Quantification of the nucleophilic reactivities of ethyl arylacetate anions

Article abstract of DOI:10.1002/ejoc.201300265

The kinetics of the reactions of substituted ethyl arylacetates with quinone methides and structurally related diethyl benzylidenemalonates have been studied in DMSO. The second-order rate constants (lg k₂) correlated linearly with the electrop

Full text of DOI:10.1002/ejoc.201300265

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FULL PAPER
Carbanions
F. Corral-Bautista, H. Mayr* ........... 1–8
Quantification of the Nucleophilic Reactiv-
ities of Ethyl Arylacetate Anions
Keywords: Carbanions / Kinetics / Linear
The kinetics of the reactions of the anions
of ethyl arylacetates with quinone methides
and diethyl benzylidenemalonates were in-
vestigated in DMSO solution. The re-
sulting rate constants follow the linear free-
energy relationship lgk2 = sN(N + E),
which allowed us to derive their reactivity
parameters N and sN.
free-energy relationships
dition / Substituent effects
/ Michael ad-
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F. Corral-Bautista, H. Mayr
FULL PAPER
DOI: 10.1002/ejoc.201300265
Quantification of the Nucleophilic Reactivities of Ethyl Arylacetate Anions
Francisco Corral-Bautista[a] and Herbert Mayr*[a]
Dedicated to Professor Manfred Braun on the occasion of his 65th birthday
Keywords: Carbanions / Kinetics / Linear free-energy relationships / Michael addition / Substituent effects
The kinetics of the reactions of substituted ethyl arylacetates
with quinone methides and structurally related diethyl
benzylidenemalonates have been studied in DMSO. The sec-
ond-order rate constants (lgk2) correlated linearly with the
tionship lgk2 = sN(N + E), allowing us to determine the nu-
cleophilicity parameters N and sN for these anions. The nu-
cleophilic reactivities of the carbanions vary from N = 27.5 for
the parent compound to N = 20.0 for the 4-nitro-substituted
electrophilicities E according to the linear free-energy rela- derivative.
Introduction
The anions of ethyl arylacetates are frequently used as
nucleophiles in Michael additions[1] and Claisen condensa-
tions.[2] Furthermore, they can easily be alkylated or added
to carbonyl groups, imines, or acetylenes, leading to a wide
variety of products of biological and medicinal inter-
est.[1d,3–5]
During the last decades, we have constructed a compre-
hensive nucleophilicity scale, which is based on reactions of
π-, n-, and σ-nucleophiles with benzhydrylium ions, struc-
turally related quinone methides, and diethyl benzyl-
idenemalonates.[6–11] The second-order rate constants of
these reactions have been described by Equation (1), where
E is an electrophile-specific parameter, and N and sN are
nucleophile-specific parameters.[12]
1
Scheme 1. Anions of the ethyl arylacetates 1, the H NMR chemi-
cal shifts of the signals of the corresponding benzylic protons and
λmax (in nm) of the anions in DMSO solution. [a] 1H NMR in [D6]
DMSO solution at 200 MHz. [b] Due to H/D exchange with the
solvent, δ(1a) was not observable.
Table 1. Quinone methides 2 and diethyl benzylidenemalonates 3
as reference electrophiles employed in this work.
lgk2 (20 °C) = sN(N + E)
(1)
We now report on the kinetics of the reactions of the
anions of ethyl arylacetates 1 (Scheme 1) with the reference
electrophiles 2 and 3 (Table 1) in DMSO solution, and use
these data to include the anions 1a–f in our nucleophilicity
scale.[6f] Subsequently, we determine the rate constants for
the reactions of the ethyl 4-nitrophenylacetate anion (1e)
with different types of electrophiles and compare the results
with the rate constants calculated by Equation (1).
[a] Department Chemie, Ludwig-Maximilians-Universität
München,
Butenandtstrasse 5-13 (Haus F),
81377 München, Germany
Fax: +49-89-2180-77717
E-mail: Herbert.mayr@cup.uni-muenchen.de
Homepage: http://www.cup.uni-muenchen.de/oc/mayr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300265.
[a] Electrophilicity parameters from refs.[6b,6e,13] [b] Used only for
product studies.
2
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Quantification of the Reactivities of Ethyl Arylacetate Anions
Only 14% of 5a was obtained when 1a was combined
Results and Discussion
with the benzylidenemalonate 3a in DMSO, even when
10 equiv. of 1a were employed. Combinations of 1a with
less reactive electrophiles, such as 3d, gave complex product
mixtures, from which the addition products 5 could not be
separated. The adducts 5 could be isolated as the only prod-
ucts after acidic workup, however, when the reactions where
carried out in THF (Scheme 3). While the reactions of the
unsubstituted anion 1a and the m-chloro-substituted anion
1b with 3a gave around 45% of 5a and 5b, respectively, al-
most quantitative yields of 5d and 5f were obtained from
the reactions of the less reactive anions 1d and 1f with 3a.
Methylation of the initially formed anionic Michael adducts
(5Ј and 5ЈЈ) yielded different types of products: 6a for Ar =
Ph, and 6d for Ar = 4-CN-C6H4. The HMBC spectra of
Product Studies
Solutions of the anions 1 were generated by treatment
of the esters 1-H with potassium tert-butoxide (KOtBu, ca.
1.05 equiv.) in DMSO and then combined with solutions of
2 in DMSO (with 5–10% dichloromethane as cosolvent).
After aqueous, acidic workup, the crude reaction products
4 were purified by chromatography and characterized by
NMR spectroscopy and mass spectrometry. In all cases, the
products 4 were obtained in good to excellent yields as mix-
tures of two diastereoisomers (Scheme 2).
3
both diastereoisomers of 6a show JCH couplings of the
methyl group to the two carbonyl carbon atoms of the ma-
lonate group. On the other hand, the HMBC spectra of
3
both diastereoisomers of 6d show JCH couplings from the
2
methyl group to only one carboxyl carbon atom, and JCH
couplings of the CH group to the two carboxyl carbon
atoms of the malonate group (Scheme 3). Though it is quite
likely that the formation of 6a and 6d indicates that 1a and
3a yield an adduct with a malonate anion structure (5Ј),
while 1d and 3a yield an ester-stabilized p-cyano-substituted
benzyl anion (5ЈЈ), this conclusion is not unequivocal, be-
cause we do not know the relative rates of methylation and
proton transfer.
Scheme 2. Products of the reactions of the anions of ethyl arylacet-
ates (1) with quinone methides 2 in DMSO at 20 °C. [a] Deter-
The reaction of ethyl (4-nitrophenyl)acetate (1e-H) with
the (E)-β-nitrostyrene 7a catalyzed by 10 mol-% of 1,5-di-
1
mined by H NMR spectroscopy after purification by chromatog-
raphy.
Scheme 3. Products of the reactions of the anions of ethyl arylacetates 1 with diethyl benzylidenemalonates 3 in THF at ambient tempera-
1
ture, and HMBC correlations (double-headed arrows in formula of 6). [a] Determined by H NMR spectroscopy after purification by
chromatography.
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F. Corral-Bautista, H. Mayr
FULL PAPER
Scheme 4. Reaction of 1e-H with the (E)-β-nitrostyrene 7a with catalytic amounts of DBN in dichloromethane at 20 °C. [a] Determined
1
by H NMR spectroscopy.
Scheme 5. Reaction of the anion 1e with the 1,2-diaza-1,3-diene 9a in DMSO at ambient temperature. [a] Determined by 1H NMR
spectroscopy.
Scheme 6. Reaction of the anion 1e with 11 in [D6]DMSO.
azabicyclo[4.3.0]non-5-ene (DBN) in dichloromethane gave stability, the potassium salts of the ethyl arylacetates (1a–
52% of 8 as a 1:1.1 mixture of two diastereoisomers f)-K were not isolated, but were generated by deprotonation
(Scheme 4).
of the corresponding CH acids (1a–f)-H with KOtBu (typi-
From the reaction of 1e (generated from 1e-H and cally 1.05 equiv.) in DMSO prior to the measurements. The
KOtBu) with the 1,2-diaza-1,3-diene 9a in DMSO, 10 was complete deprotonation of the CH acids was demonstrated
obtained in 87% yield as a 1:1 mixture of diastereoisomers by combining solutions of (1a–f)-H with 1.05 equiv. of
(Scheme 5).
KOtBu in DMSO. After completion of the deprotonation,
As the reactions of the anions 1 with the benzylidenema- the concentrations of the carbanions (determined by UV/
lononitrile 11 in DMSO were highly reversible, the addition Vis spectroscopy) remained constant and did not increase
products could not be isolated. However, when the CH acid even when additional 2–5 equiv. of KOtBu were sub-
1e-H was mixed with 1 equiv. of KOtBu and 1 equiv. of 11 sequently added.
in [D6]DMSO, the formation of the adduct 12 (as a mixture
of two diastereisomers) was observed by NMR spec- of the reactants, either the nucleophile or the electrophile,
troscopy (Scheme 6). depending on the corresponding absorption spectra, was
To simplify the evaluation of the kinetic experiments, one
1
Though not all H NMR signals could be assigned to used in large excess (Ͼ 10 equiv.). Thus, the concentrations
the reaction product 12, the signals of the benzylic protons of the major components remained almost constant
and carbon atoms could unequivocally be assigned. With 3J throughout the reactions, and pseudo-first-order kinetics
= 12 Hz, the vicinal coupling constant between the benzylic were obtained in all runs. The first-order rate constants kobs
doublets is of similar magnitude as in the structurally anal- were derived by least-squares fitting of the time-dependent
ogous products 4 and 5.
absorbances At of the minor component to the exponential
function At = A0exp(–kobst) + C. Second-order rate con-
stants were obtained as the slopes of plots of kobs vs. the
Kinetic Investigations
The reactions of the ethyl arylacetate anions 1a–f with concentrations of the compound used in excess (Figure 1).
the electrophiles 2, 3, 7, 9, and 11 were performed in For all reactions described in Tables 2 and 3, second-or-
DMSO solution at 20 °C and monitored by UV/Vis spec- der rate constants were derived as the slopes of the linear
troscopy at or close to the absorption maximum of one of plots of kobs vs. the concentrations of the compounds used
the reagents (see Supporting Information). Due to their low in excess.
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Quantification of the Reactivities of Ethyl Arylacetate Anions
Figure 1. Plot of the absorbance At (521 nm) vs. time for the reaction of 1a (1.77ϫ10–5 molL–1) with 2h (1.95ϫ10–4 molL–1) in DMSO
at 20 °C. Inset: Plot of the first-order rate constants kobs vs. the concentration of 1a.
Table 3. Experimental and calculated [by Equation (1)] second-or-
der rate constants for the reactions of ethyl (4-nitrophenyl)acetate
anion (1e) with electrophiles 7, 9 and 11 in DMSO at 20 °C.
Table 2. Second-order rate constants k2 for the reactions of the
carbanions 1a–f with the reference electrophiles 2 and 3 in DMSO
at 20 °C.
[a] Electrophilicity parameters from refs.[14–16] [b] Calculated with
Equation (1) from E in this table and N and sN from Table 2.
For all investigations in DMSO solution, the CH acids
(1a–f)-H were deprotonated with KOtBu leading to anions
with potassium as counterion, (1a–f)-K. It was found that
the first-order rate constants kobs obtained in the presence
and in the absence of 18-crown-6 ether were on the same
kobs vs. concentration plots (see Supporting Information),
indicating that the nature of the counterion does not play
a role, i.e., that the determined rate constants reflect the
reactivities of the free anions.
Correlation Analysis
Plots of lgk2 for the reactions of the carbanions 1 with
the reference electrophiles 2 and 3 against the electrophilic-
ity parameters E were linear, as shown for some representa-
tive examples in Figure 2. As depicted in the Supporting
Information, all reactions studied in this work followed
analogous linear correlations, indicating that Equation (1)
is applicable to these reactions. From the slopes of these
correlations, the nucleophile-specific parameters sN were
derived, and the negative intercepts on the abscissa (lgk2 =
0) corresponded to the nucleophilicity parameters N
(Table 2).
[a] Monitored wavelength.
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F. Corral-Bautista, H. Mayr
FULL PAPER
lation between nucleophilic reactivities of 1a–e and Ham-
mett’s σp– substituent constants[17] was observed (Figure 3).
The downward curvature of the graph indicates that the
conjugative interaction between the nitro group and the
carbanionic reaction center is much stronger than in the
–
phenoxides that were employed for calibrating the σp val-
ues. Accordingly, Kiyooka et al.[18] reported that the 1H and
13C NMR chemical shifts of the anionic center of ethyl aryl-
acetates and the corresponding infrared absorption maxima
are affected more strongly by acceptor substituents in the
p-position than expected from the correlations with σ and
–
σp parameters. Obviously, the nonlinearities of the Ham-
mett correlations depicted in Figure 3 and reported by Ki-
yooka have the same origin, as Figure 4 shows a good linear
correlation between the nucleophilic reactivities of the carb-
1
anions 1b–e and their H NMR chemical shifts in DMSO
solution.
Figure 2. Correlation of the rate constants lgk2 for the reactions of
the nucleophiles 1 with the electrophiles 2 and 3 in DMSO with
their electrophilicity parameters E.
In order to examine the applicability of the N and sN
parameters thus derived to predict rate constants for reac-
tions with other classes of electrophiles, we investigated the
rate constants for the reactions of the ethyl (4-nitrophenyl)
acetate anion (1e) with the (E)-β-nitrostyrenes 7a,b, the 1,2-
diaza-1,3-dienes 9a,b, and the benzylidenemalononitrile 11
in DMSO at 20 °C by the photometric method used above.
Table 3 shows that in all cases the experimental rate con-
stants agreed within a factor of 3 with those calculated by
Equation (1), confirming the applicability of the reactivity
parameters N and sN reported in Table 2 for predicting rate
constants with other types of electrophiles.
Figure 3. Correlation of the lgk2 values for the reactions of 1a–e
with the quinone methide 2g in DMSO at 20 °C with Hammett’s
–
substituent constants σp
.
Structure–Reactivity Relationships
The narrow range of sN for all nucleophiles listed in
Table 2 (0.53 Ͻ sN Ͻ 0.71), which is illustrated by the al-
most parallel correlation lines in Figure 2, implies that the
relative reactivities of these anions depend only slightly on
the electrophilicities of the reaction partners. The reactivit-
ies towards the quinone methide 2g, for which rate con-
stants with all carbanions 1a–f were determined, therefore
reflect general structure–reactivity trends. The m-chloro-
(1b) and p-bromo-substituted (1c) ethyl phenylacetate
anions react approximately two times more slowly with the
electrophile 2g than the unsubstituted ethyl phenylacetate
anion (1a), which indicates only a little stabilization of the
negative charge by the halogen substituents. The anion of
the p-cyano-substituted ethyl arylacetate (1d), which is as
reactive as the ethyl 2-(pyridin-4-yl)acetate anion (1f), is
more than one order of magnitude less reactive than the
unsubstituted anion 1a. The influence of the p-nitro group
Figure 4. Correlation of the lgk2 values for the reactions of 1b–e
1
with the quinone methide 2g in DMSO at 20 °C vs. the H NMR
chemical shifts (from Scheme 1) of the benzylic proton of the
anions.
Scheme 7 shows how the reactivities of benzyl anions are
is tremendous: 1e is 7600 times less reactive than the unsub- affected by α-acceptor substituents (reference quinone
stituted anion 1a. methide 2g): the anion of ethyl phenylacetate has a similar
As previously reported for the reactivities of other α-ac- nucleophilicity as the anion of phenylacetonitrile. While the
ceptor-substituted benzyl anions,[11d] only a poor corre- phenylsulfonyl group reduces the nucleophilic reactivity by
6
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Quantification of the Reactivities of Ethyl Arylacetate Anions
one order of magnitude relative to ethoxycarbonyl, a ben- DMSO, indicating the important role of the intrinsic barri-
zoyl group reduces the reactivity by more than two orders ers.[20] It is obvious, however, that the α-ethoxycarbonyl-
of magnitude. Benzyl anions with an α-nitro group or an α- substituted benzyl anions are among the most nucleophilic
trifluoromethylsulfonyl group are five orders of magnitude as well as most basic carbanions of the series depicted in
less reactive.
Figure 5.
Conclusions
The rate constants for the reactions of the anions of ethyl
arylacetates with quinone methides and diethyl benzyl-
idenemalonates in DMSO followed the linear free-energy
relationship [Equation (1)], allowing us to include these
compounds in our comprehensive nucleophilicity scale and
to compare their nucleophilicities with those of other nu-
cleophiles (Figure 2). Variation of the substituents on the
arene ring from X = H to X = 4-NO2 decreased the reactiv-
ities by four orders of magnitude. Their nucleophilic reac-
tivities were comparable to those of analogously substituted
α-cyano-substituted benzyl anions, and 105 times higher
than those of the corresponding α-nitro- and α-trifluoro
methyl-substituted benzyl anions with the same substituents
at the arene ring. The agreement of the experimental and
calculated [by Equation (1)] rate constants for the reactions
of 1e with the electrophiles 7a,b, 9a,b, and 11 within a fac-
tor of three demonstrated the applicability of the N and sN
parameters in Table 2 for predicting the rates of their reac-
tions with various electrophiles. The ethyl arylacetate
anions 1a–c belong to the most reactive nucleophiles
studied so far, and therefore, they should be applicable for
deriving reactivity parameters of very weak electrophiles.
Scheme 7. Comparison of the relative second-order rate constants
for the reactions of different benzyl anions with the quinone
methide 2g in DMSO at 20 °C (refs.[11b,11d–11f,19]). The rate con-
stants for the reactions of the ethyl arylacetates with 2g were set to
unity. [a] Rate constant was calculated by Equation (1).
The Brønsted correlation in Figure 5 depicts that the nu-
cleophilic reactivities of α-acceptor-substituted carbanions
correlate only poorly with their Brønsted basicities in
Experimental Section
Reaction of the Anions 1 with the Quinone Methides 2: The anions
1 were generated by addition of the ethyl arylacetates 1-H (50–
70 mg, 1 equiv.) to a solution of KOtBu (30–40 mg, 1.05 equiv.) in
dry DMSO (5 mL). A solution of the quinone methide 2 in DMSO
(approx. 5 mL with 5–10% dichloromethane as cosolvent) was then
added. The mixture was stirred for 5 min, before 0.5% aqueous
acetic acid (ca. 50 mL) was added. The mixture was extracted with
ethyl acetate (3ϫ 20 mL), and the combined organic phases were
washed with brine (2ϫ 20 mL), dried with sodium sulfate, and the
solvent was evaporated under reduced pressure. The crude reaction
products were purified by column chromatography on silica (pent-
ane/ethyl acetate) and subsequently characterized by NMR spec-
troscopy and mass spectrometry.
Reaction of the Anions 1 with the Diethyl Benzylidenemalonates 3:
The anion 1 was generated in situ by addition of the ethyl arylacet-
ates 1-H (50–80 mg, 1 equiv.) to a solution of KOtBu (40–60 mg,
1.05 equiv.) in dry THF (10 mL). After 2 min, the diethyl benzyl-
idenemalonate 3 was added. After stirring at room temperature for
5 min, the mixture was poured into 0.5% aqueous acetic acid (ca.
50 mL). The mixture was extracted with diethyl ether (3ϫ 30 mL),
and the combined organic layers were washed with brine (2ϫ
20 mL), dried with sodium sulfate, and the solvent was evaporated
under reduced pressure. The crude reaction products were purified
by column chromatography on silica (dichloromethane/methanol)
and subsequently characterized by NMR spectroscopy and mass
spectrometry.
Figure 5. Correlation of lgk2 for the reactions of the anions of the
ethyl arylacetates 1a and 1e and other benzyl anions[11b,11d–11f,19]
with the quinone methide 2g in DMSO at 20 °C vs. the pKa val-
ues[21] of their conjugated acids.
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F. Corral-Bautista, H. Mayr
FULL PAPER
Schimmel, J. Am. Chem. Soc. 2001, 123, 9500–9512; b) R. Lu-
cius, R. Loos, H. Mayr, Angew. Chem. 2002, 114, 97–102; An-
gew. Chem. Int. Ed. 2002, 41, 91–95; c) H. Mayr, B. Kempf,
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ter, N. Hampel, T. Singer, A. R. Ofial, H. Mayr, Eur. J. Org.
Chem. 2009, 3203–3211; f) for a comprehensive listing of nu-
cleophilicity parameters N, sN and electrophilicity parameters
E, see: http://www.cup.uni-muenchen.de/oc/mayr/DBintro.html.
Reactivities of amines: a) F. Brotzel, Y. C. Chu, H. Mayr, J.
Org. Chem. 2007, 72, 3679–3688; b) T. Kanzian, T. A. Nigst,
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6385.
Kinetics: Because the reactions of colored quinone methides 2 with
colorless nucleophiles 1 or of colored anions 1 with colorless diethyl
benzylidenemalonates 3 result in colorless products (or products
with a different absorption range than the reactants), the reactions
could be monitored by UV/Vis spectroscopy. Because all reactions
were fast (τ1/2 Ͻ 10 s), the kinetics were monitored by using
stopped-flow techniques. The temperature of all solutions was kept
constant at 20.0Ϯ0.1 °C by using a circulating bath thermostat. In
all runs, the concentration of the colorless compound was at least
10 times higher than the concentration of the colored compound,
resulting in pseudo-first-order kinetics with an exponential decay
of the concentration of the minor compound. First-order rate con-
stants kobs were obtained by least-squares fitting of the absorbances
to a single-exponential At = A0 exp(–kobst) + C. The second-order
rate constants k2 were obtained as the slopes of the linear plots of
kobs against the concentration of the excess components.
[7]
[8]
[9]
Reactivities of solvents: S. Minegishi, S. Kobayashi, H. Mayr,
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Chem. Soc. 2009, 131, 704–714; b) R. Appel, N. Hartmann, H.
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Chem. 2011, 123, 7047–7052; Angew. Chem. Int. Ed. 2011, 50,
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Reactivities of carbanions: a) R. Loos, S. Kobayashi, H. Mayr,
J. Am. Chem. Soc. 2003, 125, 14126–14132; b) T. Bug, T. Le-
mek, H. Mayr, J. Org. Chem. 2004, 69, 7565–7576; c) T. B.
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Supporting Information (see footnote on the first page of this arti-
cle): UV spectra of compounds 1a–f; kobs vs. concentration plots,
lgk2 vs. E plots.
[10]
[11]
Acknowledgments
We thank the Deutsche Forschungsgemeinschaft (SFB 749) for
support of this work, Nathalie Hampel for preparation of the refer-
ence electrophiles, Professor Orazio A. Attanasi (Univ. Urbino, It-
aly) for providing electrophiles 9a and 9b, Dominik Allgäuer for
helpful discussions and Dr. A. R. Ofial for help during the prepara-
tion of this manuscript.
[12]
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Received: February 20, 2013
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