Nucleophilic reactivities of imide and amide anions

Article abstract of DOI:10.1021/jo1009883

(Figure presented) The kinetics of the reactions of amide and imide anions 2a-o with benzhydrylium ions 1a-i and structurally related quinone methides 1j-q have been studied by UV-vis spectroscopy in DMSO and acetonitrile solution. The second-order rate constants (log k₂) correlated linearly with the electrophilicity parameters E of 1a-q according to the correlation log k ₂ = s(N + E) (Angew. Chem., Int. Ed. Engl. 1994, 33, 938-957), allowing us to determine the nucleophilicity parameters N and the nucleophile-specific parameters s for these nucleophiles. The reactivities of all sulfonamide and diacylimide anions are found in a relatively small range (15 < N < 22). Comparison with structurally related carbanions revealed that amide and imide anions are less reactive than carbanions of the same pK _aH. These effects can be attributed to the absence of resonance stabilization of one of the lone pairs in the amide or imide anions. As amide and imide anions are exclusively attacked at nitrogen by benzhydrylium ions, Kornblums interpretation of the ambident reactivity of amide anions has to be revised.

Full text of DOI:10.1021/jo1009883

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Nucleophilic Reactivities of Imide and Amide Anions
Martin Breugst, Takahiro Tokuyasu,† and Herbert Mayr*
€
€
Department Chemie, Ludwig-Maximilians-Universitat, Butenandtstrasse 5-13, 81377 Munchen, Germany.
†Present address: Hitachi Chemical Co. Ltd., Chiba, Japan.
herbert.mayr@cup.uni-muenchen.de
Received May 25, 2010
The kinetics of the reactions of amide and imide anions 2a-o with benzhydrylium ions 1a-i and
structurally related quinone methides 1j-q have been studied by UV-vis spectroscopy in DMSO and
acetonitrile solution. The second-order rate constants (log k2) correlatedlinearlywiththeelectrophilicity
parameters Eof 1a-qaccordingtothecorrelationlogk2 =s(N þ E) (Angew. Chem., Int. Ed. Engl. 1994,
33, 938-957), allowing us to determine the nucleophilicity parameters N and the nucleophile-specific
parameters s for these nucleophiles. The reactivities of all sulfonamide and diacylimide anions are found
ina relatively small range(15< N <22). Comparisonwithstructurally related carbanions revealedthat
amide and imide anions are less reactive than carbanions of the same pKaH. These effects can be
attributed to the absence of resonance stabilization of one of the lone pairs in the amide or imide anions.
As amide and imide anions are exclusively attacked at nitrogen by benzhydrylium ions, Kornblum’s
interpretation of the ambident reactivity of amide anions has to be revised.
Introduction
Amide anions, like lithium benzamide or phthalimide,
have furthermore been reported to be effective Lewis base
catalysts in Mannich-type reactions between silyl enol ethers
and N-tosylaldimines.7
Gabriel’s phthalimide method, which has been reported
more than 120 years ago,1 has repeatedly been optimized2
and is still an important synthesis for primary amines.
Hendrickson modified Gabriel’s procedure by replacing
the divalent protecting group in phthalimide by two mono-
valent ones which can subsequently be removed (Scheme 1).3
Over the years, Hendrickson’s procedure was further opti-
mized for the synthesis of a wide range of primary and
secondary amines,4 alkylated hydrazines,5 and amino acids.6
Despite the importance of amide anions in organic synthe-
sis and materials, there is only little quantitative data on
their nucleophilic reactivity.8,9 In 1971, Bunnett and Beale
studied the kinetics of the reactions of several imide and sulfon-
amide anions with methyl iodide8a and methyl methanesul-
fonate8b in methanol and reported that the nucleophilic
reactivities of these anions correlate with their basicities.
Bordwell and Hughes investigated the reactivities of several
amide anions toward benzyl chloride in DMSO and con-
cluded that the anion of 1,2,3,4-tetrahydrochinolin-2-one is
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5250 J. Org. Chem. 2010, 75, 5250–5258
Published on Web 07/12/2010
DOI: 10.1021/jo1009883
r
2010 American Chemical Society

Breugst et al.
JOCArticle
SCHEME 1. Modified Gabriel Synthesis with Monovalent
TABLE 1. Reference Electrophiles Employed in this Work and Wave-
lengths Monitored in the Kinetic Experiments
Protective Groups PG1 and PG2
9 times more reactive than the anion of acetanilide and 280
times more reactive than the anion of benzanilide.8c Later,
Kondo and co-workers examined the SN2 reactions of
several imide anions with ethyl iodide in acetonitrile and
acetonitrile-methanol mixtures.9 Although the pKaH values
of succinimide and phthalimide anions differ by more than 1
order of magnitude (9.66 vs 8.30 in water), the second-order
rate constants in acetonitrile vary by less than a factor of 3
(1.65 ꢀ 10-1 vs 6.43 ꢀ 10-2 L mol-1 s-1).9a
In earlier work we have reported that benzhydrylium ions
(Table 1) can be used as reference electrophiles with tunable
reactivity10 for characterizing a large variety of π-nucleo-
philes (e.g., alkenes,11 arenes,11 enol ethers,11 ketene acetals,11
enamines,11 delocalized carbanions12), n-nucleophiles (e.g.,
amines,13 alcohols14), and σ-nucleophiles like hydrides.10,15
The rate constants at 20 °C of the reactions of these nucleo-
philes with benzhydrylium ions have been described by
eq 1,16 where s and N are nucleophile-specific parameters
and E is an electrophile-specific parameter.
aElectrophilicity parameters from refs 10 and 18. bWavelength λ used
to follow the kinetics of the reactions.
log k20°C ¼ sðN þ EÞ
ð1Þ
SCHEME 2. Reaction of Amide Anions with Benzhydrylium
Ions
We now report on the kinetics of the reactions of imide and
amide anions with the reference electrophiles listed in Table 1
in order to determine the nucleophile-specific parameters N
and s of these N-centered nucleophiles (Scheme 2) and to
include them into our comprehensive nucleophilicity scale.17
Results
Reaction Products. As ambident nucleophiles, imide and
amide anions may react with benzhydrylium ions at either
the nitrogen or the oxygen atom (Scheme 3). NMR spec-
troscopy shows that in all cases examined in this work,
SCHEME 3. Reactions of the Imide and Amide Anions 2a-o
with the Electrophiles 1a-i in DMSO
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J. Org. Chem. Vol. 75, No. 15, 2010 5251

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TABLE 2. Second-Order Rate Constants for the Reaction of Reference Electrophiles 1e-o with Imide andAmide Potassium Salts 2a-n in DMSO at 20 °C
aRef 19. bRef 9a. cNMe4þ salt, not included in correlation. dRef 20. eNBu4þ salt. fRef 21. gRef 22. hRef 23. iRef 24. jRef 25. kRef 26. lRef 27. mRef 28. nRef 29.
oIn situ deprotonation with P2-tBubase(1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2Λ5,4Λ5-catenadi(phosphazene)), ref 34 pRef 30. qRef 31. rRef 32. sRef 33.
amides are formed exclusively (N-attack), but we cannot
exclude a preceding reversible attack at oxygen. This result is
in accordance with the findings of Bordwell and Hughes,
who observed selective N-benzylation in the reactions of
several amide anions with benzyl chloride in DMSO.8c
When equimolar amounts of the potassium or tetraalkyl-
ammonium salts of 2a-o and representative benzhydrylium
SCHEME 4. Reversible Reaction of the Saccharin Anion (2o)
with 1c
-
salts (1a-i)-BF4 were combined in dry DMSO (saccharin
(2o) in dry CH3CN), complete decolorization of the solu-
tions was observed, indicating quantitative consumption of
the electrophiles. The fact that some of the reaction products
were obtained in only moderate yields (Table 2) is due to
nonoptimized workup procedures. As shown by the low
pKaH values in water (Table 2), many of the investigated
amide and imide anions are weak bases, with the conse-
quence that their adducts with stabilized benzhydrylium ions
undergo heterolytic cleavage during aqueous workup, as
illustrated for 3oc in Scheme 4. In such cases, the products
could not be isolated and identified by mass spectrometry or
elemental analysis and the product studies were performed
by NMR spectroscopy in d6-DMSO solution (see the Sup-
porting Information for NMR spectra).
The reactions were monitored by UV-vis spectroscopy at or
close to the absorption maxima of the electrophiles (354 < λ <
635 nm) (Table 1). Due to the low reactivity of the saccharin
anion (2o), more electrophilic carbocations (1a-d) had to be
employed for determining its nucleophilicity. Since these benz-
hydrylium ions react with DMSO, the corresponding kinetic
investigations were performed in acetonitrile.
To simplify the evaluation of the kinetic experiments, the
nucleophiles were generally used in large excess over the elec-
trophiles. Therefore, the concentrations of 2a-o remained
almost constant throughout the reactions, and pseudo-first-
order kinetics were obtained in all runs. The first-order rate
Kinetic Investigations. The reactions of the imide and amide
anions 2a-nwith the benzhydrylium ions 1a-iand structurally
related quinone methides 1j-q were studied in DMSO at 20 °C.
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91–95. (b) Richter, D.; Hampel, N.; Singer, T.; Ofial, A. R.; Mayr, H. Eur.
J. Org. Chem. 2009, 3203–3211.
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TABLE 3. Second-Order Rate Constants for the Reaction of Reference
Electrophiles with Imide Anions 2a,b,o in Acetonitrile at 20 °C and
Relative Reactivities r in Acetonitrile and DMSO
ar = k2(in AN)/k2(in DMSO). bEmployed as NMe4þ salt. cEmployed
as NBu4þ salt. dpKaH(2o, CH3CN) = 14.6 (ref 35). eNucleophile-specific
parameters for 2o: N = 10.78, s = 0.89. Product 3oc was isolated in
f
FIGURE 1. Plot of the absorbance (627 nm) vs time for the reaction
of 1g with the potassium salt of diacetamide (2g-K) in DMSO at
20 °C, and correlation of the first-order rate constants kobs with the
concentration of 2g (insert).
31% yield.
constants kobs were then derived by least-squares fitting of the
time-dependent absorbances At of the electrophiles to the
exponential function At = A0 exp(-kobst) þ C. Second-order
rate constants were obtained as the slopes of the plots of kobs
versus the concentrations of the nucleophiles (Figure 1).
In DMSO solution, where most investigations have been
performed, the potassium salts (2a-n)-Kþ are dissociated
into free ions in the concentration range under investigation
(c < 3.4 ꢀ 10-3 mol L-1).12a,18a Consequently, there is no
significant change in k2 when changing the counterion from
potassium to tetraalkylammonium as demonstrated for the
reactions of 2a with 1e,i,k and of 2j with 1i (Table 2).
Furthermore, for several examples it has been shown that
kobs values, which were obtained for potassium salts 2-Kþ in
the presence and in the absence of crown ether, are on the
same kobs vs [2] plots (see the Supporting Information).
FIGURE 2. Plots of the rate constants log k2 for the reactions of
imide and amide anions with reference electrophiles in DMSO
versus their electrophilicity parameters E.
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Some kinetic measurements were also performed in aceto-
nitrile. From the linear dependence of the pseudo-first-order
rate constants kobs on the concentrations of the potassium
amides, it is concluded that ion-pairing also is not significant
in acetonitrile under these conditions. Table 3 shows that the
reactivities toward benzhydrylium ions and quinone methides
are differently affected by the change of the solvent. Whereas
the reactions with the positively charged reference electro-
philes are 4-6 times faster in acetonitrile than in DMSO, the
reactions with neutral electrophiles proceed with almost
equal rates in both solvents.
Correlation Analysis. According to eq 1, linear correla-
tions were obtained when log k2 for the reactions of the imide
and amide anions 2a-o with the reference electrophiles 1a-q
were plotted against their electrophilicity parameters E, as
shown for some representative examples in Figure 2. All
reactions investigated in this work followed analogous linear
correlations as depicted in the Supporting Information,
indicating that eq 1 is applicable. The linearity over a wide
range of reactivity furthermore supports the assumption that
there is no change in the regioselectivity (N- vs O-attack)
when varying the electrophile. The slopes of these correla-
tions correspond to the nucleophile-specific parameter s,
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TABLE 4. Rate Constants k2 (L mol-1 s-1) for the Reactions of 2l,n
with the Michael Acceptors 5a,b in DMSO at 20 °C
aElectrophilicity parameters E from ref 36.
FIGURE 3. Correlation of the rate constants (log k2)/s for the reac-
tions of the imide anions 2a, 2b, and 2f with ethyl iodide in acetonitrile
(from ref 9c) with their nucleophilicity parameters N in DMSO.
whereas the negative intercepts on the abscissa (log k2 = 0)
yield the nucleophilicity parameter N.
promotes the alkylation at the more electronegative oxygen
atom.41 Our observation that only N-substituted amides are
isolated when amide anions are combined with benzhydry-
lium ions and that the linear correlations in Figure 2 do not
give any clue that the more electrophilic benzhydrylium ions
initially give O-alkylated products, which subsequently rear-
range to the isolated N-alkylated products, disagrees with this
interpretation. It appears more likely that the selective O-attack
in the presence of silver salts is due to the coordination of the
silver ion to the nitrogen atom of the imide anion, which is well
documented by numerous X-ray studies.42 In this way, attack
at the nitrogen is blocked. The selective formation of isonitriles
from alkylation agents and [Ag(CN2)]- has analogously been
explained by the blocking of carbon attack by Agþ.43
Structure Reactivity Relationships. The narrow range of s
for all nucleophiles listed in Table 2 (0.53 < s < 0.76), which is
illustrated by the almost parallel correlation lines in Figure 2
(exception: saccharin anion 2o,s=0.89inCH3CN) implies that
the relative reactivities of these compounds depend only slightly
on the electrophilicity of the reaction partner. The reactivities
toward the benzhydrylium ion 1i, for which most rate constants
have directly been measured, can therefore be assumed to reflect
general structure reactivity trends (Scheme 5).
To examine the suitability of the nucleophilicity para-
meters N and s given in Table 2 for the prediction of rate
constants of reactions with other types of electrophiles, we
studied the kinetics of the reactions of the amide anions 2l
and 2n with the Michael acceptors 5a and 5b. As shown in
Table 4, the agreement between calculated and experimental
data is better than a factor of 2 in the case of 2n and better
than a factor of 21 for the reactions of 2l, i.e., the three-
parameter eq 1, which presently covers a reactivity range of
more than 40 orders of magnitude, can also be employed for
the semiquantitative prediction of the rates of ordinary
Michael additions of amide anions.
In previous work, we have shown that the relative reactiv-
ities of nucleophiles in SN2 reactions also correlate with the N
and s parameters which were derived from their reactions
with benzhydrylium ions.37 The linear correlation of (log k2)/
s for the reactions of the imide anions 2a,b,f with ethyl
iodide,9c shown in Figure 3, is in line with this observation,
though the paucity of data inhibits a more detailed analysis.
As the nucleophilic reactivities of the amide anions 2 can
be expected to be strongly reduced by hydrogen bond donor
solvents, a comparison of our data with the SN2 reactivities
of these anions in alcoholic solvents8a,b,9a is not possible.
The decreasing nucleophilicity of the amide anions RNH-
in the series R = CN > SO2CH3 ≈ SO2Tol > COCF3 (left
column of Scheme 5) correlates neither with Hammett’s σp
nor σp- constants of these substituents (see the Supporting
Information for correlations) indicating that the mode of
interaction of the substituents with N- differs from the type
of interaction with neutral or negatively charged Csp2 centers.
From the comparison of 2d and 2e one can derive that
replacement of N-H by N-CH3 has little effect on nucleo-
philic reactivity, and the similar reactivities of the cyanamide
anion 2n and Evans’ auxiliary 2m reveal the comparable
effects of cyano and ester groups.
Discussion
Ambident Reactivity of Amide and Imide Anions. Although
all reactions discussed above proceed via nitrogen attack,
amide and imide anions are ambident nucleophiles, and
oxygen attack is also conceivable. While alkylation reactions
of neutral amides often give product mixtures arising from
O- and N-attack,38 amide anions typically react at nitrogen.39
However, oxygen-alkylation has only been observed when
silver salts were employed,40 and Kornblum rationalized this
change of regioselectivity by the fact that silver ion enhances
the carbocationic character of the electrophile and thus
A second acceptor group reduces the nucleophilic reacti-
vity only slightly, and the comparison of 2i (left column) and
2g (middle column) shows that the effect of one sulfonyl
group is comparable to that of two acetyl groups. The anion
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SCHEME 5. Comparison of the Reactivities of Imide and Amide
Anions with the Benzhydrylium Ion 1i in DMSO (20 °C)a
SCHEME 6. Reactivities toward Benzhydrylium Ion 1i and
N-Values of Imide Anions (20 °C)
SCHEME 7. Comparison of the Reactivity of Amide Anions and
Carbanions toward the Quinone Methide 1o in DMSO (20 °C)a
aEntries for 2l-n were calculated by using eq 1, N and s parameters
from Table 2, and E(1i) from Table 1.
of saccharin (2o), which is simultaneously stabilized by a
sulfonyl and an acyl group, is approximately 104 times less
nucleophilic than ordinary sulfonamide or diacylimide an-
ions (Table 3, not included in Scheme 5).
aRate constants for 2i and for the sulfonyl stabilized carbanion were
calculated by eq 1, using N and s from Table 2 (this work) and ref 44.
Reduction of the ring size (2f f 2b) is associated with a
5-fold reduction of nucleophilicity (possibly because of a
reduced p-character of the nonconjugated lone pair at N in
the smaller ring 2b), and the replacement of the ethano-
bridge in 2b by a benzo- or etheno-bridge causes a further
2-fold reduction of nucleophilic reactivity (Scheme 6). The
slight reduction of reactivity from succinimide 2b to phthal-
imide 2a and maleimide 2c toward 1i can be explained by the
higher electronegativity of sp2- compared to sp3-hybridized
carbon atoms. It shall be noted, that due to slightly different
values of the slope parameter s, relative reactivities of
compounds with similar reactivities may be inverted when
the electrophile is changed, as indicated by the different order
of k2 and the N parameters in Scheme 6.
SCHEME 8. Comparison of the Nucleophilic Reactivities of
Structurally Related Imide Anions and Carbanions towards the
Benzhydrylium Ion 1i (20 °C)
Comparison of Amide Anions and Carbanions. A direct
comparison of the electrophilic reactivities of amide anions
and carbanions, which carry only one acceptor group, is not
possible, because the high reactivities of monoacceptor sub-
stituted carbanions have so far prevented the characteriza-
tion of their nucleophilicities. On the other hand, the larger
electronegativity of nitrogen enabled us to investigate amide
anions carrying only one acceptor substituent. The observa-
tion that carbanions, which are stabilized by a trifluoro-
methyl substituted phenyl group in addition to a sulfonyl or
cyano group,44 are 103 times more nucleophilic than amide
anions that carry a hydrogen atom instead of the acceptor-
substituted phenyl group reflects the tremendous difference
(44) (a) Seeliger, F.; Mayr, H. Org. Biomol. Chem. 2008, 6, 3052–3058.
(b) Kaumanns, O.; Appel, R.; Lemek, T.; Seeliger, F.; Mayr, H. J. Org.
Chem. 2009, 74, 75–81.
in reactivity of amide anions and carbanions with a single
acceptor substituent (Scheme 7).
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FIGURE 4. Relaxed potential energy surface scan (at B3LYP/6-31þG(d,p) level of theory) of the anion of diacetamide 2g.
A completely different situation is found for imide anions
and carbanions bearing two acceptor groups. Coincidently,
the reactivities of the structurally analogous cyclic compounds,
glutarimide anion 2f, an n-nucleophile, and dimedone anion
4c, a π-nucleophile, are almost identical (Scheme 8). Even
when the ring is opened, dicarbonyl-substituted imide anions
and analogously substituted carbanions differ by less than 102
in reactivity, as shown in Scheme 8. While ring-opening leads
to a slight decrease of the reactivities of the imide anions
(f 2g,h), the reactivities of the acyclic carbanions (f 4e,f) are
somewhat higher than that of the cyclic analogue 4c. Whereas
acetyl groups stabilize carbanions better than ethoxycarbonyl
groups, similar stabilizing effects on imide anions are found
for acetyl and ethoxycarbonyl substituents (Scheme 8).
Calculated Structures of the Diacetamide Anion. To ratio-
nalize why a second carbonyl acceptor group causes only a
weak reduction of nucleophilicity in the imide anion series
(see Scheme 5), we have investigated the structures of the N,
N-diacetylamide anion by quantum chemical calculations on
the B3LYP/6-31þG(d,p) level of theory using Gaussian 03.45
For that purpose, we have systematically varied the dihedral
angles φ and j in the anion 2g by relaxed potential energy
surface scans. When φ is varied (Figure 4a), j remains at
approximately 0°, andwhen j is varied (Figure 4b), φ remains
at about 180°. For the sake of clarity, the small deviations of
the nonrotating groups from planarity are neglected in the
drawings of Figure 4. Figure 4a shows that a slight change of
φ from -180 to -160° leads to the global minimum 2g-I, an
almost planar conformation, where both carbonyl groups are
in conjugation with the same lone pair on nitrogen. When the
acetyl group is further turned out of plane (φ f -90°), one
observes only a small increase of energy, because now the
rotating carbonyl group gets into conjugation with thesecond
lone pair on nitrogen. The transition state 2g-II with almost
perpendicular arrangement of the two carbonyl groups is only
17 kJ mol-1 above the global minimum. Further rotation
(45) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision E.01,
Gaussian, Inc.: Wallingford, CT, 2004.
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SCHEME 9. Reaction Enthalpy (Gas Phase, in kJ mol-1) for
the Methyl Hydrogen -Exchange between Carbon and Nitrogen50
carbanions 4. Thus, the cyanamide anion 2n and the trifluo-
roacetamide anions 2d and 2e, anions of similar basicity,
differ by 103 in nucleophilic reactivity. Despite the low quality
of the correlations for both classes of compounds, it is evident
from the two Brønsted plots in Figure 5 that nitrogen
centered anions 2 are generally less nucleophilic than carb-
anions of similar pKaH. Bordwell has analogously reported
that the anions of substituted anilines (ArNH-) react more
FIGURE 5. Relationship between Brønsted basicity and log k2 for
the reaction of 1i with several amide and imide anions (b) as well as
with some acceptor-stabilized carbanions (0) in DMSO. [pKaH in
DMSO (from ref 20): 4a: Meldrum’s acid 7.3; 4b: malodinitrile 11.1;
4c: dimedone 11.0; 4e: acetylacetone 13.3; 4f: ethyl acetylacetate
14.2; 4g: 3-methylacetylacetone 15.05; 4h: diethyl malonate 16.4;
pKaH in DMSO (from ref 48): 4d: ethyl cyanoacetate 13.1].
slowly with n-butyl chloride in DMSO than carbanions
(ArCHCN-) of the same pKaH
47
.
Two effects have to be considered when explaining the
separation of these Brønsted plots. While the Brønsted basi-
cities refer to reactions with the proton (Hþ), the nucleophilic
reactivities refer to the formation of a bond to carbon. The
isodesmic reaction in Scheme 9 shows that the transfer of a
methyl group from carbon to nitrogen is endothermic by 25 kJ
mol-1, i.e., hydrogen prefers to sit atnitrogen and CH3 prefers
carbon. As a consequence, carbanions that have a similar
leads to a shallow minimum (2g-III), which corresponds to a
slightly distorted conformation of the planar U-shaped
conformer 2g-IV, the energy maximum of this rotation.
Figure 4b describes the rotation of the second acetyl group
around the C-N bond (variation of j). When j is increased
from 0 to 15°, a decrease of energy is found and one arrives at
the minimum structure 2g-V. Though structures 2g-I and 2g-
V look different in the drawings of Figure 4a,b, they are
identical in reality because also the nonrotating amide bonds
deviate slightly from planarity. A further increase of j yields
the transition state 2g-VI with almost perpendicular arrange-
ment of the two carbonyl groups. The 11 kJ mol-1 energy
difference between 2g-II and 2g-VI can be explained by the
more favorable orientation of the dipole moment of the in-
plane carbonyl group with the nitrogen lone pair in 2g-II
than in 2g-VI. A shallow minimum is reached for j = 150°,
but further increase of j did not lead to 2g-VIII as the
transition state of the j-rotation, because the structure
converged to 2g-O, when j was fixed at 180°. The W-shaped
arrangement 2g-VIII was, therefore, calculated with fixed
dihedral angles and found 43 kJ mol-1 above the global
minimum 2g-V. Steric hindrance of the two methyl groups in
the W-conformer and unfavorable interactions of the dipole
moments of the carbonyl groups with the lone pair on
nitrogen account for its low stability.
affinity toward protons as amide anions (comparable pKaH
)
have a higher affinity toward carbon, a trend that is also
reflected by the kinetics, i.e., the higherk2 values of carbanions
toward carbon-centered electrophiles shown in Figure 5.
On the other hand, alkylations at nitrogen generally have
lower intrinsic barriers than alkylations at carbon,49 which
should result in higher reactivities of the amide anions.
Figure 5 shows that the intrinsic preference for reactions at
nitrogen cannot compensate the thermodynamic term, which
is responsible for the higher reactivities of carbanions.
Conclusion
The reactions of imide and amide anions with benzhydry-
lium ions and quinone methides follow the correlation (1)
which allows us to include these compounds into our com-
prehensive nucleophilicity scales and compare their nucleo-
philicity with those of other nucleophiles (Figure 6). Despite
the poor correlation between pKaH and nucleophilic reacti-
vity, carbanions are generally stronger nucleophiles than
amide anions of similar basicity. Figure 6 furthermore shows
that phthalimide and maleimide anions have similar nucleo-
philicities in DMSO as primary alkylamines and are weaker
nucleophiles than secondary alkylamines though the amide
anions are significantly stronger bases. The latter compar-
ison again illustrates that Brønsted basicities are a poor guide
for estimating nucleophilic reactivities, even when reagents
with the same central atom are compared. The knowledge of
carbon basicities51 is needed to elucidate the reason for the
breakdown of the Brønsted correlations.
In line with previous studies by Wurthwein,46 the C-N-C
€
angle remains almost constant (122-124°) during both rota-
tions, and not even the 90° transition states, where the two
carbonyl groups interact with different lone pairs at nitro-
gen, adopt allenic structures with a quasi-linear CdNdC
fragment. Since in the global minimum one of the two lone
pairs at nitrogen is almost unaffected by the substituents, it is
not surprising that the second electron acceptor substituent
affects the nucleophilicity of imide anions only slightly,
contrasting the situation in carbanions.
(47) Bordwell, F. G.; Cripe, T. A.; Hughes, D. L. In Nucleophilicity;
Harris, J. M., McManus, S. P., Eds.; American Chemical Society: Chicago,
IL, 1987; pp 137-153.
(48) Bordwell, F. G.; Branca, J. C.; Bares, J. E.; Filler, R. J. Org. Chem.
1988, 53, 780–782.
Correlation with Brønsted Basicities. Figure 5 shows that
the correlation between nucleophilicity and Brønsted basicity
is even worse for the amide and imide anions 2 than for the
(49) Hoz, S.; Basch, H.; Wolk, J. L.; Hoz, T.; Rozental, E. J. Am. Chem.
Soc. 1999, 121, 7724–7725.
€
(46) (a) Funke, W.; Wurthwein, E.-U. Chem. Ber. 1992, 125, 1967–1968.
€
(50) Pedley, J. B.; Naylor, R. D.; Kirby, S. P. Thermochemical data of
organic compounds, 2nd ed.; Chapman and Hall: London, UK, 1986.
(51) Hine, J.; Weimar, R. D., Jr. J. Am. Chem. Soc. 1965, 87, 3387–3396.
€
(b) Hesse, N.; Frohlich, R.; Humelnicu, I.; Wurthwein, E.-U. Eur. J. Inorg.
Chem. 2005, 2189–2197.
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description for the preparation of all other products 2 and 3 is
given in the Supporting Information.
Maleimide-potassium (2c-Kþ). Maleimide (3.0 g, 31 mmol)
was dissolved in dry dimethoxyethane (25 mL) under nitrogen
atmosphere and KOtBu (3.4 g, 30 mmol) was added at 0 °C.
After 10 min of stirring, the solvent was evaporated under
reduced pressure. The solid residue was washed several times
with dry diethyl ether and filtrated under N2. The salt 2c-K
(2.2 g, 27 mmol, 95%) could be isolated as a white solid. 1H NMR
(400 MHz, d6-DMSO) δ 6.28 ppm (s). 13C NMR (100 MHz, d6-
DMSO) δ 126.6 (d), 180.1 ppm (s).
2-(Bis(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)iso-
indoline-1,3-dione (3af). In a carefully dried nitrogen-flushed
Schlenk flask, a solution of 1a-Kþ (223 mg, 1.20 mmol) in DMSO
(5 mL) was added dropwise to a solution of the benzhydrylium
tetrafluoroborate 1f (393 mg, 1.00 mmol) in DMSO (5 mL).
After stirring at ambient temperature for several minutes, cold
water (ca. 50 mL) was added. Subsequently, the precipitated
material was collected by filtration. After washing with water,
the solid was dried under reduced pressure. 3af (230 mg, 0.509
mmol, 51%) was isolated as a white solid; mp 151-152 °C (from
dichloromethane-cyclohexane).
Kinetics. As the reactions of colored benzhydrylium ions or
quinone methides with colorless imide or amide anions result in
colorless products, the reactions were followed by UV-vis
spectroscopy. Slow reactions (τ1/2 > 10 s) were determined by
using conventional UV-vis spectrophotometers. Stopped-flow
techniques were used for the investigation of rapid reactions
(τ1/2 < 10 s). The temperature of solutions was kept constant at
20.0 ( 0.1 °C during all kinetic studies by using a circulating
bath thermostat. The nucleophile concentration was always at
least 10 times higher than the concentration of the electrophile,
resulting in pseudo-first-order kinetics with an exponential
decay of the electrophile concentration. First-order rate con-
stants kobs (s-1) were obtained by least-squares fitting of the
absorbance data to a single-exponential At = A0 exp(-kobst) þ
C. The second-order rate constants k2 (L mol-1 s-1) were
obtained from the slopes of the linear plots of kobs against the
nucleophile concentration.
FIGURE 6. Comparison of the nucleophilicities N of imide and
amide anions with other C- and N-nucleophiles in DMSO (data
referring to other solvents are marked).
Experimental Section
Materials. Commercially available DMSO and acetonitrile
(both: H2O content <50 ppm) were used without further
purification. The reference electrophiles used in this work were
synthesized according to literature procedures.10 Ethyl acetyl-
carbamate was synthesized according to ref 52. Tetrabutylam-
moniumsuccinimide andpotassium phthalimide werepurchased.
Tetramethylammonium phthalimide and tetramethylammo-
nium saccharin were synthesized according to ref 9a. Potassium
salts of 2,2,2-trifluoroacetamide and of other amides were
prepared by treatment of the corresponding amide with KOtBu
in dimethoxyethane.53
Acknowledgment. We thank the Fonds der Chemischen
Industrie (scholarship to M.B.) and the Deutsche Akade-
mische Austauschdienst (scholarship to T.T.). Financial
support by the Deutsche Forschungsgemeinschaft (SFB
749) is gratefully acknowledged. We are grateful to Professor
€
Ernst-Ulrich Wurthwein, Professor Hendrik Zipse, and Dr.
Armin R. Ofial for helpful discussions and to Nathalie
Hampel for experimental support.
The synthetic procedures for 2c and 3af are described as
representative examples for the product studies. A complete
Supporting Information Available: Details of the computa-
tional data, kinetic experiments, synthetic procedures, and
NMR spectra of all characterized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(52) Atkinson, M. R.; Polya, J. B. J. Chem. Soc. 1954, 3319–3324.
(53) Neale, R. S. Ind. Eng. Chem. Prod. Res. Dev. 1980, 19, 648–654.
5258 J. Org. Chem. Vol. 75, No. 15, 2010