reactions, resulting in
pseudo-first-order kinetics in all runs (Eq. 2).
–d[2]/dt = k2[1][2];
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for [1]>>[2] => –d[2]/dt = kobs[2] with kobs = k2[1]
(2)
As a consequence, monoexponential decays of the concentrations of the UV/Vis-active
electrophiles were observed. The first-order rate constants kobs [s-1] were derived by least-
squares fitting of the exponential function At = A0exp(–kobst) + C to the time-dependent
absorbances At of the electrophiles (Fig. 1). Plots of kobs against the concentrations of the
nucleophiles [1] were linear as illustrated in Fig. 1 (insert); the small negative intercepts may
be due to partial decomposition of the carbanions 1. Second-order rate constants k2 [L mol–1
s–1] (Table 2) for the reactions of carbanions 1a-f with the reference electrophiles 2a-e were
derived from the slopes of these plots.
Fig. 1. Exponential decay of the absorbance of 1a ([1a]0 = 4.52 × 10-5 mol L-1) at 425 nm
during its reaction with 2d ([2d]0 = 5.15 × 10-4 mol L-1) at 20 °C in DMSO solution. Inset:
Correlation of the rate constants kobs with [1a] in DMSO at 20 °C. The tagged data point
refers to the depicted absorption-time trace. Open circles: In the presence of 18-crown-6 ether
(1.1 equiv. with respect to 1a-K). Filled circles: Without 18-crown-6 ether.
We also investigated the effect of ion-pairing on the measured rate constants by using 18-
crown-6 ether as an additive. As depicted by the open symbols in Fig. 1, the pseudo-first-
order rate constants kobs, measured in the presence and in the absence of 18-crown-6 ether (1.1
equiv. with respect to 1a), were on the same plots of kobs versus concentration [1], indicating
that interaction of the carbanion with K+ does not play a significant role, and the rate
constants listed in Table 2 refer to the reactivities of the free carbanions 1a-f.
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Table 2. Second-order rate constants k2 for the reactions of the carbanions 1a-f with the
reference electrophiles 2a-e in DMSO at 20 °C.
N
k2 /
Carbaniona
Electrophilec
(sN)b
26.95
(0.52)
L mol-1 s-1
3.16 × 104
2.69 × 104 d
4.92 × 104
8.01 × 104
6.78 × 104 d
8.97 × 104 e
3.84 × 105 e
4.88 × 104
7.13 × 104
7.71 × 104
3.59 × 105 e
1a
2a
2b
2c
2d
2e
2b
2c
2d
2e
27.77
(0.47)
1b
≈ 29.1f
3.82 × 105
1c
2b
1d
2.79 × 105
5.55 × 105
2.22 × 105
3.97 × 105
29.02
(0.49)
30.82
(0.41)
2b
2d
2b
2d
1e
≈ 29.5f
6.65 × 105
1f
2b
a
b
Counterion K+. The nucleophilicity parameters N and sN were determined by correlation
c
d
analysis using Eq. (1); see text. Minor component in the pseudo-first order kinetics.
e
Pseudo-first order kinetics measured with 1a as a minor component. The decays of
absorbances were not strictly monoexponential; therefore, only the initial 50% of the decays
f
were used for evaluation of the pseudo-first-order rate constants kobs. For an estimated sN =
0.50.
As the 2-aza-allyl anions 1 are colored, we have also conducted kinetic experiments, where
diethyl benzylidene malonates 2a and 2c were employed in excess (≥ 10 equiv.) over the
anion 1a and monitored the exponential decays of the UV/Vis-absorbances of 1a. In these
cases second-order rate constants k2 were obtained from the slopes of the plots of kobs against
the concentrations of 2a and 2c. The resulting second-order rate constants differed by a factor
of 1.2 from those determined with an excess of carbanion, indicating the error limits of the
measured rate constants.
2.3. Correlation analysis
As shown in Fig. 2, plots of lg k2 for the reactions of the anions 1a and 1b with the reference
electrophiles 2 versus the electrophilicity parameters E of 2 are linear. The slopes of these
correlations equal the nucleophile-specific parameters sN, and the negative intercepts on the
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abscissa (lg k2 = 0) correspond to the nucleophilicity parameters N, which are listed in Table
2.
Fig. 2. Correlations of lg k2 for the reactions of the carbanions 1 with reference electrophiles
2a–e at 20 °C in DMSO with their electrophilicity parameters E.
Since similar slopes sN have also been found for the 2-point correlations for 1e and 1d (0.42
and 0.52, Table 2), one can conclude that the relative reactivities of these carbanions depend
only slightly on the electrophilicity of the reaction partners. The relative rate constants
towards electrophile 2b, which are depicted in Fig. 3, can, therefore, be considered to be
representative for the relative reactivities.
Fig. 3 shows that the nature of the ester group (tert-butyl or ethyl) has no effect on the
reactivity of the benzophenone derived Schiff bases 1a,b. Removal of one phenyl group to
give the benzaldehyde derivative 1c increases nucleophilicity by a factor of 7.8, and the p-Cl
substitution in 1d reduces reactivity by a factor of 1.4. In analogy to previously reported
relative reactivities of secondary and tertiary carbanions,20a the comparison of 1c and 1e
shows that an extra methyl group at the carbanionic center has only a slight effect on
nucleophilic reactivity. The cyano-substituted carbanion 1f is 13.5 times more reactive than
the corresponding ester derivative 1a.
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Fig. 3. Relative reactivities of the nucleophiles 1a-f towards the quinone methide 2b (DMSO,
20 °C).
In previous work20a we have shown that the nucleophilic reactivities of carbanions in water as
well as in DMSO correlate only poorly with the corresponding pKaH values in these solvents.
O’Donnell and co-workers have systematically studied the pKaH values of the Schiff base
derivatives of amino acids and related compounds that were of interest for the synthesis of the
amino acids by phase-transfer alkylations.21 The Brønsted correlation in Fig. 4, which plots
the second-order rate constants for the reactions of various carbanions with quinone methide
2b against the corresponding pKaH values,21,23 is of low quality and again demonstrates the
limitation of pKa values for predicting nucleophilic reactivities. It is obvious, however, that the
2-aza-allyl anions 1 are more reactive than expected from the pKa values of the conjugate CH-
acids 1-H. We have not examined whether the positive deviations of anions 1 from the
Brønsted plots are due to lower intrinsic barriers for these reactions or due to the fact that the
rate constants refer to reactions with a carbon center whereas the pKaH values correspond to
associations with the proton.24
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Fig. 4. Brønsted correlation for the reactions of the quinone methide 2b with carbanions
derived from amino acid derivatives 1 and related carbanions in DMSO at 20 °C. pKaH from
ref 21 (for anions 1) and ref 23 (for other carbanions); second-order rate constants k2 from
Table 2 (for reactions of 2b with anions 1) and refs 20d,e,f and 25 (for reactions of 2b with
other carbanions).
3. Conclusion
The second-order rate constants of the reactions of the α-iminoesters 1a and 1b, derived from
benzophenone and glycine esters, with quinone methides and arylidene malonates 2a–e
(reference electrophiles) correlate linearly with the electrophilicity parameters E of 2, which
allowed us to calculate the susceptibilities sN (slopes in Fig. 2) and the nucleophilicities N
(negative intercepts on the abscissa in Fig. 2) of 1a,b. Since the corresponding two-point
correlations for 1d and 1e yield similar susceptibilities sN, we concluded that the relative
reactivities of the carbanions 1a-f are almost independent of the electrophilicity of their
reaction partners. The structure-reactivity relationships derived from the reactivities toward
the quinone methide 2b were, therefore, considered to be representative for the reactivities of
these carbanions. Comparison of 1a and 1c shows that the benzophenone-derived iminoester
is 8 times less reactive than the benzaldehyde-derived iminoester and that the cyano derivative
1f is 13 times more reactive than the ester derivative 1a.
In line with earlier investigations of the kinetics of the reactions of carbanions with quinone
methides and other Michael acceptors,25 the rates of the reactions of the azaallyl anions 1
were independent of the nature of the counterions, which can be explained by complete
dissociation of the ion pairs in dilute DMSO solution ([1] < 10–4 mol L–1). Because of the low
solubilities of the carbanion salts in nonpolar solvents, where ion pairing was shown to reduce
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their reactivities significantly,26 we have not been able to study kinetics of their reactions in
toluene-CHCl3 or CH2Cl2 solution, i.e., the organic solvents in which enantioselective
alkylations of 1 under phase-transfer conditions were performed.1
Since kinetics of the reactions of the quinone methide 2b with other carbanions have
previously been reported, we can also compare the nucleophilicities of the iminoesters 1 with
those of other types of carbanions. Fig. 5, which compares the influence of various α-
substituents on ethyl acetate anions, shows that the imino substituted carbanions have a
similar nucleophilicity as the anion derived from ethyl phenylacetate. Even though the relative
reactivities of the carbanions in Fig. 5 will somewhat vary with the nature of the electrophile
because of the different magnitude of sN, one can see that replacement of the imino group in
1a,c by cyano, alkoxycarbonyl, acyl, phosphoryl, and sulfonyl groups leads to a significant
reduction of nucleophilicity. One, therefore, can expect that all electrophiles known to react
with these types of carbanions will also react with the corresponding imino-substituted
carbanions 1. More precise predictions of potential electrophilic reaction partners can be
obtained by using Eq. (1), which combines the N and sN parameters determined in this work
with the electrophilicity parameters accessible through ref 19g.
Fig. 5. Comparison of second-order rate constants (lg k2) for the reactions of the quinone
methide 2b with the carbanions derived from α-imino esters 1 and related carbanions. N and
sN are given below each nucleophile (reactivities refer to DMSO as solvent). a From ref 20f. b
From ref 19b. c From ref 20e.d From ref 20g.
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Acknowledgements
We thank the Deutsche Forschungsgemeinschaft for financial support (SFB 749, project B1),
Nathalie Hampel for the preparation of the electrophiles 2a-f. D.T. is grateful to Dr. Ángel
Puente for helpful discussions.
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