Nucleophilicity parameters for alkyl and aryl isocyanides

Article abstract of DOI:10.1002/anie.200605205

How nucleophilic are isocyanides? The kinetics of the reactions of alkyl and aryl isocyanides with benzhydrylium ions indicate that isocyanides are 10 orders of magnitude less reactive than the cyanide ion and their nucleophilic reactivity is comparable t

Full text of DOI:10.1002/anie.200605205

Angewandte
Chemie
DOI: 10.1002/anie.200605205
Nucleophilicity
Nucleophilicity Parameters for Alkyl and Aryl Isocyanides**
Vasily V. Tumanov, Alexander A. Tishkov, and Herbert Mayr*
Dedicated to Professor LutzF. Tietze on the occasion of his 65th birthday
Alkyl and aryl isocyanides have a unique carbene-like
structure with a formally divalent carbon atom. Their
electronic structure can be represented by the resonance
formula 1’ and 1’’. They are readily accessible by a variety of
For that reason, compounds 2a–h (Table 1) were selected as
reference electrophiles for this investigation.[7]
Treatment of the colored solutions of 2-BF4 and 2-ZnCl3
with isocyanides 1a–e in CH2Cl2 resulted in decolorization,
which we attributed to the formation of the colorless nitrilium
ions 3 (Scheme 1). In accord with this interpretation, the
iminoesters 5d and 5e were isolated when solutions of
chlorobis(4-methoxyphenyl)methane 2a-Cl and ZnCl2/Et2O
in CH2Cl2 were combined with 1d and 1e to give the nitrilium
ions 3d and 3e (Scheme 1), respectively, and successively
treated with the silyl ketene acetal 4 (Scheme 2). Treatment of
the nitrilium salt 3a-ZnCl3 with 4 did not yield the iminoester
methods and are important substrates for several useful
synthetic transformations including the Passerini and Ugi
reactions.[1] Many of these reactions proceed by the attack of a
carbon electrophile at the isocyano group,[2] but there is only
little information about the thermodynamics and kinetics of
these reactions.[3–5]
The most comprehensive nucleophilicity scale presently
available is based on the benzhydrylium method, which uses
reference electrophiles of comparable structure but widely
differing reactivity (24 orders of magnitude).[6] We report now
on the use of this method for determining the nucleophilic
reactivities of the isocyanides 1a–e (Ts = toluene-4-sulfonyl).
Table 1: Reference electrophiles used in this work for determining the
nucleophilic reactivities of isocyanides 1a–e.
Ar2CH+
E[a]
2a
0.00
2b
ꢀ1.36
ꢀ2.64
2c[b]
2d
2e
2 f
ꢀ3.14
ꢀ3.85
ꢀ4.72
ꢀ5.53
ꢀ5.89
We observed that the rates of the reactions of isocyanides 1a–
e with benzhydrylium ions 2 having electrophilicity values E
between ꢀ6 and 0 were in a conveniently measurable range.
2g
2h
[*] 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
Homepage: http://www.cup.uni-muenchen.de/oc/mayr
[a] Electrophilicities E of reference electrophiles from Ref. [7]. [b] Fc=
ferrocenyl.
V. V. Tumanov
N. D. Zelinsky Institute of Organic Chemistry
Russian Academy of Sciences
Leninsky prosp. 47, 119991 Moscow (Russia)
[**] We thank the Deutsche Forschungsgemeinschaft (Ma673/19-2) for
support of this work and Dr. A. R. Ofial for helpful discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. Reaction of benzhydrylium ions 2a–h with isocyanides 1a–e
in CH2Cl2 to give nitrilium ions 3.
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Scheme 2. Reactions of nitrilium ions 3d and 3e with the silyl ketene
acetal 4 to give the imino esters 5d and 5e.
Figure 1. Kinetics of the reaction of 2e-BF4 with tBuNC (1a) in CH2Cl2
at 208C.
5a (R = tBu), but resulted in the formation of nitrile 6 when
the reaction was carried out at 208C (Scheme 3). Compound 7
was produced when this reaction was performed at ꢀ308C.
Whereas the reaction of the silyl ketene acetal 4 with the
nitrilium salt 3c-ZnCl3, arising from 1c and 2a-ZnCl3, yielded
a mixture of 7 and the iminoester 5c (R = 2,6-dimethyl-
phenyl), only polymeric material could be isolated from the
reactions of benzhydrylium salts with benzyl isocyanide (1b).
Table 2: Rate constants for the reactions of isocyanides 1a–e with
benzhydrylium ions 2a–h (CH2Cl2, 208C).
Isocyanide
Ar2CH+
k2 [mꢀ1 sꢀ1
]
N/s for 1a–e
1a
2d
2e
2 f
57.2
20.9
3.67
5.47/0.77
2g
2h
0.892
0.460
1b
2d
2e
2 f
2g
21.8
6.04
1.09
0.392
4.90/0.74
1c
1d
1e
2c
2d
2e
52.4
17.9
4.55
4.59/0.87
3.50/0.76
3.57/0.72
2a
2b
2c
421
46.5
4.24
2a
2b
380
39.6
Equation (1), where electrophiles are characterized by one
Scheme 3. Reaction of nitrilium ion 3a to give 6 (at 208C) and 7 (at
ꢀ308C).
lg k20 ꢁ ¼ sðE þ NÞ
ð1Þ
C
parameter (electrophilicity E) and nucleophiles are charac-
terized by two parameters (slope s and nucleophilicity N).
Equation (1) also holds for the reactions of nucleophiles with
other types of carbocations[8] including metal-coordinated C
electrophiles[7] and Michael acceptors.[9] Recently, it has been
demonstrated that the nucleophilicity parameters s and N
derived by the benzhydrylium method[6,7] can also be used for
describing SN2 reactions, if Equation (1) is extended by an
electrophile-specific slope parameter sE.[10]
The linear correlations between lgk2 and the electro-
philicity parameters E of the benzhydrylium ions 2 in Figure 2
show that Equation (1) holds also for the reactions of
isocyanides 1 with benzhydrylium ions 2. In this way we can
derive the N and s values for the isocyanides 1a–e listed in the
last column of Table 2.
When solutions of benzhydrylium tetrafluoroborates or
triflates 2-X were treated with more than 10 equivalents of
isocyanides 1a–e in CH2Cl2, the formation of the colorless
nitrilium ions 3 was accompanied by an exponential decay of
the benzhydrylium absorbances as a result of the almost
constant concentration of 1. Plots of the resulting first-order
rate constants kobs versus the concentrations of 1a–e are
linear, as shown for one example in Figure 1 and for all other
kinetic runs in the Supporting Information. The slopes of
these correlations gave the second-order rate constants k2
listed in Table 2.
The benzhydrylium-based nucleophilicity scale[6,7] rests on
the fact that the second-order rate constants for the reactions
of nucleophiles with benzhydrylium ions can be described by
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nucleophilicity of the carbon atom by more than ten units on
the logarithmic N-scale (Scheme 5).
Scheme 5. Nucleophilicity parameters of CNꢀ and alkly and aryl
isocyanides.
Additional work is needed to elucidate whether the
nucleophilicity parameters s and N of isocyanides can also be
applied to SN2 reactions as previously shown for the
nucleophilicity parameters of alcohols, amines, phosphanes,
and some carbanions.[10]
Figure 2. Plots of lgk2 (CH2Cl2, 208C) for the reactions of the isocya-
nides 1a–e with benzhydrylium ions 2a–h versus their electrophilicity
parameters E.
Received: December 22, 2006
Published online: March 30, 2007
Table 2 and Figure 2 show that tert-butyl isocyanide (1a) is
the most reactive nucleophile in this series, followed by benzyl
isocyanide (1b) and 2,6-dimethylphenyl isocyanide (1c).
Remarkably, the acceptor-substituted isocyanides 1d and 1e
are only one to two orders of magnitude less nucleophilic than
the isocyanides 1a–c, which bear only hydrocarbon moieties.
Therefore, it can be expected that the nucleophilicities of
most isocyanides are in this range, comparable to the
reactivities of furans, pyrroles, allylsilanes, and silyl enol
ethers (Scheme 4). This ranking is in good agreement with the
Keywords: carbocations · isocyanides · kinetics · nitrilium ions ·
.
reactivity
[1]Reviews: a) I. Ugi, S. Lohberger, R. Karl in Comprehensive
Organic Synthesis, Vol. 2 (Ed.: C. H. Heathcock), Pergamon,
Oxford, 1991, pp. 1083 – 1109; b) A. Dömling, Chem. Rev. 2006,
106, 17 – 89; c) L. Banfi, R. Riva, Org. React. 2005, 65, 1 – 140;
d) M. Suginome, Y. Ito in Science of Synthesis, Vol. 19, Thieme,
Stuttgart, 2004, pp. 445 – 530; e) S.-I. Murahashi in Science of
Synthesis, Vol. 19, Thieme, Stuttgart, 2004, pp. 1 – 16; f) V. Nair,
C. Rajesh, A. U. Vinod, S. Bindu, A. R. Sreekanth, J. S. Mathen,
L. Balagopal, Acc. Chem. Res. 2003, 36, 899 – 907; g) R. V. A.
Orru, M. de Greef, Synthesis 2003, 1471 – 1499; h) J. Zhu, Eur. J.
Org. Chem. 2003, 1133 – 1144; i) C. Rꢀchardt, M. Meier, K. Haaf,
J. Pakusch, E. K. A. Wolber, B. Mꢀller, Angew. Chem. 1991, 103,
907 – 915; Angew. Chem. Int. Ed. Engl. 1991, 30, 893 – 901; j) I.
Ugi, B. Werner, A. Dömling, Molecules 2003, 8, 53 – 66; k) G.
Dyker in Organic Synthesis Highlights IV (Ed.: H.-G. Schmalz),
Wiley-VCH, Weinheim, 2000, pp. 53 – 57; l) I. Ugi, Pure Appl.
Chem. 2001, 73, 187 – 191; m) A. Dömling, I. Ugi, Angew. Chem.
2000, 112, 3300 – 3344; Angew. Chem. Int. Ed. 2000, 39, 3168 –
3210.
[2]J. Campo, M. Garcia-Valverde, S. Marcaccini, M. J. Rojo, T.
Torroba, Org. Biomol. Chem. 2006, 4, 757 – 765.
[3]Proton affinities: a) J. S. Knight, C. G. Freeman, M. J. McEwan,
J. Am. Chem. Soc. 1986, 108, 1404 – 1408; b) J. E. Del Bene, J.
Am. Chem. Soc. 1993, 115, 1610 – 1611; c) M. Meot-Ner, Z.
Karpas, C. A. Deakyne, J. Am. Chem. Soc. 1986, 108, 3913 –
3919.
Scheme 4. Comparison of the nucleophilicities of isocyanides 1a–e
and other C nucleophiles (N parameters of the other nucleophiles
from Refs. [6,7]).
[4]Kinetics of acid-catalyzed hydrolysis: a) Y. Y. Lim, A. R. Stein,
Can. J. Chem. 1971, 49, 2455 – 2459; b) K. Sung, C.-C. Chen,
Tetrahedron Lett. 2001, 42, 4845 – 4848.
[5]Hydrogen-bond-donor abilities: a) A. C. Legon, J. Chem. Soc.
Perkin Trans. 2 1992, 329 – 330; b) M. Meot-Ner, L. W. Sieck,
K. K. Koretke, C. A. Deakyne, J. Am. Chem. Soc. 1997, 119,
10430 – 10438.
[6]a) R. Lucius, R. Loos, H. Mayr, Angew. Chem. 2002, 114, 97 –
102; Angew. Chem. Int. Ed. 2002, 41, 91 – 95; b) H. Mayr, B.
Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36, 66 – 77; c) H.
Mayr, A. R. Ofial in Carbocation Chemistry (Eds.: G. A. Olah,
G. K. S. Prakash), Wiley, Hoboken, NJ, 2004, Chap. 13, pp. 331 –
358; d) H. Mayr, A. R. Ofial, Pure Appl. Chem. 2005, 77, 1807 –
relative proton affinities of these compounds: Meot-Ner et al.
determined proton affinities of 868 kJmolꢀ1 for tert-butyl
isocyanide (1a) and 867 kJmolꢀ1 for PhNC,[3c] values similar
to those reported for 2-methylfuran (866 kJmolꢀ1) and
pyrrole (875 kJmolꢀ1).[11]
Analogous kinetic investigations have recently yielded a
nucleophilicity parameter of N = 16.3 for free CNꢀ in
acetonitrile solution,[12] showing that attachment of an alkyl
or aryl group to the N terminus of the cyanide ion reduces the
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1821; e) for a collection of reactivity parameters E, N, and s, see:
Mayr, J. Phys. Org. Chem. 2003, 16, 431 – 437; c) F. Terrier, S.
Lakhdar, T. Boubaker, R. Goumont, J. Org. Chem. 2005, 70,
6242 – 6253.
http://www.cup.uni-muenchen.de/oc/mayr/DBintro.html.
[7]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.
[8]a) H. Mayr, C. Fichtner, A. R. Ofial, J. Chem. Soc. Perkin Trans.
2 2002, 1435 – 1440; b) C. Fichtner, G. Remennikov, H. Mayr,
Eur. J. Org. Chem. 2001, 4451 – 4456.
[10]T. B. Phan, M. Breugst, H. Mayr, Angew. Chem. 2006, 118, 3954 –
3959; Angew. Chem. Int. Ed. 2006, 45, 3869 – 3874.
[11]E. P. Hunter, S. G. Lias, J. Phys. Chem. Ref. Data 1998, 27, 413 –
658.
[12]A. A. Tishkov, H. Mayr, Angew. Chem. 2005, 117, 145 – 148;
Angew. Chem. Int. Ed. 2005, 44, 142 – 145.
[9]a) T. Lemek, H. Mayr, J. Org. Chem. 2003, 68, 6880 – 6886;
b) G. Ya. Remennikov, B. Kempf, A. R. Ofial, K. Polborn, H.
3566
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