Nucleophilicities of the anions of arylacetonitriles and arylpropionitriles in dimethyl sulfoxide

Article abstract of DOI:10.1021/jo802241x

(Chemical Equation Presented) The rates of the reactions of the colored para-substituted phenylacetonitrile anions 1a-c and the pfienylpropionitrile anions 2a-c with Michael acceptors (3a-u) were determined by UV-vis spectroscopy in DMSO at 20°C. The reac

Full text of DOI:10.1021/jo802241x

Nucleophilicities of the Anions of Arylacetonitriles and
Arylpropionitriles in Dimethyl Sulfoxide
Oliver Kaumanns, Roland Appel, Tadeusz Lemek,† Florian Seeliger,‡ and Herbert Mayr*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen, Butenandtstr.
5-13 (Haus F), 81377 Mu¨nchen, Germany
herbert.mayr@cup.uni-muenchen.de
ReceiVed October 7, 2008
The rates of the reactions of the colored para-substituted phenylacetonitrile anions 1a-c and the
phenylpropionitrile anions 2a-c with Michael acceptors (3a-u) were determined by UV-vis spectroscopy
in DMSO at 20 °C. The reactions follow second-order kinetics, and the corresponding rate constants k2
obey the linear-free-energy relationship log k2(20 °C) ) s(N + E), from which the nucleophile-specific
parameters N and s of the carbanions 1a-c and 2a-c have been derived. With nucleophilicity parameters
from 19 < N < 29, they are among the most reactive nucleophiles which we have so far parametrized.
In DMSO, the nucleophilicity of the tert-butoxide anion is comparable to that of the p-cyanophenylac-
etonitrile anion 1b.
Introduction
cently, we investigated the reactivities of different carbanions5-10
including trifluoromethylsulfonyl-stabilized carbanions,6 phe-
nylsulfonyl-stabilized carbanions,7 nitronates,8,9 as well as the
bis(4-nitrophenyl)methyl anion10 and demonstrated that their
additions to benzhydryl cations and structurally related quinone
methides can be described by eq 1, where E is an electrophile-
specific parameter and N and s are nucleophile-specific param-
eters.
The comparison of the nucleophilicities of different classes
of compounds is of considerable importance for our understand-
ing of organic reactivity. The most comprehensive nucleophi-
licity scale presently available is based on the reactions of
benzhydrylium ions and structurally related quinone methides
with different nucleophiles.1 With this method, we have been
able to directly compare n-nucleophiles (amines, alcohols,
phosphanes), π-nucleophiles (alkenes, arenes, organometallics),
and σ-nucleophiles (hydride donors) with each other.1-4 Re-
log k2(20 ° C) ) s(N + E)
(1)
Vice versa, the second-order rate constants k2 for the reactions
of carbanions with Michael acceptors11-14 have been used to
determine the electrophilicities of these electron-deficient
π-systems.
Because UV-vis spectroscopy is an efficient method to
determine reaction rates, we have selected a set of colored
benzhydrylium ions,2 quinone methides,4 and benzylidene
malonates14 as reference electrophiles for characterizing the
† Current address: Department of Chemistry, Agricultural University of
Cracow, Cracow, Poland.
‡ Current address: Department of Chemistry, Carnegie Mellon University,
Pittsburgh, PA.
(1) (a) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66–77.
(b) Mayr, H.; Ofial, A. R. In Carbocation Chemistry; Olah, G. A., Prakash,
G. K. S., Eds.; Wiley: Hoboken, NJ, 2004; pp 331-358. (c) Ofial, A. R.; Mayr,
H. Macromol. Symp. 2004, 215, 353–367. (d) Mayr, H.; Ofial, A. R. Pure Appl.
Chem. 2005, 77, 1807–1821. (e) Mayr, H.; Ofial, A. R. J. Phys. Org. Chem.
2008, 21, 584–595.
(2) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.;
Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am. Chem.
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Int. Ed. 1994, 33, 938–955.
(4) Lucius, R.; Loos, R.; Mayr, H. Angew. Chem. 2002, 114, 97–102; Angew.
Chem., Int. Ed. 2002 41 91–95.
(5) Bug, T.; Mayr, H. J. Am. Chem. Soc. 2003, 125, 12980–12986.
(6) Berger, S. T. A.; Ofial, A. R.; Mayr, H. J. Am. Chem. Soc. 2007, 129,
9753–9761.
(7) Seeliger, F.; Mayr, H. Org. Biomol. Chem. 2008, 6, 3052–3058.
(8) Bug, T.; Lemek, T.; Mayr, H. J. Org. Chem. 2004, 69, 7565–7576.
(9) Phan, T. B.; Mayr, H. Eur. J. Org. Chem. 2006, 2530–2537.
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10.1021/jo802241x CCC: $40.75
Published on Web 11/26/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 75–81 75

Kaumanns et al.
TABLE 1. Michael Acceptors 3a-u and Their Electrophilicity
Parameters E
SCHEME 1. Phenylacetonitrile Anions 1a-c,
Phenylpropionitrile Anions 2a-c, and Their pKaH Values in
DMSO
a From ref 16a. b From ref 16b. c pKaH values in DMSO not available.
reactivities of a large variety of nucleophiles. On the other hand,
we do presently not yet have a comprehensive set of colored
nucleophiles, which might be employed for the systematic
investigation of the reactivities of electrophiles. So far, only
colored carbanions of relatively low nucleophilicity (N < 20)
have been characterized.5-10
In view of the frequent use of cyano substituted carbanions
in organic synthesis, we have selected the carbanions 1a-c and
2a-c for systematic studies of the relationship between structure
and nucleophilic reactivity of highly reactive carbanions.15
Although the correlations between nucleophilicity (N) and
basicity (pKaH) of carbanions are not of high quality,6 the pKaH
values of the phenylacetonitrile anions 1a-c and that of the
phenylpropionitrile anion 2a (Scheme 1) suggested that these
carbanions have considerably higher reactivities than R-nitro-
and R-trifluoromethylsulfonyl-stabilized benzyl anions.
Relative nucleophilicities of carbanions derived from R-sub-
stituted phenylacetonitriles 2 toward methyl iodide and other
alkyl halides in liquid ammonia have previously been investi-
gated by competition experiments.17
Recent studies of the oxidative nucleophilic substitution of
hydrogen revealed that the phenylpropionitrile anion 2a and its
derivatives add to nitrobenzene and some nitrobenzene deriva-
tives in liquid ammonia to form persistent σH-adducts, from
which hydride was abstracted when treated subsequently with
KMnO4.18 When these σH-adducts were combined with di-
methyldioxirane, replacement of the nitro group by hydroxyl
took place prior to rearomatization, and the corresponding
phenols were isolated as major products.19
a Electrophilicity parameters E of 3a-f were taken from ref 4, of
3g-j from ref 13, of 3k,l from ref 12, and of 3m-u from ref 14.
We will now report on the kinetics of the reactions of the
phenylacetonitrile anions 1a-c and the phenylpropionitrile
anions 2a-c with the electrophiles 3a-u (Table 1) in DMSO
at 20 °C. The second-order rate constants k2 will subsequently
be used to derive the nucleophile-specific parameters N and s
of the carbanions 1a-c and 2a-c.
(11) (a) Lemek, T.; Mayr, H. J. Org. Chem. 2003, 68, 6880–6886. (b)
Kaumanns, O.; Mayr, H. J. Org. Chem. 2008, 73, 2738–2745.
(12) Seeliger, F.; Berger, S. T. A.; Remennikov, G. Y.; Polborn, K.; Mayr,
H. J. Org. Chem. 2007, 72, 9170–9180.
(13) Berger, S. T. A.; Seeliger, F. H.; Hofbauer, F.; Mayr, H. Org. Biomol.
Chem. 2007, 5, 3020–3026.
(14) Kaumanns, O.; Lucius, R.; Mayr, H. Chem.sEur. J. 2008, 14, 9675–
9682.
(15) (a) Collier, S. J.; Langer, P. In Science of Synthesis; Murahashi, S.-I.,
Ed.; Thieme: Stuttgart, 2004; Vol. 19, Chapter 19.5.15, pp 403-425. (b)
Murahashi, S. I. In Science of Synthesis; Murahashi, S.-I., Ed.; Thieme: Stuttgart,
2004; Vol. 19, Chapter 19.5.14, pp 345-402. (c) Fleming, F. F.; Zhang, Z.
Tetrahedron 2005, 61, 747–789. (d) Fleming, F. F.; Wang, Q. Chem. ReV. 2003,
103, 2035–2077. (d) Fleming, F. F.; Gudipati, S. Eur. J. Org. Chem. 2008, 5365–
5374.
(16) (a) Bordwell, F. G.; Bausch, M. J. J. Am. Chem. Soc. 1986, 108, 1979–
1985. (b) Bordwell, F. G.; Cheng, J.-P.; Bausch, M. J.; Bares, J. E. J. Phys.
Org. Chem. 1988, 1, 209–223.
(17) Smith, H. A.; Bissell, R. L.; Kenyon, W. G.; MacClarence, J. W.; Hauser,
C. R. J. Org. Chem. 1971, 36, 2132–2137.
(18) (a) Makosza, M.; Stalinski, K.; Klepka, C. Chem. Commun. 1996, 837–
838. (b) Makosza, M.; Stalinski, K. Chem.sEur. J. 1997, 3, 2025–2031. (c)
Makosza, M.; Stalinski, K. Tetrahedron 1998, 54, 8797–8810. (d) Makosza,
M.; Stalinski, K. Synthesis 1998, 1631–1634.
Results and Discussion
Product Studies. Products of representative combinations of
nucleophiles with electrophiles have been characterized. The
phenylacetonitrile anions 1a-c, which were generated from
(1a-c)-H with KO-t-Bu in DMSO or DMSO/MeOH mixtures,
reacted with the quinone methides 3c-f to give the addition
products 4ad-4cd (eq 2) in good yields. Their 1H NMR spectra
showed doublets for Ha and Hb at δ ) 4.11-4.54 ppm and a
signal for the hydroxy group. Generally, two sets of signals in
1
the H NMR spectra of the products 4 indicated the formation
of almost equal amounts of two diastereomers.
The reactions of the carbanions 1b,c with the benzylidene
indandiones 3h-j and of 1c with the benzylidene barbituric
(19) (a) Adam, W.; Makosza, M.; Zhao, C.-G.; Surowiec, M. J. Org. Chem.
2000, 65, 1099–1101. (b) Adam, W.; Makosza, M.; Stalinski, K.; Zhao, C.-G.
J. Org. Chem. 1998, 63, 4390–4391.
76 J. Org. Chem. Vol. 74, No. 1, 2009

Nucleophilicities of the Anions of Arylacetonitriles and Arylpropionitriles
acid 3l showed the analogous formation of the addition products
as a mixture of two diastereomers (≈1:1, eqs 3 and 4).
in Scheme 1 (pKaH < 23.0) should be generated quantitatively
when the corresponding CH acids were treated with 1 equiv of
KO-t-Bu. Analogously, the deprotonation of (1a-c)-H and
(2a-c)-H should also be quantitative with 1 equiv of the
phosphazene base P4-t-Bu (pKBH+ ) 30.2).23 In order to verify
the complete deprotonation of the CH acids (1a-c)-H, KO-t-
Bu was added stepwise to solutions of (1a-c)-H and 2a-H in
DMSO. UV-vis spectroscopy showed that in all cases, the
limiting absorbances of the corresponding carbanions were
achieved after the addition of one equivalent of KO-t-Bu,
indicating quantitative deprotonation of these CH acids. While
the absorbance of 1c was persistent under these conditions, the
absorbances of the carbanions 1a and 1b decreased slowly, when
only 1 equiv of KO-t-Bu was added (Figures S1-S3, Supporting
Information). Persistent absorbances of the carbanions 1a,b
could be observed, however, when they were generated from
their conjugate acids (1a,b)-H with 2 equiv of KO-t-Bu. The
unsubstituted phenylpropionitrile anion 2a, which was also
formed quantitatively with 1 equiv of KO-t-Bu or P4-t-Bu, was
not even persistent when generated with an excess (2-3 equiv)
of base (Figure S4, Supporting Information).
The reaction of the phenylpropionitrile anion 2c with the
quinone methide 3c yielded 5cc as a 1:1 pair of diastereomers,
indicated by two singlets for Ha at δ ) 3.95 and 4.04 ppm, and
for the hydroxy group at δ ) 5.04 and 5.20 ppm (eq 5).
The kinetic experiments with the nitro-substituted carbanions
1c and 2c were unproblematic: Because of their stability, stock
solutions of the potassium salts 1c-K and 2c-K were employed.
On the other hand, solutions of the reactive carbanions 1a,b
and 2a,b were generated immediately before the kinetic experi-
ments by treatment of the corresponding CH acidic compounds
with strong bases, and the kinetic investigations were restricted
to reactions with active electrophiles, which proceeded faster
than the decomposition of the carbanions.
The reaction of the carbanion 2c with 3k was investigated
by 1H NMR spectroscopy, which shows the formation of equal
amounts of diastereomers of the anionic adduct 5ck (eq 6).
For all reactions described in Table 2, first-order rate constants
kobs (s-1) were obtained by least-squares fittings of the mo-
noexponential function At ) A0 exp(-kobst) + C to the time-
dependent absorbances A of the minor components. Plots of
kobs versus the concentrations of the compounds used in excess
were generally linear with negligible intercepts and the second-
order rate constants k2 (L mol-1 s-1) as slopes (Figure 1, Table
2). Some exceptions are discussed below.
In contrast, the reactions of the benzylidene malonates 3m-u
with the carbanions 1b,c in methanol resulted in the formation
of R-cyano stilbenes 6bm-6cu via Michael addition, proton
shift, and retro-Michael addition (eq 7). Compounds 6 were
previously employed for the determination of HR-acidity
scales.20
Kinetics. The rates of the reactions of the carbanions 1a-c
and 2b-c with the electrophiles 3a-u were determined
photometrically under first-order conditions by using either the
nucleophile or the electrophile in high excess as specified in
Table 2.
As mentioned above, we were not able to obtain persistent
solutions of the carbanion 2a. When its reactions with 3s (used
as the minor component) were followed photometrically,
(21) Arnett, E. M.; Small, L. E. J. Am. Chem. Soc. 1977, 99, 808–816.
(22) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980,
45, 3295–3299.
(23) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.; Willaredt, J.; Dam-
bacher, T.; Breuer, T.; Ottaway, C.; Fletschinger, M.; Boele, J.; Fritz, H.; Putzas,
D.; Rotter, H. W.; Bordwell, F. G.; Satish, A. V.; Ji, G. Z.; Peters, E. M.; Peters,
K.; v. Schnering, H. G.; Walz, L. Liebigs Ann. 1996, 1055–1081.
Because of the large pKa value of t-BuOH in DMSO (29.4
or 32.2 from refs 21 and 22, respectively), all carbanions listed
(20) Kroeger, D. J.; Stewart, R. Can. J. Chem. 1967, 45, 2163–2171.
J. Org. Chem. Vol. 74, No. 1, 2009 77

Kaumanns et al.
TABLE 2. Second-Order Rate Constants k2 for the Reactions of
the Phenylacetonitrile Anions 1a-c and the Phenylpropionitrile
Anions 2a-c with the Michael Acceptors 3a-u in DMSO at 20 °C
FIGURE 1. Determination of the second-order rate constant k2 ) 2.80
× 102 L mol-1 s-1 for the reaction of the p-cyanophenylacetonitrile
anion 1b with the Michael acceptor 3p in DMSO at 20 °C.
exponential decays of the electrophile (3s) absorbance were
observed. Plots of kobs vs the concentration of 2a (calculated
from [2a-H] assuming complete deprotonation) were linear, and
the slopes, which equal the second-order rate constants k2, were
almost identical (Table 2), independent of the quantity of the
base (1.05 equiv of P4-tBu or 1, 2, or 3 equiv of KO-t-Bu) used
for the deprotonation of 2a. However, significant negative
intercepts of variable magnitude were observed in all cases
(Tables S31-S35, Supporting Information), indicating fast and
irreversible consumption of certain fractions of the carbanion
2a. Similar observations, i.e., negative intercepts of variable
magnitude and slopes, corresponding to second-order rate
constants, which are almost independent of the nature and
quantity of base used for the deprotonation of 2a-H, were made
for the analogous reactions of the carbanion 2a with the
electrophiles 3t,u (see Tables S36-S41, Supporting Informa-
tion).
On the other hand, significant positive intercepts in plots of
the first-order rate constants (kobs) against the concentrations of
the major component were observed for the reactions of the
p-nitrophenylacetonitrile anion (1c) with the benzylidene ma-
lonates 3m and 3n. Positive intercepts are indicative of reversible
reactions, and by theory, reflect the rate constants of the reverse
reactions.24 However, as discussed above, the intercepts are also
affected by side reactions that we refrain to employ the intercepts
of these plots for calculating the rates of the reverse reactions
and the equilibrium constants K.
As shown in Table 2, the addition of 18-crown-6 caused only
insignificant changes of the second-order rate constants k2 for
the reactions of 1b with 3j and 3m and of 1c with 3c and 3d.
These results confirm that ion-pairing is negligible in dilute
DMSO solution, in accordance with literature reports25 and
earlier findings of our group.6,8,26
Nucleophilicity of tert-Butoxide. As discussed above, per-
sistent solutions of the more basic carbanions have only been
obtained when more than 1 equiv of KO-t-Bu was used for the
deprotonation of the corresponding CH acids. In order to
elucidate the influence of excess KO-t-Bu on the kinetics, we
have studied the reaction of 2b with the quinone methide 3e in
the presence of variable excess of KO-t-Bu. As shown in Figure
2, the slope of the plot of kobs vs [KO-t-Bu] was higher when
[KO-t-Bu] > [2b-H], and from the different slopes in the range
a Minor component in the pseudo-first-order kinetics and monitored
wavelength. b In the presence of 1 equiv of KOtBu. c In the presence of
18-crown-6. d In the presence of 3 equiv of 1b-H. e Measurement at 25
°C. f Reversible reactions, see text and Supporting Information.
g Deprotonation of acid 2a-H with P4-t-Bu phosphazene base. h In the
presence of 2 equiv of KO-t-Bu. i In the presence of 3 equiv of
KO-t-Bu. j Deprotonation of 2b-H with P2-t-Bu phosphazene base. k In
the presence of 2c-H.
(24) The InVestigation of Organic Reactions and Their Mechanisms; Maskill,
H., Ed.; Blackwell Publishing: Oxford, 2006. (b) Schmid, R.; Sapunov, V. N.
Non-Formal Kinetics; VCH: Weinheim, 1982.
(25) Binev, I. G.; Tsenov, J. A.; Velcheva, E. A.; Juchnovski, I. N. J. Mol.
Struct. 1995, 344, 205–215.
(26) Lucius, R.; Mayr, H. Angew. Chem., Int. Ed. 2000, 39, 1995–1997.
78 J. Org. Chem. Vol. 74, No. 1, 2009

Nucleophilicities of the Anions of Arylacetonitriles and Arylpropionitriles
FIGURE 4. Plot of log k2 for the reactions of the nucleophiles 2a-c
with the electrophiles 3 in DMSO versus their electrophilicity param-
eters E.
FIGURE 2. Plot of the observed first-order rate constants kobs for the
reactions of electrophile 3e (c0 ) 2.00 × 10-5 mol L-1) with the
nucleophile 2b against the concentration of KO-t-Bu used for the
deprotonation of 2b-H (c0 ) 4.69 × 10-4 mol L-1) in DMSO at 20
°C.
FIGURE 3. Plot of log k2 for the reactions of the nucleophiles 1a-c
with the electrophiles 3 in DMSO versus their electrophilicity param-
eters E.
of [KO-t-Bu] < [2b-H] and [KO-t-Bu] > [2b-H] one can derive
that KO-t-Bu is approximately two times more nucleophilic than
2b. As a consequence, KO-t-Bu cannot be used in excess when
nucleophiles with N e 27 are investigated. On the other hand,
an excess of KO-t-Bu used for the deprotonation of 2a-H will
hardly affect the pseudo-first-order rate constant because 2a
reacts considerably faster than KO-t-Bu (Figure S6, Supporting
Information).
Correlation Analysis. In order to determine the nucleophile-
specific parameters N and s for the phenylacetonitrile anions
1a-c (Figure 3) and the phenylpropionitrile anions 2a-c (Figure
4), the logarithmic second-order rate constants log k2 of their
reactions with electrophiles 3a-u were plotted against the
electrophilicity parameters E of 3a-u.
The linear correlations for the reactions of the phenylaceto-
nitrile anions 1a-c (R2 > 0.98, Figure 3) allow us to determine
the nucleophile-specific parameters N and s for these carbanions.
The correlations for the reactions of the phenylpropionitrile
anions 2a-c (R2 g 0.95, Figure 4) show larger deviations from
linearity than those of the phenylacetonitrile anions 1a-c. In
particular, the reactions of the carbanion 2b with benzylidene-
malonate 3p, as well as the reaction of carbanion 2c with
quinone methide 3a, are two times faster than expected. On
the other hand, the reactions of 2b with the benzylidene
malonates 3m,n are approximately two times slower than
FIGURE 5. Comparison of the nucleophilicity parameters N of the
phenylacetonitrile anions 1a-c and the phenylpropionitrile anions 2a-c
with those for R-nitro- and R-trifluoromethylsulfonyl-stabilized car-
banions in DMSO. Key: (a) λmax in DMSO; (b) λmax in MeOH; (c) λmax
in DMSO/H2O 10:90 (v/v); (d) λmax in DMSO/H2O 30:70 (v/v); (e)
this work; (f) see ref 9; (g) see ref 27.
expected. Taking into account that many different classes of
Michael acceptors have been used as electrophiles, these
deviations can be considered as rather small, and the correlation
lines in Figure 4 were employed to determine the nucleophile-
specific parameters N and s for the phenylpropionitriles 2a-c.
As expected, electron-withdrawing groups at the para-position
of the aromatic ring decrease the nucleophilicities N of the
carbanions 1a-c and 2a-c. A comparison between the reac-
tivities of the phenylacetonitrile anions 1a-c and the phenyl-
propionitrile anions 2a-c (Table 2 and Figure 5) shows that
replacement of one hydrogen by a methyl group at the R-carbon
of phenylacetonitrile anions does not significantly affect the
J. Org. Chem. Vol. 74, No. 1, 2009 79

Kaumanns et al.
FIGURE 6. Correlation of the nucleophilicity parameters N of different carbanions versus the pKa values of their corresponding CH acids in
DMSO. Overall correlation: N ) 0.802pKa + 8.278, R2 ) 0.750 (nucleophilicity parameters N and pKa values used for this diagram are compiled
in the Supporting Information).
nucleophilicities. The inductive effect of the methyl group and
its steric demand obviously compensate each other resulting in
similar reactivities of the analogously substituted carbanions 1b/
2b and 1c/2c.
example, the correlation between nucleophilicities of primary
and secondary amines versus their pKaH values in water is very
poor.28c Figure 6 shows a moderate correlation between the
nucleophilicity parameters N of carbanions and the pKa values
of their conjugate CH acids (cf Scheme 1) in DMSO. It is
obvious that the phenylacetonitrile anions 1a-c and carbanion
2a are considerably more nucleophilic than expected from the
pKa values of the corresponding CH acids,29 indicating the
limitation of pKa for predicting nucleophilic reactivities. In
accordance with earlier reports,5,8,30 the positive deviations of
the cyano-substituted carbanions are indicative of lower intrinsic
barriers of their reactions.
In order to determine reliable nucleophilicity or electrophi-
licity parameters, reaction partners should be employed, which
differ by several orders of magnitude. The correlation lines for
compounds 2a-c fulfill this condition. However, it should be
noted that the slopes of the correlation lines for compounds 2a
and 2b are largely controlled by the reactions with the
electrophiles 3f and 3b, respectively. The situation for com-
pounds 1b,c is much better because their N and s parameters
can be derived from a balanced series of rate constants (Figure
3). Because the parameters N and s for carbanion 1a have only
been derived from three rate constants, which differ by less than
1 order of magnitude, the nucleophilicity parameters N and s
for 1a should be regarded with caution.
Figure 5 compares the colored R-acceptor-substituted benzyl
anions whose nucleophilicity parameters N have so far been
determined. They cover a reactivity range of almost 15 orders
of magnitude. It is obvious that the phenylacetonitrile anions
1a-c are much stronger nucleophiles than the analogously
substituted R-triflinate and R-nitro-substituted benzyl anions,
whose reactivities have recently been determined.6,8 Because
of the paucity of available data, Hammett plots for the differently
substituted phenylacetonitrile anions 1a-c and phenylpropi-
onitrile anions 2a-c are not informative. Figure 5 reveals,
however, that variation of the para substituents in both series
1a-c and 2a-c have considerably larger effects on the
nucleophilic reactivities than in the series of R-triflinate and
much more than in the series of R-nitro substituted carbanions.
Obviously, more negative charge is localized in the aromatic
rings of the carbanions 1a-c and 2a-c than in the correspond-
ing R-triflinate and R-nitro-substituted benzyl anions.
Conclusions
R-Cyano-substituted benzyl anions are several orders of
magnitude more nucleophilic than R-SO2CF3- and R-NO2-
substituted benzyl anions. The high reactivities of the cyano
substituted species 1a-c and 2a-c are only partially caused
by their higher basicities (pKaH). Lower intrinsic barriers for
the reactions of these carbanions are indicated by positive
deviations from the Brønsted plots and also contribute to their
high nucleophilicities. Variation of the para substituent in the
aromatic ring has a considerably larger effect on the nucleo-
philicities of 1a-c and 2a-c than in the corresponding
R-SO2CF3- and R-NO2-substituted counterparts, indicating a
larger delocalization of the negative charge in the aromatic ring
of carbanions 1a-c and 2a-c. As colored species of high
nucleophilicities, these carbanions complement our series of
reference nucleophiles, which can be employed for the photo-
metric determination of electrophilic reactivities.
Experimental Section
Arylacetonitriles (1a-c)-H and Arylpropionitriles (2a-c)-
H. Arylacetonitriles 1 are commercially available compounds and
pKa values are generally considered to be a useful tool for
estimating the nucleophilic reactivities of many compounds. We
have already shown that this assumption only holds within
groups of structurally closely related nucleophiles.6,28 For
(28) (a) Nigst, T. A.; Westermaier, M.; Ofial, A. R.; Mayr, H. Eur. J. Org.
Chem. 2008, 2369–2374. (b) Brotzel, F.; Kempf, B.; Singer, T.; Zipse, H.; Mayr,
H. Chem.sEur. J. 2007, 13, 336–345. (c) Brotzel, F.; Chu, Y. C.; Mayr, H. J.
Org. Chem. 2007, 72, 3679–3688.
(29) pKa values for 2b and 2c have not been reported.
(30) (a) Bernasconi, C. F.; Zitomer, J. L.; Fox, J. P.; Howard, K. A. J. Org.
Chem. 1984, 49, 482–486. (b) Bernasconi, C. F. Acc. Chem. Res. 1987, 20, 301–
308. (c) Bernasconi, C. F.; Wenzel, P. J. J. Org. Chem. 2003, 68, 6870–6879.
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2003, 1, 1741–1748.
80 J. Org. Chem. Vol. 74, No. 1, 2009

Nucleophilicities of the Anions of Arylacetonitriles and Arylpropionitriles
have been recrystallized from n-pentane/MeOH prior to use.
Compounds (2a-c)-H have been prepared by methylation of the
corresponding arylacetonitriles by using methyl iodide as described
in the literature.31
The synthetic procedures for 4cd and 6bn are described as
representative examples for the product studies. A complete
description for the preparation of all other products 4-6 is given
in the Supporting Information.
CHar), 8.34 (s, 1 H, C)CH). 13C NMR (DMSO-d6, 100 MHz): δ
) 111.9 (s), 112.8 (s), 116.6 (s), 118.2 (s), 126.8 (d, CHar), 129.8
(d, CHar), 132.7 (d, CHar), 133.0 (d, CHar), 137.5 (s), 143.8 (d,
CdCH). MS (EI) m/z ) 256 (33), 255 (M+•, 100), 254 (82), 228
(39), 215 (63), 200 (14). HR-MS: calcd 255.0796 (C17H9N3), found
255.0786. Mp: 303-304 °C (dec, lit.32 302-303 °C).
Kinetics. The reactions of carbanions 1a-c and 2a-c were
studied in DMSO at 20 °C. The rates of the reactions of carbanions
1a-c and 2a-c with the Michael acceptors 3a-u were determined
photometrically under first-order conditions using either a large
excess of the electrophiles 3a-u or of the carbanions 1a-c and
2a-c (for details, see the text and Supporting Information), which
were generated by deprotonation of the corresponding CH acid
(1a-c)-H and (2a-c)-H by using potassium tert-butoxide or
Schwesinger’s phosphazene bases P2-t-Bu and P4-t-Bu.
The reactions were studied with conventional stopped-flow
instruments as described earlier. The experiments were initiated
by mixing equal volumes of solutions of the base and the CH acidic
compounds (1a-c)-H and (2a-c)-H to generate the corresponding
carbanions. After a delay time of t ) 1 s, the resulting solutions of
the carbanions were mixed with equal volumes of solutions of the
electrophiles. From the exponential decay of the absorptions of the
minor components, first-order rate constants were obtained by least-
squares fittings of the monoexponential function At ) A0 exp(-kobst)
+ C to the absorbance data.
3-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-(4-methoxyphenyl)-
2-(4-nitrophenyl)propanenitrile (4cd). A mixture of 1c-H (25.0
mg, 154 µmol), NaOMe (8.30 mg, 170 µmol), and 3d (50.0 mg,
154 µmol) was stirred in MeOH (10 mL) for 1 h under N2
atmosphere. After workup with diluted acetic acid and chromatog-
raphy on silica gel (i-Hex/EtOAc 4:1, Rf ) 0.38), the product was
obtained as a yellow foam (71.0 mg, 146 µmol, 95% as a mixture
of diastereomers in a ratio of 1:1.2). 1H NMR (CDCl3, 300 MHz):
δ ) 1.32, 1.38 (2s, 18 H, 2 × C(CH3)3), 3.76, 3.80 (2s, 3 H, OCH3),
4.19-4.24 (m, 1 H, CH), 4.51 (d, 3J ) 8.4 Hz, 0.50 H, CH), 4.57
(d, 3J ) 8.1 Hz, 0.47 H, CH), 5.13, 5.17 (2s, 1 H, OH), 6.78-6.81
(m, 1 H, CHar), 6.85-6.89 (m, 2.20 H, CHar), 6.97 (s, 1 H, CHar),
7.10-7.13 (m, 1 H, CHar), 7.19-7.27 (m, 3 H, CHar) 8.07-8.11
(m, 2 H, CHar). 13C NMR (CDCl3, 75.5 MHz): δ ) 30.15, 30.23
(2q, CH3), 34.32, 34.35 (2s), 43.64, 43.73 (2d, CH), 55.22, 55.23
(2q, CH3), 55.82, 56.07 (2d, CH), 114.07, 114.12 (2d, CHar), 119.13,
119.20 (2s, CN), 123.61, 123.66 (2d, CHar), 124.55, 125.10 (2d,
CHar), 128.95, 129.32, 129.43 (3d, CHar, signal for the other
diastereomer superimposed), 129.35, 130.08 (s), 131.30, 132.00 (2s),
135.93, 136.12 (2s), 142.44, 142.47 (2s), 147.48, 147.50 (2s),
152.96, 153.26 (2s), 158.69, 158.99 (2d). HR-MS (ESI) [M - H+]:
calcd 485.2435 (C30H33N2O4), found 485.2440.
Acknowledgment. We thank Dr. Armin R. Ofial for as-
sistance during the preparation of the manuscript. Financial
support by the Deutsche Forschungsgemeinschaft (SFB 749)
andtheFondsderChemischenIndustrieisgratefullyacknowledged.
4,4′-(Cyanoethene-1,2-diyl)dibenzonitrile (6bn). Equimolar
amounts of 1b-H (81 mg, 0.57 mmol) and NaOMe were stirred in
MeOH, when electrophile 3n was added subsequently. The resulting
precipitate was filtered, washed, and dried to yield the pure product
6bn as colorless solid (0.11 g, 0.43 mmol, 75%). 1H NMR (DMSO-
d6, 400 MHz): δ ) 7.98-8.06 (m, 6 H, CHar), 8.09-8.12 (m, 2 H,
Supporting Information Available: Details of the 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.
JO802241X
(31) Bailey, W. F.; Jiang, X.-L.; McLeod, C. E. J. Org. Chem. 1995, 60,
7791–7795.
(32) Bell, F.; Waring, D. H. J. Chem. Soc. 1948, 1024–1026.
J. Org. Chem. Vol. 74, No. 1, 2009 81