Determination of the electrophilicity parameters of diethyl benzylidenemalonates in dimethyl sulfoxide: Reference electrophiles for characterizing strong nucleophiles

Article abstract of DOI:10.1002/chem.200801277

The second-order rate constants of the reactions of nine substituted diethyl benzylidenemalonates 1a-i with the carbanions 2a-e have been determined spectrophotometrically in dimethyl sulfoxide (DMSO). Product studies show that the nucleophiles attack regioselectively at the electrophilic C=C double bond of the Michael acceptors to form the carbanionic adducts 4. The correlation log k(20°C) = s(N+E) allows the determination of the electrophilicity parameters E for the electrophiles 1a-i from the rate constants determined in this work and the previously published N and s parameters for the nucleophiles 2a-e. The electrophilicities E for compounds 1a-i cover a range of six units (-17.7> E >-23.8) and correlate excellently with Hammett's substituent constants σ_p. The title compounds are roughly ten orders of magnitude less reactive than analogously substituted benzylidene Meldrum's acids, their cyclic analogues. Due to their low reactivities, compounds 1a-i are suitable reference electrophiles for determining the reactivities of highly reactive nucleophiles, such as carbanions with 16

Full text of DOI:10.1002/chem.200801277

FULL PAPER
DOI: 10.1002/chem.200801277
Determination of the Electrophilicity Parameters of Diethyl
Benzylidenemalonates in Dimethyl Sulfoxide: Reference Electrophiles for
Characterizing Strong Nucleophiles
Oliver Kaumanns, Roland Lucius, and Herbert Mayr*[a]
Abstract: The second-order rate con-
stants of the reactions of nine substitut-
ed diethyl benzylidenemalonates 1a–i
with the carbanions 2a–e have been
determined spectrophotometrically in
dimethyl sulfoxide (DMSO). Product
studies show that the nucleophiles
attack regioselectively at the electro-
philic C=C double bond of the Michael
acceptors to form the carbanionic ad-
the electrophilicity parameters E for
the electrophiles 1a–i from the rate
constants determined in this work and
the previously published N and s pa-
rameters for the nucleophiles 2a–e.
The electrophilicities E for compounds
1a–i cover a range of six units (À17.7>
E>À23.8) and correlate excellently
with Hammettꢀs substituent constants
sp. The title compounds are roughly
ten orders of magnitude less reactive
than analogously substituted benzyli-
dene Meldrumꢀs acids, their cyclic ana-
logues. Due to their low reactivities,
compounds 1a–i are suitable reference
electrophiles for determining the reac-
tivities of highly reactive nucleophiles,
such as carbanions with 16<N<30.
Keywords: carbanions · electrophi-
licity · kinetics · linear free-energy
relationships · Michael addition
ducts 4. The correlation log k
A
s
ACHTREUNG
Introduction
With the set of colored reference electrophiles defined in
references [1,2,8] it has become possible to determine the
reactivity parameters N for nucleophiles up to Nꢁ22.
The characterization of more reactive nucleophiles has
been problematic until now, because the least reactive elec-
trophile parameterized had an electrophilicity parameter of
E=À17.9, that is, its reactions with nucleophiles of N>22
are very fast and cannot easily be determined.
Recently we demonstrated that Equation (1) also holds
for the reactions of carbanions with ordinary Michael ac-
ceptors, such as benzylidene malononitriles,[11] benzylidene
indandiones,[12] benzylidene barbituric acids,[13] and benzyli-
dene Meldrumꢀs acids.[14] We now report on the reactivities
of diethyl benzylidenemalonates, which are less electrophilic
than benzylidene Meldrumꢀs acids, their cyclic analogues,
and therefore may be suitable for extending the scale of ref-
erence electrophiles on the low-reactivity end.
In recent years, large efforts have been made to develop nu-
cleophilicity scales for comparing the reactivities of structur-
ally different compounds, such as alkenes and arenes,[1–3] al-
cohols and amines,[4–6] carbanions,[7,8] and organometallics[1,9]
or hydride donors.[1,10] To characterize the nucleophilicities
of these compounds, the kinetics of their reactions with
benzhydrylium ions (Ar2CH+) and structurally related qui-
none methides have been investigated and evaluated by
using the linear free energy relationship given in Equa-
tion (1), in which N and s are nucleophile-dependent para-
meters and E is an electrophile-dependent parameter.
log k20 ¼ sðN þ EÞ
ð1Þ
ꢀ
C
Oh and Lee showed that the reactions of substituted
benzyl amines with 2-benzylidene-1,3-diketones[15] and di-
ethyl benzylidenemalonates[16] are much slower than the
analogous reactions with benzylidene malononitriles,[17] ben-
zylidene Meldrumꢀs acids,[18] and benzylidene indandiones.[19]
The considerably higher CH acidity of Meldrumꢀs acid rela-
tive to those of acyclic esters, such as dimethyl malonate,
has been ascribed to the fixed E conformation of the ester
linkage in the bislactone structure of Meldrumꢀs acid.[20]
[a] Dipl.-Chem. O. Kaumanns, Dr. R. Lucius, Prof. Dr. H. Mayr
Department Chemie and Biochemie
Ludwig-Maximilians-Universität München (Germany)
Fax : (+49)89-2180-77717
E-mail: Herbert.Mayr@cup.uni-muenchen.de
Supporting information for this article contains details of the kinetic
experiments, synthetic procedures, and NMR spectra of characterized
compounds, and is available on the WWW under http://dx.doi.org/
10.1002/chem.200801277.
Chem. Eur. J. 2008, 14, 9675 – 9682
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9675

This rationalization has been supported by quantum chemi-
cal calculations by Houk and Wiberg, who showed that the
deprotonation of the E conformer of methyl acetate re-
quires approximately 20 kJmolÀ1 less energy than deproto-
nation of the Z conformer.[21]
Benzylidene malonates 1 have found synthetic applica-
tions as Michael acceptors in reactions with propargyl alkox-
ides to create a variety of heterocycles, such as highly substi-
tuted tetrahydrofurans under mild reaction conditions,[22]
and in diastereoselective oxy-Michael additions of 6-methyl
d-lactol to yield protected b-hydroxy ester derivatives.[23] Or-
ganocatalytic enantioselective additions of ketones to ben-
zylidene malonates,[24] and copper-catalyzed nucleophilic ad-
ditions of indoles with formation of enantiomerically en-
riched 3-substituted indoles have been reported.[25]
Scheme 1. Synthesis of diethyl benzylidenemalonates 1a–i by Knoevena-
gel condensation.
Benzylidene dimalonates, which have been claimed to
serve as bone affinity agents, have previously been synthe-
sized by tandem Michael additions of aryl sulfonimines with
diethyl malonate.[26]
We now report on the kinetics of the additions of carban-
ions towards electrophiles 1a–i in dimethyl sulfoxide
(DMSO) and show that the second-order rate constants of
these reactions can be described by Equation (1).
The electrophiles 1a–f are colorless compounds with ab-
sorption maxima between 277 and 316 nm, while their
amino-substituted analogues 1g–i are yellow with absorption
maxima between 383 and 407nm (Figure 1). The molar
decadic absorption coefficients e in DMSO were found to
be similar to those previously reported for some of these
compounds in dioxane.[28]
Results and Discussion
The previously reported compounds 1a–g and the novel
substrates 1h,i (Scheme 1) were prepared by Knoevenagel
condensation from diethyl malonate (2b-H) and the corre-
sponding aldehyde in boiling toluene following a modified
protocol of Zabicky.[27]
Abstract in German: Geschwindigkeitskonstanten 2. Ord-
nung für die Reaktionen von neun substituierten Benzyliden-
malonsäurediethylestern 1a–i mit den Carbanionen 2a–e in
DMSO wurden photometrisch bestimmt. Die Produktstudien
zeigen, dass die Nucleophile regioselektivdie elektrophile
Kohlenstoff–Kohlenstoff Doppelbindung der Michael-Akzep-
toren angreifen, wobei die carbanionischen Addukte 4 gebil-
det werden. Mit den in dieser Arbeit bestimmten Geschwin-
digkeitskonstanten und den bereits verçffentlichten N- und s-
Parametern der Nucleophile 2a–e ermçglicht die Korrelation
Figure 1. UV/Vis spectra of the electrophiles 1a–i in DMSO, lmax in pa-
rentheses. Molar decadic absorption coefficient e for 1a: 17200, 1b:
22500, 1c: 17300, 1d: 16500, 1e: 20700, 1 f: 25100, 1g: 32800, 1h:
33700, and 1i: 32400 LmolÀ1 cmÀ1 (for e values for 1a, 1d, 1 f, and 1g in
dioxane see ref. [28]).
To characterize the electrophilic reactivities of compounds
1a–i, the kinetics of their reactions with the carbanions 2a–e
(Table 1) were investigated.
log k
A
G
rameter E für die Elektrophile 1a–i. Die Elektrophilie E der
Verbindungen 1a–i deckt einen Bereich von sechs Grç-
ßenordnungen ab (À17.7>E>À23.8) und korreliert ausge-
zeichnet mit Hammettꢀs Substituentenkonstanten sp. Die Ti-
telverbindungen sind ca. zehn Grçßenordnungen weniger re-
aktivals analog substituierte Benzyliden-Meldrum-Säuren,
ihre cyclischen Analoga. Wegen ihrer geringen Reaktivität
sind die Verbindungen 1a–i passende Referenzelektrophile
zur Bestimmung der Reaktivitäten hoch reaktiver Nucleo-
phile, z. B. von Carbanionen mit 16<N<30.
Product studies: To confirm the course of the investigated
Michael additions (Scheme 2), the products of representa-
tive combinations of the arylidene malonates 1a–i with the
carbanions 2a–f were studied by NMR spectroscopy
(Table 2).
As depicted in Scheme 2, the nucleophilic additions of the
carbanions 2a–f to the diethyl benzylidenemalonates 1a–i
initially yield the anionic adducts 3, which may undergo a
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Chem. Eur. J. 2008, 14, 9675 – 9682

Electrophilicity of Diethyl Benzylidenemalonates
FULL PAPER
Table 1. Nucleophilicity parameters of carbanions 2a–f in DMSO.
Table 2. Characterized Michael adducts 4 and 5.
Nucleophile
N[a]
s[a]
Entry
Electrophile
Nucleophile
Product
Yield/%
1
2
3
4
5
6
7
8
1c
1d
1e
1 f
1a
1b
1b
1c
1d
1e
1 f
1a
1a
1a
2b
2b
2b
2b
2c
2c
2c
2c
2c
2c
2c
2d
2 f
2 f
5cb
5 db
5eb
5 fb
4ac
47
83
47
2a
2b
21.54
0.62
20.22
19.62
18.82
0.65
0.67
0.69
78
[a]
[a]
4bc
2c
2d
[b]
25
[a]
4cc
4dc
4ec
4 fc
5ad
4af
5af
[a]
[a]
[a]
9
10
11
12
13
14
2e
2 f
19.92
19.36
0.67
0.67
71[c]
[a]
35
[a] Adducts 4 were not isolated, but identified in the crude reaction mix-
ture by 1H and 13C NMR spectroscopy. [b] Retro-Michael adduct
(Scheme 2 bottom right, see text and Supporting Information). [c] The
yield of the isolated major diastereomer is 47%.
[a] For N and s-parameters of 2a see reference [11], for 2b–d,f see refer-
ence [8], for 2e see reference [29]
2c-H reacted in the presence of K2CO3 in a dimethoxy-
ethane/DMSO mixture to yield the retro-Michael product
shown at the bottom right of Scheme 2 (Table 2, entry 7).
The reaction of 1a with 2d and subsequent acidic workup as
described for entries 1–4 in Table 2 gave the product 5ad as
a mixture of diastereoisomers in a ratio of 2:1 in 71% yield.
The malononitrile anion 2 f reacted with electrophile 1a to
yield 4af, which was converted into 5af by acidic workup
(Table 2, entries 13 and 14). Michael additions of the nitro-
ethyl anion 2a,[13,14] and the dinitrobenzhydryl anion 2e[29] to
similar electrophiles have recently been shown to proceed
analogously. Therefore we have not identified the adducts of
2a and 2e with the benzylidenemalonates 1a–i.
Kinetic measurements: To obtain pseudo-first-order kinetics,
solutions of the electrophiles 1a–i (1.0”10À5–1.0”
10À3 molLÀ1) were mixed with more than ten equivalents of
the compounds 2a–d. (For the reactions of 1a–c with the
green dinitrobenzhydryl anion 2e the first-order rate con-
stants kobs were determined with 2e as the minor compo-
nent). The decay of the absorptions of the electrophiles was
then followed spectrophotometrically either with stopped-
flow instruments or, for reactions with half-lives of more
than ꢁ15 s, with conventional UV/Vis diode-array spec-
trometers equipped with fiber optics and a submersible
probe. From the fit of the absorbance At to the exponential
Scheme 2. Addition of the carbanions 2a–f to the benzylidenemalonates
1a–i and possible subsequent protonation, elimination, or cyclization
paths.
proton transfer with formation of the tautomeric carbanions
4. Acidic workup of 4 then yields compounds 5.
Thus, mixing the Michael acceptors 1c–f with two equiva-
lents of 2b-K+ in dry DMSO, subsequent workup with
aqueous HCl solution, and distillation gave products 5cb–
5 fb in moderate to good yields (Table 2, entries 1–4). The
NMR spectra of 5 db–5 fb (Supporting Information) agree
with those previously described in reference [26]. The reac-
tions of 1a–f with the anion of ethyl cyanoacetate 2c were
studied by NMR spectroscopy and showed the predominant
formation of anions 4ac–4 fc (Table 2, entries 5, 6, and 8–
11), in accordance with the higher acidity of ethyl cyanoace-
function At =A0exp
A
kobs were derived. Because the UV absorption maxima of
the electrophiles 1a–f are close to those of the carbanions
2a-d, the combinations of these substrates were not fol-
lowed at the absorption maxima of the electrophiles, but at
shoulders of the absorption bands of the electrophiles, at
which neither the carbanions 2 nor the resulting products
showed significant absorptions.
Figure S1 (Supporting Information) shows the develop-
ment of a weak absorption band at lmax ꢁ360 nm during the
reaction of the p-cyano-substituted benzylidenemalonate 1b
with 2c; this observation may be typical for this electrophile,
tate (pKa
A
(pKa
ACHTREUNG
the presence of a second compound, potentially the corre-
sponding anions 3. Electrophile 1b and ethyl cyanoacetate
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9677

H. Mayr et al.
Table 3. Second-order rate constants k2 for the reactions of the electro-
philes 1a–i with the nucleophiles 2a–e in DMSO at 208C.
because
a
comparable weak band (lmax ꢁ350 nm) was
formed during the reaction of 1b with 2a.
Electrophile
E[a]
Nucleophile
k2 [LmolÀ1 sÀ1
]
Similar observations were made when the p-nitro-substi-
tuted benzylidenemalonate 1a was combined with the nucle-
ophiles 2a–d. Orange products with weak absorptions at
lmax =455–470 nm were formed, and for the reaction of 1a
with the anion of diethyl malonate the rate of the formation
of the 455 nm band was found to equal the rate of the decay
of the absorption band of 1a at l=325 nm. Though the
nature of these colored side products is not clear, it is con-
ceivable that in the presence of p-NO2 or p-CN groups (i.e.,
in the reactions with 1a and 1b) the initially-formed adducts
4 undergo cyclization with formation of intramolecular Mei-
senheimer–Jackson complexes,[32] as shown for the adduct
from 2b and 1a at the bottom left of Scheme 2.
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1d
1d
1e
1e
1e
1e
1 f
1 f
1 f
1g
1g
1h
1i
À17.67
2a
2.41”102
4.29”101
2.12”101
2.24”101
6.58
2b[b]
2c
2c[c]
2d[c]
2e
1.09”101
1.45”102
2.86”101
9.77
À18.06
À18.98
2a
2b[c]
2c
2e
5.94
6.03
2e[c]
2a
3.71”101
6.81
2b[c]
2c
2.68
2.51
1.67
2c[c]
2e
Generally, plots of the first-order rate constants (kobs
)
À20.55
À21.11
2b[c]
2c
5.93”10À1
2.43”10À1
2.99
against the concentrations of the carbanions were linear
with slopes k2 and negligible intercepts (Figure 2, Table 3).
2a
2b[c]
2b[d]
2c
2.37”10À1
2.33”10À1
1.11”10À1
1.70
À21.47
À23.1
2a
2b[c]
2c
1.41”10À1
4.27”10À2
1.68”10À1
8.85”10À3
6.96”10À2
3.94”10À2
2a
2b[d]
2a
À23.4
À23.8
2a
[a] Calculated from Equation (1); see section “Correlation Analysis”.
[b] From the increase of the absorbance at l=425 nm one derives k2 =
42.6 LmolÀ1 sÀ1. [c] In the presence of [18]crown-6. [d] Reaction in the
presence of the conjugate CH acid 2b-H.
Figure 2. Determination of the second-order rate constant for the reac-
tion of 1a with 2b-K in DMSO at 208C (k2 =43.0 LmolÀ1 sÀ1).
Equilibrium constants: Although most of the Michael addi-
tions listed in Table 3 proceeded quantitatively, as indicated
by negligible end absorptions of the solutions at the absorp-
tion maxima of the benzylidenemalonates 1, several reac-
tions of the malonate anion 2b turned out to be reversible.
Thus, the p-dimethylamino-substituted benzylidenemalo-
nate 1g did not react at all when combined with the carban-
ion 2b-K+. However, in the presence of 3–5 equivalents of
the conjugate acid 2b-H (ꢁ2”10À2 molLÀ1) almost quanti-
tative conversion of 1g was achieved, and the k2 value listed
in Table 3 refers to these conditions. Similar behavior was
expected for other additions of the carbanions 2b–f to the
amino-substituted benzylidenemalonates 1g–i. However, be-
cause of the expected low reaction rates, these additions
have not been investigated.
Figure 3. Reaction of the electrophile 1e (1”10À4 molLÀ1) with the carb-
*
anion 2b without addition of 2b-H ( , kobs =0.237[ 2b] + 0.0004) and in
*
the presence of 2–6 equivalents of 2b-H ( , kobs =0.223 [2b] - 0.0001) in
DMSO at 208C.
the reverse reaction.[33] Complete consumption of 1e was
achieved when the reaction of 1e with 2b-K+ was per-
formed in the presence of the conjugate CH acid 2b-H (2–
6 equivalents). The linear plot of kobs versus [2b] obtained
under these conditions had almost the same slope (Figure 3,
lower graph) as the one obtained in the absence of 2b-H, in-
dicating that the rate-determining step is the same in both
cases, that is, the proton transfer from 2b-H to 3 (=4 for
R1, R2 =CO2Et) is a fast subsequent reaction. Analogously,
The reactions of 2b-K+ with 1e,f also proceeded incom-
pletely, as indicated by significant end absorptions of the
mixtures at the absorption maxima of the electrophiles. In
line with the assumption of a reversible Michael addition,
the linear plot of kobs versus [2b] had a positive intercept
(Figure 3, upper graph), which equals the rate constant of
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Electrophilicity of Diethyl Benzylidenemalonates
FULL PAPER
the linear plot of kobs versus [2b] for the reaction of 2b with
1 f showed a positive intercept (Supporting Information,
Table S23).
carbanion 2b (N=20.22). How can this behavior be ex-
plained?
Scheme 2 shows that DG0 for the reaction of 1 with 2 to
give 4 includes the difference in “carbanion stabilization” of
anions 2 and 4. Because pKa values for the Michael adducts
5, the conjugate acids of 4, are not available, we estimated
the influence of alkyl groups on the CH acidities of these
compounds from a comparison of the carbanions 2 with
their methyl analogues, as illustrated in Table 5.
By theory,[33] it is now possible to calculate the equilibri-
um constants K for the reactions of 2b with 1e and 1 f as
the ratio of the forward (k2, slope of kobs vs. [2b] plot) and
backward (kÀ, intercept of kobs vs. [2b] plot) rate constants
[Eq. (2)]. However, because of the uncertainty in the deter-
mination of kÀ as the intercept of such correlations, the
equilibrium constants K have been determined directly from
the absorbances of 1e and 1 f in the presence of variable
concentrations of 2b using Equation (3).
Table 5. Influence of methyl groups on the basicities of carbanions
(DMSO).
Carbanion
pKaH (R=H)
16.7[a] (2a)
pKaH (R=CH3)
K ¼ k2=kÀ
½3ꢂeq
ð2Þ
ð3Þ
16.8[a]
½1ꢂ0À½1ꢂeq
½1ꢂeq½2 bꢂeq ½1ꢂeqð½2 bꢂ0À½1ꢂ0 þ ½1ꢂeqÞ
K ¼
¼
16.4[b] (2b)
11.1[d] (2 f)
18.7[c]
12.4[d]
The equilibrium constants K derived from Equation (3),
which are listed in Table 4, can then be combined with the
rate constants k2 from Table 3 to give the values of k- listed
in the fourth line of Table 4. The values for the reverse reac-
tions derived in the two different ways differ by factors of
1.1 and 1.7, and we consider the values in the fourth line of
Table 4 to be more reliable.
[a] From reference [35]. [b] From reference [31]. [c] From reference [36].
[d] From reference [37].
Although pKaH values are not available for all methyl an-
alogues of carbanions 2a–f, the examples shown in Table 5
indicate that introduction of a methyl group leads to a par-
ticularly large decrease in carbanion stabilization in the case
of malonate 2b. This effect may account for the observation
that the Michael additions of 2b are less exergonic than the
analogous reactions of the other carbanions of Table 1.
Table 4. Equilibrium and rate constants for the reactions of carbanion
2b with the electrophiles 1e,f in DMSO at 208C.
1e
1 f
kÀ[a] [sÀ1
]
4”10À4[a]
5.3”102[b]
4.5”10À4[c]
1”10À3 [a]
2.3”102 [b]
6.0”10À4 [c]
K [LmolÀ1
]
[c]
kÀ [sÀ1
]
Correlation analysis: In Figure 4, the logarithmic second-
order rate constants (logk2) for the reactions of the carban-
ions 2a–d with the arylidene malonates 1a–i and the refer-
DG0 [kJmolÀ1
]
À15.3[d]
75.3[e]
82.8[f]
À13.3[d]
76.5[e]
83.0[f]
DG° [kJmolÀ1
DG°0 [kJmolÀ1
]
]
[a] Intercept on the Y-axis for the plot of kobs versus [2b] (as shown in
Tables S20 and S23, Supporting Information). [b] From Equation (3)
using the initial absorptions of the electrophiles 1e and 1 f and the equi-
librium absorptions after addition of carbanion 2b (see Tables S1 and S2,
Supporting Information). [c] Calculated on the basis of Equation (2) and
the second-order rate constants listed in Table 3. [d] Calculated from the
equilibrium constants K. [e] Forward reaction; from second-order rate
constants k2 in Table 3. [f] Calculated on the basis of Equation (4) and
DG0 and DG° from this table.
Substitution of DG° and DG0 for these reactions into the
Marcus equation[34]
[Eq. (4)], in which the work term has
E
been neglected, yields intrinsic barriers of DG°0 =
83 kJmolÀ1.
2
DG° ¼ DG°0 þ 0:5DG0 þ ðDG0Þ =ð16DG°0 Þ
ð4Þ
This value is considerably higher than those previously re-
ported for the additions of pyridines[4c] and tertiary alkyl
amines[5,6] to structurally related Michael acceptors.
Interestingly, the addition reactions of the carbanion 2c to
the electrophiles 1e,f proceed quantitatively, although 2c
reacts more slowly (N=19.62) than the reversibly reacting
Figure 4. Plot of log k2 for the reactions of carbanions 2a–d with electro-
philes 1a–i (open symbols) and with reference electrophiles 6a–f (filled
symbols) in DMSO versus the electrophilicity parameter E of the em-
ployed electrophiles.
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9679

H. Mayr et al.
ence electrophiles 6a–f (quinone methides) are plotted
against the corresponding electrophilicity parameters E. The
E parameters of 6a–f were taken from reference [8], and
those for 1a–i were calculated from the rate constants for
their reactions with the carbanions 2a–d (reference nucleo-
philes). For that purpose, the nonlinear solver “Whatꢀs
Best!” was used to minimize the square of the deviations
(D2) between calculated and experimental rate constants
the temptation to improve the reliability of the correlations
by the addition of correction terms. Rather, we keep the
correlation simple and unambiguous, and emphasize that
the use of Equation (1) implies errors up to factors of 10–
100, which we consider acceptable in a reactivity range of
more than thirty orders of magnitude.
Figure 6 shows that the electrophilicities of the benzylide-
nemalonates 1a–i cover a range of more than six orders of
magnitude from À17.7>E>À23.8. Hence, the title com-
pounds 1a–i are roughly ten to eleven orders of magnitude
less reactive than their cyclic analogues 10a–d. Thus, fixa-
tion of the two ester groups of 1 in a six-membered ring has
an enormous effect on the reactivity of these Michael
acceptors.
D2 =ꢀ
A
N
are given in Table 1 and the corresponding rate constants k2
are listed in Table 3, the electrophilicity parameters E for
1a–i could be obtained.
Figure 5. Correlation of log k2 versus E for the reactions of carbanion 2e
with different Michael acceptors in DMSO: structures of 1a–c in
Scheme 1; structures of 6a–e in Figure 4; structures of (7–9)-X see text;
for “jul”-substituent see 1i in Scheme 1.
Figure 5 illustrates that the rate constants of the reactions
of the dinitrobenzhydryl anion 2e with various classes of
electrophiles follow separate logk versus E correlations. The
upper correlation line for the reactions of 2e with the qui-
none methides 6a–e was used for the calculation of the N
and s parameters of 2e.[29] The benzylidenemalonates 1a–c
are on the same, somewhat lower correlation line as the Mi-
chael acceptors indandiones 7-X and the barbiturates 8-X.
Figure 6. Comparison of the electrophilicity parameters E of diethyl ben-
zylidenemalonates 1a–i with those of some reference electrophiles 6a–f
and benzylidene Meldrumꢀs acids 10a–d. For “jul”-substituent see 1i in
Scheme 1.
According to Figure 7, the electrophilicity parameters E
for the benzylidenemalonates 1a–i correlate excellently with
Hammettꢀs sp values.[38] Comparison with the corresponding
Hammett plot for benzylidene Meldrumꢀs acids shows that
the electrophilicities of the acyclic Michael acceptors 1a–i
are less affected by substituent variation than the electrophi-
licities of their cyclic analogues 10a–d. For reactions with
typical amines and carbanions (sꢁ0.65, Table 1) the slopes
given in Figure 7correspond to Hammett reaction constants
of 1ꢁ2.4 (for 1) and 1ꢁ3.5 (for 10).
As a consequence, the logk2 values for the reactions of 2e
with 1a–c, 7-X, and 8-X, which are calculated using Equa-
tion (1), are 2–4 times higher than the experimental values.
The benzylidene malononitriles 9-X deviate even more, and
the observed rate constants are approximately one order of
magnitude smaller than those calculated by Equation (1).
Though a similar split-up of the correlation lines for differ-
ent classes of electrophiles was reported earlier,[14] we resist
The fact that compound 1i with the “julolidyl” substituent
(for definition see Scheme 1) fits nicely on this correlation
line confirms the validity of the Hammett substituent con-
stant sp
ACHTREUNG
related experiments.[14] Analogously, sp
AHCTREUNG
9680
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Chem. Eur. J. 2008, 14, 9675 – 9682

Electrophilicity of Diethyl Benzylidenemalonates
FULL PAPER
(100.6 MHz, [D6]DMSO): d=13.7(q), 14.0 (q), 21.1 (t), 27.0 (t), 38.2 (q;
NCH3), 50.2 (t; NCH2), 60.5 (t; OCH2), 60.9 (t; OCH2), 110.0 (d), 118.1
(s), 118.5 (s), 121.7(s), 130.1 (d), 130.5 (d), 141.7(d; =CH), 148.6 (s),
164.2 (s), 167.1 ppm (s); HR-MS: m/z calcd for C18H23O4N: 317.1627;
found: 317.1610; elemental analysis calcd (%) for C18H23O4N: C 68.12, H
7.30, N 4.41; found: C 67.96, H 7.28, N 4.38.
Diethyl 2-{(1,2,3,5,6,7-hexahydropyrido
ACHTREUNG
malonate (1i): A mixture of 1,2,3,5,6,7-hexahydropyrido
AHCTREUNG
line-9-carbaldehyde (1.00 g, 4.98 mmol), diethyl malonate (0.79 g,
4.93 mmol), and piperidine (350 mL) was stirred in toluene under reflux
until TLC indicated full conversion (3 h). After washing the crude reac-
tion mixture as described in the general procedure (Supporting Informa-
tion), the resulting oily residue was crystallized from EtOAc/isohexane
(1:3). The solid was filtered and washed with isohexane. Yield: 1.1 g,
65%; yellow solid; m.p. 83.2–83.48C; 1H NMR (600 MHz, CDCl3,): d=
1.30 (t, J=6.2 Hz, 3H; CH3), 1.35 (t, J=6.2 Hz, 3H; CH3), 1.93 (quint,
J=6.2 Hz, 2”2H; CH2), 2.69 (t, 3J=5.6 Hz, 2”2H; CH2), 3.23 (t, J=
5.6 Hz, 2”2H; NCH2), 4.25 (q, J=7.2 Hz, 2H; OCH2), 4.35 (q, J=
7.2 Hz, 2H; OCH2), 6.91 (s, 2H; ArH), 7.52 ppm (s, 1H, 1H; C=CH);
13C NMR (150 MHz, CDCl3): d=14.0 (q), 14.2 (q), 21.4 (t), 27.6 (t), 49.9
(t; NCH2), 60.9 (t; OCH2), 61.2 (t; OCH2), 118.5 (s), 119.0 (s), 120.6 (s),
129.7(d), 143.0 (d, =CH), 145.2 (s), 165.3 (s), 168.2 ppm (s); HR-MS:
m/z calcd for C20H25O4N: 343.1784; found: 343.1775; elemental analysis
calcd (%) for C20H25O4N: C 69.95, H 7.34, N 4.08; found: C 69.66, H
7.35, N 4.09.
Figure 7. Correlation between the electrophilicity parameters E of elec-
trophiles 1a–i and 10a–d in DMSO with Hammettꢀs sp values (for 1a–i:
E=3.68sp À 20.57; for 10a-d: E=5.37sp À 9.08). sp for “thq” in 1h has
not been reported but is derived from this correlation.
derived by substituting the E parameter for 1h into the cor-
relation equation given in Figure 7.
Conclusion
Diethyl benzylidenemalonates 1a–i are more than 1010 times
less reactive than benzylidene Meldrumꢀs acids 10, their
cyclic counterparts. They extend our electrophilicity scale on
the low-reactivity end by more than six orders of magnitude,
from À17.7>E>À23.8, and are, therefore, recommended as
reference electrophiles for determining the nucleophilicities
of highly reactive nucleophiles, with N values of 16<N<30.
A report on the use of 1a–i for the characterization of the
anions of arylacetonitriles and arylpropionitriles is in
preparation.
Procedure for the reactions of electrophiles 1 with nucleophile 2b: Com-
pound 2b-K+ (4.0–7.5 mmol) was dissolved in dry DMSO (20 mL), and a
solution of 1a–f (2.0–2.5 mmol) in dry DMSO was added under a nitro-
gen atmosphere. Stirring was continued for 5 h at room temperature, and
the solution was diluted with diethyl ether (25 mL). The reaction mixture
was then poured on water (50 mL), cooled with ice, and acidified with
acetic acid. After extraction with diethyl ether, the combined organic
fractions were washed with water and dried over Na2SO4. After removal
of the solvent under reduced pressure, the crude product was purified by
distillation.
Tetraethyl 2-(4-methoxyphenyl)propane-1,1,3,3-tetracarboxylate (5 fb):
From 1 f (0.56 g, 2.0 mmol) and 2b-K (0.79 g, 4.0 mmol). Yield: 0.68 g,
78%; colorless oil; b.p. 210–2208C (1.3”10À2 bar); 1H NMR (300 MHz,
CDCl3): d=1.04 (t, J=7.1 Hz, 2”3H; CH3), 1.23 (t, J=7.1 Hz, 2”3H;
CH3), 3.75 (s, 3H; OCH3), 3.95 (q, J=7.1 Hz, 2”2H; OCH2), 4.04–4.18
(m, 7H), 6.76–6.79 (m, 2H; ArH), 7.24–7.27 ppm (m, 2H; ArH);
13C NMR (75.5 MHz, CDCl3): d=13.6 (q), 13.8 (q), 43.0 (d; Cb), 54.9 (q;
OCH3), 55.1 (d; Ca), 61.1 (t), 61.4 (t), 113.1 (d), 129.0 (s), 130.4 (d), 158.7
(s), 167.4 (s), 167.9 ppm (s); the NMR chemical shifts are in agreement
with the data reported in ref. [26].
Experimental Section
Diethyl benzylidenemalonates 1a–i: Diethyl benzylidenemalonates 1a–i
were prepared following a modified method of Zabicky.[27] Diethyl malo-
nate and the corresponding benzaldehyde (1 equiv) were stirred under
reflux in toluene for 3–4 h using piperidine (ꢁ10 mol%) as a catalyst.
The product formation was followed by TLC. The reaction mixture was
consecutively washed with aqueous HCl, aqueous NaHCO3 solution, and
water. After drying the solution, the solvent was evaporated. The residue
was either distilled or recrystallized from ethanol to obtain the diethyl
benzylidenemalonates. 1H NMR spectra and melting points for the thus
obtained compounds 1a–g were in agreement with literature reports (see
Supporting Information).
Kinetics: For fast kinetic experiments (t1/2 <15 s), standard stopped-flow
UV/Vis spectrophotometer systems were used in their single mixing
mode. Solutions of the electrophiles 1 in DMSO were mixed with solu-
tions of the carbanions 2 in DMSO (either generated by deprotonation
of 2-H with 1.05 equiv KOtBu in DMSO or by dissolving 2-K+ in
DMSO). CAUTION: Because of explosion hazards, the isolation of 2a-
K+ should be avoided.[39] We therefore recommend generating 2a in situ
1
Diethyl 2-(1-methyl-1,2,3,4-tetrahydroquinoline-6-ylmethylene)malonate
(1h): Diethyl malonate (1.15 g, 7.18 mmol), 6-formyl-1-methyl-1,2,3,4-tet-
rahydroquinoline (1.26 g, 7.19 mmol), and piperidine (300 mL) gave a
crude product that was washed as described in the general procedure
(Supporting Information) and further purified using MPLC (SiO2, di-
chloromethane/isohexane=1/1). The fractions were combined, the sol-
vents evaporated in vacuum, and the residue was crystallized from etha-
nol/isohexane at À58C. Yield: 1.50 g, 4.7mmol, 65%; yellow solid; m.p.
56.2–56.78C; 1H NMR (400 MHz, [D6]DMSO): d=1.22 (t, J=7.1 Hz,
3H; CH3), 1.26 (t, J=7.1 Hz, 3H; CH3), 1.85 (quint, J=6.3 Hz, 2H;
CH2), 2.64 (t, J=6.3 Hz, 2H; CH2), 2.92 (s, 3H; NMe), 3.31 (t, J=6.3 Hz,
2H; NCH2), 4.17(q, J=7.1 Hz, 2H; OCH2), 4.27(q, J=7.1 Hz, 2H;
OCH2), 6.57(d, J=8.7 Hz, 1H; ArH), 7.02 (s, 1H; ArH), 7.18 (dd, J=
8.8 Hz, 2.3 Hz, 1H; ArH), 7.45 ppm (s, 1H; C=CH); 13C NMR
from the corresponding CH acid 2a-H. Kinetics of slow reactions (t =
>
2
15 s) were determined by UV/Vis spectrometry using a J&M TIDAS
diode array spectrophotometer. To obtain pseudo-first-order kinetics, the
carbanions 2 were used in large excess (10 to 100 equivalents) over the
electrophiles (except for kinetics with nucleophile 2e, which was used as
the minor component, see section “Kinetic Measurements”). The temper-
ature of the solutions was kept constant (20ꢃ0.18C) by using circulating
bath thermostats. Rate constants kobs (sÀ1) were obtained by fitting the
single exponential At =A0 exp
A
electrophile absorbance (the evaluated wavelengths are given in the Sup-
porting Information). As depicted in the Supporting Information, the
second-order rate constants k2 (Table 3) were obtained from the slopes of
the linear plots of kobs versus the carbanion concentrations [2].
Chem. Eur. J. 2008, 14, 9675 – 9682
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9681

H. Mayr et al.
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Received: June 26, 2008
Published online: September 12, 2008
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Chem. Eur. J. 2008, 14, 9675 – 9682