Ambident reactivity of the cyanide ion: A failure of the HSAB principle

Full text of DOI:10.1002/anie.200461640

Communications
Reaction Mechanisms
Ambident Reactivity of the Cyanide Ion:
A Failure of the HSAB Principle**
Alexander A. Tishkov and Herbert Mayr*
Dedicated to Professor Christoph Rüchardt
on the occasion of his 75th birthday
The ambident reactivity of the cyanide ion is one of the
classical examples used to illustrate the application of the
Klopman–Salem equation and the hard and soft acids and
bases (HSAB) principle. Accordingto Fleming, “alkyl halides
in simple SN2 reactions are soft electrophiles; thus it is
appropriate for cyanide to react from the soft end of the ion.
When a silver ion is present (other Lewis acids like zinc and
mercuric ion behave similarly), the halide ion is assisted in
leaving the carbon atom, and in the transition state there is now
a greater development of charge on the carbon atom under-
going substitution. Carbonium ions are hard electrophiles, and
therefore it is again appropriate that on this occasion cyanide
ion should react from the harder end of the ion.”[1]
Comparable statements are found in many textbooks,
[2]
includingthe latest edition of Marchꢀs Organic Chemistry.
Although Pearson had already indicated problems of the
HSAB principle in explainingthe ambident reactivity of the
[*] Dr. A. A. Tishkov, Prof. Dr. H. Mayr
Department Chemie und Biochemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13 (Haus F), 81377 München (Germany)
Fax: (+49)89-2180-77717
E-mail: herbert.mayr@cup.uni-muenchen.de
[**] We thank the Alexander von Humboldt foundation (stipend to
A.A.T.) and the Deutsche Forschungsgemeinschaft for financial
support of this work. HSAB=hard and soft acids and bases.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200461640
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cyanide ion,[3] experimental evidence that cast doubt on this
interpretation has largely been ignored. For example, the
report by Songstad and co-workers[4a] that trityl chloride and
perchlorate react with unassociated cyanide ions to form
predominantly triphenylacetonitrile and only 10% of isocya-
notriphenylmethane received little attention (Scheme 1).
Scheme 1. Reaction of trityl chloride and perchlorate with cyanide ions
(Songstad and co-workers).[4a]
Scheme 3. Reaction of the benzhydrylium ions (1a–e)–BF4 with
nBu4N+CNꢀ.
In 1985, Carretero and Ruano reported the retention of
configuration in the reaction of erythro- and threo-2-bromo-3-
methylthiobutanes (Scheme 2) and found that “the observed
(2g) and 2126 cmꢀ1 (3g) in the IR spectrum of the crude
reaction product (Scheme 4). The 2g/3g ratio was derived
from the H NMR signals of 2-H in the chloro-substituted
1
Scheme 2. Reaction of 2-bromo-3-methylthiobutane with cyanide ions
(Carretero and Ruano).[4b]
regioselectivity with both metal cyanides cannot be explained
as variations in the hardness of the electrophilic carbon
induced by the interactions between the metal cation and the
halogen.”[4b] Their clear conclusion, “that the reactions
between alkyl halides and metal cyanides … are not a good
example for illustrating the Klopman–Salem equation” also
found little resonance.
We recently reported that the HSAB principle cannot
explain the ambident reactivity of the thiocyanate ion in
alkylation reactions, since hard carbocations as well as soft
haloalkanes preferentially attack the soft sulfur terminus.[5]
Only when diffusion control is reached, can the attack of
carbocations at the nitrogen atom compete with attack at the
sulphur atom. We now report that the knowledge of the
diffusion control limit is also key to understandingthe
ambident reactivity of the cyanide ion.
Scheme 3 shows that the highly stabilized benzhydrylium
ions (1a–e)–BF4 react with nBu4N+CNꢀ in acetonitrile to give
the correspondingdiaryl acetonitriles 2a–e.[6] As any pro-
duced isocyanomethanes would reionize and successively
yield the thermodynamically more stable nitriles 2a–e, the
outcome of the reaction presented in Scheme 3 does not give
information about the site of the kinetically controlled
attack.[7]
Treatment of 3-chlorophenyldiphenylmethyl chloride
(1g–Cl) with nBu4N+CNꢀ under the same conditions as
shown in Scheme 3 yields a mixture of nitrile 2g and isonitrile
3g, as revealed by the presence of absorptions at n˜ = 2240
Scheme 4. Product distribution in the reaction of (1 f–h)–X with cya-
nide ions.
arene rings which absorb as doublets (J = 0.4 Hz) of triplets
(J = 2.0 Hz) and can be assigned to 2g and 3g by comparison
with the NMR spectra of the pure compounds (Figure 1). An
analogous experiment with tris-(3-chlorophenyl)methyl bro-
mide (1h–Br) showed a decrease in the nitrile/isonitrile ratio
(Scheme 4, see also the SupportingInformation). In accord
with previous reports on the 3 f!2 f rearrangement[7a] the
isomerizations 3g,h!2g,h are slow under the chosen reac-
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Communications
parameter, and N and s are electrophile-independent nucle-
ophilicity parameters).[9,10]
log k20 o ¼ sðE þ NÞ
ð1Þ
C
When the reactions of (1a–e)–BF4 with nBu4N+CNꢀ were
monitored photometrically in acetonitrile by usingpreviously
described methodology,[10] second-order kinetics were
observed with the rate constants listed in Table 1.
Table 1: Rate constants for the reactions of the benzhydrylium ions 1a–e
with tetra-n-butylammonium cyanide (CH3CN, 208C).
Electrophilicity E[a]
kC [mꢀ1 sꢀ1
]
1a
1b
1c
1d
1e
ꢀ10.04
ꢀ9.45
ꢀ8.76
ꢀ8.22
ꢀ7.69
2.42”104
5.50”104
1.31”105
3.58”105
1.12”106
[a] From reference [9].
From the linear part of the logkC versus E correlation
(Figure 2) one can derive N = 16.3 and s = 0.70 for the
C nucleophilicity of CNꢀ in acetonitrile. Extrapolation indi-
cates that kC reaches diffusion control for carbocations with
Figure 1. Comparison of the 1H NMR spectrum (200 MHz, C6D6) of
the product obtained from the reaction of 1g–Cl with tetra-n-butylam-
monium cyanide (middle) with the spectra of nitrile 2g (top) and iso-
nitrile 3g (bottom), respectively.
tion conditions, indicatingthat the product ratios listed in
Scheme 4 are the result of kinetic control.
The reactions of (1 f–h)–X with [Ag(CN)2]ꢀ lead to the
selective formation of the isonitriles 3 f–h (Scheme 5).[8] Since
Figure 2. Plot of logk for the reactions of the benzhydrylium ions 1a–e
and the tritylium ions 1 f–h with the cyanide ion versus the electrophi-
licity parameters E of these carbocations.[9,10a]
Scheme 5. Selective isonitrile formation in the reaction of (1 f–h)–X
with [Ag(CN)2]ꢀ; X=Cl or Br.
E > 0.[11] As all carbocations with E > 0 can thus be assumed
to react with CNꢀ with the same rate constant of 2 ”
1010 mꢀ1 sꢀ1 (C attack), the product ratios reported in
Scheme 4 can be used to estimate kN, that is, the rate
constants for attack at the cyanide nitrogen atom. Figure 2
illustrates that the decrease in the 2/3 ratio (= kC/kN) as the
electrophilicities of the carbocations 1 f–h[10a] grow from 0.5 to
2.0 can be explained by the fact that C attack has already
reached diffusion control while N attack approaches the
diffusion limit. Even when the exact location of these borders
is problematic, it is clear from Figure 2 that carbocations that
the nucleophilic substitutions of trityl halides described in
Scheme 4 and 5 generally follow the SN1 mechanism, it is clear
that the observed reversal of regioselectivity is not due to a
change in mechanism from SN2 to SN1, but to modification of
the cyanide ion by coordination with silver.
How can the C/N ratios, reported in Scheme 4, be
explained? We recently showed that the correlation Equa-
tion (1) also describes the rates of reactions of stabilized
carbocations with anions (k is the second-order rate constant
at 208C, E is a nucleophile-independent electrophilicity
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Chemie
are less stabilized than Ph3C+ undergo barrierless combina-
tion reactions with free CNꢀ in acetonitrile. Attempts to
explain C/N ratios by traditional transition-state models must,
therefore, be obsolete.
SN1 reactions with participation of the cyanide anion are
problematic in protic solvents. As the nucleophilicity of CNꢀ
decreases significantly in protic solvents (e.g., in water N =
9.19 and s = 0.60),[10a] carbocations generated under such
conditions usually react faster with the solvent than with
CNꢀ.[12] Thus, the reaction of 1-chloro-1-(4-methoxyphenyl)-
[1] I. Fleming, Frontier Orbitals and Organic Chemical Reactions,
Wiley, Chichester, 1976, pp. 40 – 41.
[2] M. B. Smith, J. March, Marchꢀs Advanced Organic Chemistry.
Reactions, Mechanisms, and Structure, 5th ed., Wiley, New York,
2001, p. 460.
[3] R. G. Pearson, Chemical Hardness, Wiley-VCH, Weinheim,
1997, p. 7.
[4] a) T. Austad, J. Songstad, L. J. Stangeland, Acta Chem. Scand.
1971, 25, 2327 – 2336; b) J. C. Carretero, J. L. G. Ruano, Tetrahe-
dron Lett. 1985, 26, 3381 – 3384.
[5] R. Loos, S. Kobayashi, H. Mayr, J. Am. Chem. Soc. 2003, 125,
14126 – 14132.
[6] For analogous reactions of 4-amino-substituted tritylium ions
with KCN, see: M. L. Herz, J. Am. Chem. Soc. 1975, 97, 6777 –
6785.
[7] a) The rearrangement of isocyanotriphenylmethane (3 f) into
cyanotriphenylmethane (2 f) is described in: T. Austad, J.
Songstad, Acta Chem. Scand. 1971, 26, 3141 – 3147; b) for a
change in mechanism in isocyanide!cyanide rearrangements,
see: C. Rüchardt, M. Meier, K. Haaf, J. Pakusch, E. K. A.
Wolber, B. Müller, Angew. Chem. 1991, 103, 907 – 915; Angew.
Chem. Int. Ed. Engl. 1991, 30, 893 – 901.
[8] The synthesis of isocyanotriphenylmethane (3 f) from trityl
chloride 1 f–Cl and Me4N+[Ag(CN)2]ꢀ was described in refer-
ence [4a].
[9] a) H. Mayr, T. Bug, M. F. Gotta, N. Hering, B. Irrgang, B. Janker,
B. Kempf, R. Loos, A. R. Ofial, G. Remennikov, H. Schimmel, J.
Am. Chem. Soc. 2001, 123, 9500 – 9512; b) H. Mayr, B. Kempf,
A. R. Ofial, Acc. Chem. Res. 2003, 36, 66 – 77.
ethane with KCN in ethanolic solution yields the correspond-
[13]
ingethyl ether in almost quantitative yield.
Reactions of
tert-haloalkanes with alkali-metal cyanides in alcohols give
particularly low yields of substitution products owingto the
high basicity of CNꢀ. Dependingon the reaction conditions,
small amounts of tert-cyanoalkanes are formed alongwith
tertiary ethers and elimination products.[14]
In summary, C attack is generally preferred whenever
carbocations react with free CNꢀ. Let us now turn to SN2
reactions of the cyanide ion: It has longbeen known that
haloalkanes react with alkali-metal and onium cyanides with
preferential formation of nitriles.[15] Even in the reaction of
KCN with the relatively hard methylatingagent dimethyl
sulfate, the preferential formation of acetonitrile was
observed.[16,17] We have now studied the reactions of tetra-n-
butylammonium cyanide with the even harder SN2 alkylating
agents methyl triflate and trimethyloxonium tetrafluorobo-
rate in CDCl3 and observed the exclusive formation of
acetonitrile in both cases (1H and 13C NMR spectroscopy,
Scheme 6).
[10] a) S. Minegishi, H. Mayr, J. Am. Chem. Soc. 2003, 125, 286 – 295;
b) R. Lucius, R. Loos, H. Mayr, Angew. Chem. 2002, 114, 97 –
102; Angew. Chem. Int. Ed. 2002, 41, 91 – 95; c) T. Bug, H. Mayr,
J. Am. Chem. Soc. 2003, 125, 12980 – 12986; d) T. Bug, T.
Lemek, H. Mayr, J. Org. Chem. 2004, 69, 7565 – 7576.
[11] This conclusion is in accord with results obtained by Ritchie who
reported N+ = 8.64 for CNꢀ (in DMSO) and a rate constant
logk = 6.72 for the reaction of the tritylium ion with HOꢀ, from
which logk0(Ph3C+) = 1.97 can be derived: C. D. Ritchie, Can. J.
Chem. 1986, 64, 2239 – 2250
[12] For solvent nucleophilicities, see: S. Minegishi, S. Kobayashi, H.
Mayr, J. Am. Chem. Soc. 2004, 126, 5174 – 5181.
[13] R. Quelet, Bull. Soc. Chim. Fr. 1940, 205 – 215.
[14] R. N. Lewis, P. V. Susi, J. Am. Chem. Soc. 1952, 74, 840 – 841.
[15] a) D. T. Mowry, Chem. Rev. 1948, 42, 189 – 283; b) C. Grund-
mann, Methoden Org. Chem. (Houben-Weyl), Vol. E5, 1985,
pp. 1448 – 1488.
Scheme 6. Exclusive formation of acetonitrile in the reactions of tetra-
n-butylammonium cyanide with the hard SN2 alkylating agents methyl
triflate and trimethyloxonium tetrafluoroborate.
[16] a) R. Walden, Ber. Dtsch. Chem. Ges. 1907, 40, 3214 – 3217; b) it
has been claimed that traces of malodorous isocyanides can form
in this reaction; however, measurable amounts of isocyanides
(ꢁ 5%) are formed only when the reactions are conducted at
higher temperatures (> 1008C): J. Wade, J. Chem. Soc. 1902, 81,
1596 – 1617.
[17] Exclusive C attack was also reported for the reactions of KCN/
[18]crown-6 with methyl methanesulfonate in ethanol, acetoni-
trile, THF, and benzene: H. Lemmetyinen, L. Lehtinen, J.
Koskikallio, Finn. Chem. Lett. 1979, 72 – 75.
In conclusion, electrophilic alkylations at free CNꢀ occur
preferentially at carbon, regardless of whether the SN1 or SN2
mechanism is involved and whether hard or soft electrophiles
are employed. Preferred N attack, as postulated for hard
electrophiles by the HSAB principle, could not be observed
with any alkylatingaegnt. Isocyano compounds are only
formed with highly reactive electrophiles that react without
an activation barrier because the diffusion limit is approached
(Figure 2). We therefore claim that the knowledge of absolute
rate constants and not of the hardness of the reaction partners
is needed to predict the outcome of alkylations of the cyanide
ion.
Received: August 13, 2004
Keywords: ambident anions · HSAB principle · Klopman–Salem
.
equation · Kornblum rule · reaction kinetics
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