Electrophilic alkylations in neutral aqueous or alcoholic solutions

Article abstract of DOI:10.1002/anie.200460812

Acid-free Friedel-Crafts chemistry: A paradox? Nucleophilicity scales, based on reactions with benzhydrylium ions, show that many π systems are more nucleophilic than aqueous or alcoholic solutions that are generally employed as solvents for S_N1 reactions. Solvolytically generated carbocations can, therefore, be trapped by donor-substituted arenes and alkenes to form products of Friedel-Crafts-type reactions in neutral aqueous solutions (see scheme).

Full text of DOI:10.1002/anie.200460812

Communications
Friedel–Crafts Reactions
Electrophilic Alkylations in Neutral Aqueous or
Alcoholic Solutions**
Matthias Hofmann, Nathalie Hampel, Tanja Kanzian,
and Herbert Mayr*
Dedicated to Professor Johann Mulzer
on the occasion of his 60th birthday
Friedel–Crafts alkylations and mechanistically related reac-
tions, such as tert-alkylations of silyl enol ethers or alkoxy-
alkylations of allylsilanes and enol ethers, are usually
promoted by Lewis acids in inert solvents.[1] When such
reactions are carried out in aqueous or alcoholic solutions,
usually Brönsted or nonhydrolyzable Lewis acids are
employed to generate small equilibrium concentrations of
carbocations.[2] Basic and even neutral aqueous or alcoholic
[*] Dipl.-Chem. M. Hofmann, N. Hampel, T. Kanzian, 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 Deutsche Forschungsgemeinschaft for financial
support and Dr. G. Remennikov and Dipl.-Chem. M. Westermaier
for synthesizing compounds 4c and 4 f.
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.200460812
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solutions have been considered prohibitive for such reactions,
since water and alcohols are intuitively considered as strong
nucleophiles which instantaneously trap the intermediates of
SN1 reactions and do not give p nucleophiles a chance to
intercept the transient carbocations.
In numerous papers we have demonstrated that the
reactions of carbocations with nucleophiles can be described
by Equation (1),[3–5] where k is a second-order (Lmolꢀ1 sꢀ1) or
first-order (sꢀ1) rate constant at 208C, s is a nucleophile-
specific slope parameter, N (or N1) is the nucleophilicity
parameter, and E is the electrophilicity parameter.
cations should be trapped by p nucleophiles[6] (e.g., 1m
alkenes or arenes) if N of the corresponding p nucleophile
is greater than N1 of the solvent under consideration, that is, if
the corresponding nucleophile is located above the solvent in
a graphical representation such as Figure 1. We now report an
experimental verification of this forecast and thus lay the
basis for a new type of Friedel–Crafts chemistry.[7]
To examine the scope of nucleophiles we have examined
reactions of 4-methoxybenzyl halides (1-X) with arenes and
enol ethers in different solvents. Table 1 shows that electro-
log k ¼ sðN þ EÞ
ð1Þ
Recently, we reported nucleophilicity parameters N1 for
some solvents[6] (Figure 1, right), and compared them with
previously published nucleophilicity parameters N for p
systems[3,4] (Figure 1, left). The first-order rate constants
calculated from N1 and the second-order rate constants
calculated from N by Equation (1) become directly compa-
rable if 1m solutions of the p nucleophiles are considered
(pseudo-first-order rate constant k1Y = k[nucleophile]0). We
had, therefore, predicted that solvolytically generated carbo-
philic aromatic substitutions in 1m solutions of arenes with 4-
methoxybenzyl halides [Eq. (2)]have been successful in all
cases where N of the arenes is greater than N1 of the solvent.
The formation of 2a–d in 2,2,2-trifluoroethanol (T) shows
that trapping with the p nucleophiles may also be possible in
cases where the N parameter of the p system is slightly
smaller than N1 of the solvent.
Can the formation of products 2a–d in 2,2,2-trifluoro-
ethanol be explained by consecutive reactions of the initially
produced trifluoroethyl ether 1-OCH2CF3 with the arenes?
When 1-OCH2CF3 and mesitylene were dissolved in 2,2,2-
trifluoroethanol at ambient temperature, quantitative con-
version into 2b was observed [Eq. (3a)]. No reaction took
place in the presence of 2,6-lutidine, however, [Eq. (3b,c)]
indicating that the products isolated in the presence of base
(Table 1) are the results of kinetic control. We conclude,
therefore, that in 2,2,2-trifluoroethanol the 4-methoxybenzyl
cation reacts faster with mesitylene than with the solvent.
These results indicate a noticeable increase of the
nucleophilicity of p systems in hydroxylic solvents, in contrast
to previous reports which showed that the rates of the
reactions of carbocations with olefins are only slightly
affected by solvent polarity [k(CH3NO2)/k(CH2Cl2) = 4].[8]
Since the diphenylmethyl cation, which shows a similar
electrophilicity as the 4-methoxybenzyl cation,[9] did not
react with m-xylene or mesitylene, when generated from
diphenylmethyl chloride in 2,2,2-trifluoroethanol in the
Figure 1. Comparison of the nucleophilicity parameters N1 of solvents
with the N parameters of typical p systems. Mixtures of solvents are
given as vol%, for example, 80A20W=80% acetone/20% water.
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Table 1: Reactions of 4-methoxybenzyl halides (1-X) with arenes [according to Equation (2)].
considerably slower than in analogous
reactions in the presence of water and
base (Table 1). Less nucleophilic arenes,
for example, 2-methylfuran, which formed
the substitution product 4e in 68% yield in
90% aqueous acetonitrile (90AN10W)
(see below), did not react with 1-Br in
pure acetonitrile.
The isolation of the carbonyl com-
pounds 3a and 3b from the reactions of
4-methoxybenzyl bromide with alkyl enol
ethers indicates that the enol ethers react
faster with the 4-methoxybenzyl cation
than water in 90% aqueous acetonitrile
[Eq. (4), Table 2], but that water reacts
faster with the resulting a-alkoxycarbe-
nium ions under the same conditions. This
change of selectivity may be explained by
the geminal interaction of two oxygen
groups at the same carbon center in the
semiacetals formed from a-alkoxycarbe-
nium ions and water (anomeric stabiliza-
tion).[10]
H–Ar
N
Product
X
Solvent
Base
Yield
[%]
(R=4-CH3OC6H4CH2)
ꢀ3.54
Cl
Cl
Cl
H
T
T
NH4HCO3
NH4HCO3
2,6-lutidine
47
66
[b]
+
ca. ꢀ2.6
ꢀ1.18
Cl
Cl
Cl
H
T
T
NH4HCO3
NH4HCO3
2,6-lutidine
85
88
79
Cl
Cl
Cl
H
T
T
NH4HCO3
NH4HCO3
2,6-lutidine
77
86
[b]
+
0.13
Br
T
NH4HCO3
97
1.26
2.48
Cl
T
2-chloropyridine
84
Cl
Cl
T
T
2,6-lutidine
–
91
84
[b]
Br 90AN10W NH4HCO3
+
ca. 4
Cl 2,6-lutidine
T
88
65
Br 90AN10W NH4HCO3
In a third series of experiments, we
have examined the range of electrophiles
using 2-methylfuran as nucleophile
[Eq. (5), Table 3]. It is found that a wide
variety of SN1-active substrates, particu-
larly benzyl and allyl halides, can be
employed for Friedel–Crafts reactions
under these conditions, and we are pres-
ently investigating the scope and limita-
tions of this new method.
5.80
5.85
Br 80A20W
Br 80A20W
NH4HCO3
NH4HCO3
75
70
[a] Contains traces of 1,2,3-substituted product. [b] Quantitative conversion determined by GC-MS.
[c] Contains traces of 1,2-substituted product. [d] Isolated as a mixture of regioisomers. [e] Contains 7%
of 1,2,3-substituted product. [f] Contains 17% of the corresponding 2-isomer. [g] Contains 21% of the
corresponding 3-substituted product.
presence of these p nucleophiles, the solvent effects on these
reactions are still obscure.
When 4-methoxybenzyl bromide (1-Br) was mixed with 1-
methylpyrrole without a solvent or in acetonitrile, compound
2i, accompanied by numerous side products, was produced
Experimental Section
Typical procedure—preparation of 4e: At ambient temperature, 4-
methoxybenzyl bromide (1.00 g, 4.97 mmol) was added dropwise to
25 mL of a stirred solution of 2-methylfuran (2.05 g, 25.0 mmol) in
90% aqueous acetonitrile (v/v) (90AN10W) and ammonium hydro-
gencarbonate (786 mg, 9.94 mmol). After 2 h, water (20 mL) was
added and the reaction mixture was extracted with diethyl ether (3 ”
20 mL). The combined ethereal phases were dried (MgSO4), and the
solvent was evaporated under reduced pressure.
The residue was purified by column chromatog-
raphy on silica gel (pentane/ether 7:1) to yield 4e
Table 2: Reactions of 4-methoxybenzyl bromide with enol ethers [according to Equation (4)].
(737 mg, 73%) as a colorless liquid.
Enol ether
N
Product
(R=4-CH3OC6H4CH2)
Solvent
Base
Yield [%]
60
Received: May 27, 2004
ca. 4
90AN10W
NH4HCO3
5.41
6.22
90AN10W
90AN10W
2,6-lutidine
NH4HCO3
67
33
Keywords: alkylations · carbocations ·
Friedel–Crafts reactions · SN1 reactions ·
solvent effects
.
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Chemie
Table 3: Reactions of SN1-active substrates with 2-methylfuran [according to Equation (5)].
R–X
Product
(R=4-CH3OC6H4CH2)
Solvent
Base
Yield [%]
85
T
2-chloropyridine
T
2,6-lutidine
NH4HCO3
70
48
90AN10W
T
T
2,6-lutidine
2,6-lutidine
87
74
90AN10W
90AN10W
NH4HCO3
–
73
68
90AN10W
NH4HCO3
61
[a] Isolated as a mixture (84:16; NMR) of 4 f and the allylicisomer 2-methyl-5-(1-phenylallyl)furan.
[7]H. Mayr, M. Hofmann, S. Minegishi, N. Hampel, German-
Patent 10 2004 006 785.6, 2004.
[8]H. Mayr, R. Schneider, C. Schade, J. Bartl, R. Bederke, J. Am.
Chem. Soc. 1990, 112, 4446 – 4454.
[9]R. A. McClelland in Reactive Intermediate Chemistry (Eds.:
R. A. Moss, M. S. Platz, M. Jones, Jr.), Wiley, Hoboken, 2004,
pp. 3 – 40.
[10]a) P. v. R. Schleyer, E. D. Jemmis, G. W. Spitznagel, J. Am.
Chem. Soc. 1985, 107, 6393 – 6394; b) A. J. Kirby, I. V. Komarov,
P. D. Wothers, N. Feeder, P. G. Jones, Pure Appl. Chem. 1999, 71,
385 – 391; c) P. P. Graczyk, M. Mikolajczyk, Top. Stereochem.
1994, 21, 159 – 349; d) ACS Symposium Series No. 539: The
Anomeric Effect and Associated Stereoelectronic Effects (Ed.:
G. R. J. Thatcher), American Chemical Society, Washington DC,
1993; e) E. Juaristi, G. Cuevas, Tetrahedron 1992, 48, 5019 – 5087;
f) S. O. N. Lill, G. Rauhut, E. Anders, Chem. Eur. J. 2003, 9,
3143 – 3153.
[1]a) C. Friedel, J. M. Crafts, J. Chem. Soc. 1877, 32, 725; b) G. A.
Olah, Friedel-Crafts and related reactions, Vol. 1 and 2, Wiley,
New York, 1963–1964; c) R. M. Roberts, A. A. Khalaf, Friedel-
Crafts Alkylation Chemistry: A Century of Discovery, Marcel
Dekker, New York, 1984; d) R. Taylor, Electrophilic Aromatic
Substitution, Wiley, New York, 1990, pp. 187 – 203; e) A.
Hosomi, Acc. Chem. Res. 1988, 21, 200 – 206; f) I. Fleming, J.
DunoguØs, R. Smithers in Organic Reactions (Ed.: A. S. Kende),
Wiley, New York, 1989, pp. 57 – 575; g) T. Mukaiyama, M.
Murakami, Synthesis 1987, 1043 – 1054; h) R. Mahrwald, Chem.
Rev. 1999, 99, 1095 – 1120; i) M. T. Reetz, Top. Curr. Chem. 1982,
106, 1 – 54; j) Lewis Acids in Organic Synthesis, Vol. 1 and 2 (Ed.:
H. Yamamoto), Wiley-VCH, Weinheim, 2000.
[2]a) S. Kobayashi, K. Manabe, Chem. Eur. J. 2002, 8, 4094 – 4101;
b) S. Kobayashi, Eur. J. Org. Chem. 1999, 15 – 27; c) A. Corma,
H. Garcia, Chem. Rev. 2003, 103, 4307 – 4365; d) U. M. Lind-
ström, Chem. Rev. 2002, 102, 2751 – 2772; e) J. P. Richard,
Biochemistry 1998, 37, 4305 – 4309.
[3]Reviews: a) H. Mayr, M. Patz, Angew. Chem. 1994, 106, 990 –
1010; Angew. Chem. Int. Ed. Engl. 1994, 33, 938 – 957; b) 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; c) H. Mayr, B. Kempf,
A. R. Ofial, Acc. Chem. Res. 2003, 36, 66 – 77.
[4]For reactions with neutral C-nucleophiles, see: a) B. Kempf, N.
Hampel, A. R. Ofial, H. Mayr, Chem. Eur. J. 2003, 9, 2209 –
2218; b) T. Bug, M. Hartnagel, C. Schlierf, H. Mayr, Chem. Eur.
J. 2003, 9, 4068 – 4076.
[5]For reactions with anions, see: a) R. Lucius, R. Loos, H. Mayr,
Angew. Chem. 2002, 114, 97 – 102; Angew. Chem. Int. Ed. 2002,
41, 91 – 95; b) S. Minegishi, H. Mayr, J. Am. Chem. Soc. 2003,
125, 286 – 295; c) T. Bug, H. Mayr, J. Am. Chem. Soc. 2003, 125,
12980 – 12986; d) R. Loos, S. Kobayashi, H. Mayr, J. Am. Chem.
Soc. 2003, 125, 14126 – 14132.
[6]a) S. Minegishi, S. Kobayashi, H. Mayr, J. Am. Chem. Soc. 2004,
126, 5174 – 5181; b) B. Denegri, S. Minegishi, O. Kronja, H.
Mayr, Angew. Chem. 2004, 116, 2353 – 2356; Angew. Chem. Int.
Ed. 2004, 43, 2302 – 2305.
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