A new look at the friedel-crafts alkylation reaction

Full text of DOI:10.1021/jo960935r

7986
J . Org. Chem. 1996, 61, 7986-7987
Th e Electr op h ile. The nitrosoamide decomposition
introduces into the medium (eq 1) nitrogen-separated
carbocation ion-pairs1,5,8,9 by a unimolecular process. The
counterion and the aromatic substrate compete for the
carbocation in irreversible reactions,10 and the high speed
of the counterion reaction to yield ester, limited by the
rate of diffusion of N2 into the medium, results in the
carbocation having an exceedingly short time to react
with the aromatic compounds before being scavenged by
the counterion.1 The product distributions do not change
during the course of the reaction or on standing, and
product formation is under strict kinetic control. The
alkylation yields are a function of the reactivities of
the counterion, the cation, and the substrate;11 excellent
product balances can be achieved (Table 1). The carbo-
cations formed by this approach are extraordinarily
reactive,9 and they probably represent as free a carbo-
cation as can be generated in liquid media. The high
meta yields obtained in benzylation (14-26%) relative
to values found in the standard F-C studies (1.1-9.6%)3,4
indicate that the alkylating agent in the standard F-C
approach is less reactive than that acting in the de-
aminative approach; some type of carbocation-ligand
complexing must be involved in the former case,
therefore.2,3a,4
Th e Tr a n sit ion St a t e(s). Most standard Friedel-
Crafts alkylations, e.g., methylation, ethylation, and
isopropylation, follow the Brown selectivity relationship,2
which correlates intermolecular selectivity among dif-
ferent substrates with intramolecular selectivity (ortho,
meta, para distribution). A plot of our data via the
equation of Brown, et al., log pf ) bSf,13 is linear (R2 )
0.985; slope ) 1.52). This linearity of the BSR plot and
also that of log % yield of alkylated aromatics vs log %
meta isomer (data of Table 1), another type of selectivity
plot (R2 ) 0.935), indicate that the mechanism of alkyl-
A New Look a t th e F r ied el-Cr a fts
Alk yla tion Rea ction 1
Emil H. White,* Ron W. Darbeau, Yulong Chen,
Steven Chen, and David Chen
Department of Chemistry, The J ohns Hopkins University,
Baltimore, Maryland 21218
Received May 21, 1996
The bond-forming step in the Friedel-Crafts (F-C)
alkylation reaction was investigated through use of a
method for introducing essentially free carbocations into
an aromatic solvent in the absence of catalysts. This
direct approach led to elucidation of the reaction mech-
anism of the alkylation step.
Standard Friedel-Crafts alkylations involve aromatic
substitution by an electrophile generally derived from
some combination of an alkyl group and the conjugate
base of a strong acid (RX).2-4 In the alkylation of mixed
solvents (benzene and toluene, e.g.) the intermolecular
selectivity (kT/kB) is in proportion to the intramolecular
selectivity for a wide variety of reactions (the Brown
selectivity relationship, BSR).2 Benzylation is a particu-
larly important alkylation since substituent effects can
be readily examined, but most previous studies of ben-
zylation3,4 have led to the conclusion that benzylation
does not follow the BSR. This conclusion is of concern
because of general problems with the standard F-C
approach including product isomerization,3e dispro-
portionation,3e overalkylation,3b extreme sensitivity to
traces of water,4c rate of mixing,3d etc. The nitrosoamide
approach (RX, XdN2+) (eq 1) circumvents those difficul-
ties.
(2) Stock, L. M.; Brown, H. C. Adv. Phys. Org. Chem. 1963, 1, 35-
154, and cited references therein to J . Am. Chem. Soc. 1953, 1956,
1959.
(3) (a) Olah, G. A.; Kuhn, S. J .; Flood, S. H. J . Am. Chem. Soc. 1962,
84, 1688-1695. (b) Olah, G.; Olah, J . A. J . Org. Chem. 1967, 32, 1612-
1614. (c) Olah, G. A.; Tashiro, M.; Kobayashi, S. J . Am. Chem. Soc.
1970, 92, 6369-6371. (d) Olah, G. A. Acc. Chem. Res. 1971, 4, 240-
248. (e) Olah, G.; Kobayashi, S.; Tashiro, M. J . Am. Chem. Soc. 1972,
94, 7448-7461. (f) Olah, G. A.; Olah J . A.; Ohyama, T. J . Am. Chem.
Soc. 1984, 106, 5284-5290. (g) Olah, G. A. et al. J . Am. Chem. Soc.
1987, 109, 3708-3713. (h) Olah, A.; Farooq, O.; Farnia, S. M. F.; Olah,
J . A. J . Am. Chem. Soc. 1988, 110, 2560-2565.
(4) (a) DeHaan, F. P. et al. J . Am. Chem. Soc. 1984, 106, 7038-
7046. (b) DeHaan, F. P. et al. J . Org. Chem. 1984, 49, 3954-3958. (c)
DeHaan, F. P. et al. J . Am. Chem. Soc. 1990, 112, 356-363.
(5) The predominant retention of configuration observed in homolo-
gous reactions under similar conditions1 and 18O studies of “intra-
molecular inversion”6 require the existence of the carbocation for a
finite period of time. The decomposition in toluene of N-methyl-N-
nitroso-4-toluenesulfonamide (Diazald), expected to react via the
diazonium ion,7 does not yield the xylene isomers; only methyl tosylate
is formed.
(6) White, E. H.; Aufdermarsh, C. A., J r. J . Am. Chem. Soc. 1961,
83, 1179.
(7) Brosch, D.; Kirmse, W. J . J . Org. Chem. 1991, 56, 907-908.
(8) White, E. H.; DePinto, J . T.; Polito, A. J .; Bauer, I.; Roswell, D.
F. J . Am. Chem. Soc. 1988, 110, 3708.
(9) White, E. H.; McGirk, R. H.; Aufdermarsh, C. A., J r.; Tiwari, H.
P.; Todd, M. J . J . Am. Chem. Soc. 1973, 95, 8107.
(10) White, E. H.; Woodcock, D. J . in The Chemistry of the Amino
Group; Patai, S., Ed.; Wiley-Interscience: New York, 1968; pp 440-
483.
(11) Reactive aromatics lead to high yields of products; e.g., pyrrole
is benzylated in yields of ∼80%. (Pyrrole cannot be alkylated directly
by the standard F-C approach).
(12) For evidence related to rotation of the cation, see refs 1, 6, 8.
(13) pf ) 6(kT/kB)(%p/100); Sf ) log pf/[3(kT/kB)(%m/100)] (ref 2).
(14) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry, 3rd ed.; Harper and Row Publishers: New York,
1987; Chapter 7.
(1) Preceding publication: White E. H. et al. J . Am. Chem. Soc. 1992,
114, 8023-8031.
S0022-3263(96)00935-8 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 23, 1996 7987
Ta ble 1. Yield s a n d Rela tive Ra tes in Nitr osoa m id e-Med ia ted Ben zyla tion s (4-R-C6H4CH2+) of Ben zen e a n d Tolu en ea -c
yields (%)
isomer distribution (%) (4-R-benzyltoluenes)
alkylating
agent
inter/intra
selectivitiese
d
R
temp (°C)
3
4 + 5
kT/kB
ortho
meta
para
1a
1b
1b
1c
1d
1e
H
80
40
25
80
80
80
91.5
89.4
87.2
98.0
90.7
73.4
8.5
10.6
12.8
2.0
9.3
26.6
2.51
2.55
2.66
4.39
2.41
1.33
43.8
46.0
46.6
44.1
44.0
45.1
17.8
19.4
18.6
14.1
18.3
26.4
38.4
34.6
34.8
41.8
37.7
28.5
1.0
1.1
1.1
1.3
0.9
0.9
CH3
Cl
NO2
a
Solvent ) equimolar benzene and toluene. Product distributions by NMR and GLC (30 m SE-30, 0.25 mm i.d.; col temp ) 145 °C);
total yields of products ∼97%. [1a ,e] ) ∼0.05 M; pyridine present in all runs (∼0.1 M). c Standard deviations for kT/kB e 0.12, for relative
b
yields e 0.90. Values are independent of total incubation times and initial solvent ratios. e See text.
d
ation does not change over the range of para-substituents
used (1a -e).14 A single type of transition state, presum-
ably of the σ type, is thus adequate to account for our
data.
arenium ion intermediates that have undergone coupled
hydrogen, alkyl rearrangements (eq 3).18-20
A Gen er a l Rea ction Mech a n ism . Proton loss in the
deaminative benzylations is not a significant part of the
rate-determining step since no hydrogen isotope effect
was detected (kT/kB ) 2.34 ( 0.08 in fully deuterated
solvents, in C6H6 + C7D8, and in C6D6 + C7H8). In view
of the similarity in the effects of the methyl group of
toluene on inter- and intramolecular selectivity in ben-
zylation [6/5(kT/kB)/2/3(o + p)/m ) ∼1] (Table 1), it would
appear that the same transition states that determine
the intramolecular selectivity (those leading to 6 and 8
relative to the transition state leading to 7, benzene-like
with respect to the methyl substituent) also largely
determine (relative to the transition state for the alkyl-
ation of benzene) the intermolecular selectivity; differ-
ences in four activation energies would thus determine
both types of selectivity (eq 2). This interpretation
Benzylation via the standard F-C approach utilizing
substituted benzyl chlorides has been reported not to
follow the BSR,3c-e,4a,15 and to account for that observation
two types of transition states were proposed for the
alkylations: a π-type for the more reactive benzyl elec-
trophiles (including the parent “benzyl cation”) “which
determines substrate selectivity”, “followed by σ-complex
formation determining positional selectivity”3d and a
σ-type for the less reactive ones.3c-e These conclusions
have been criticized on the basis of theory16 and
experiment;4b further, if the published data3c for only the
para-substituted benzyl chlorides are considered (to
minimize steric effects and complications due to over-
alkylation), the BSR plot obtained is linear (R2 ) 0.918),
consistent with the single transition state model.
Th e Ar en iu m Ion In ter m ed ia te a n d th e Sou r ce
of th e Meta Isom er . The decomposition of nitrosoamide
1e in 2,4,6-trideuteriotoluene was carried out and the
(nitrobenzyl)toluenes formed (5, R′ ) 4-nitrobenzyl)
(Table 1) were analyzed by GC-MS17 for their deuterium
content. The local electron ionization of the nitrophenyl
ring permits an MS analysis of the deuterium content of
the other ring. The data: ortho, 2.0; meta, 2.93; para,
2.0 D/molecule indicate that the ortho and para isomers
and 90% of the meta isomer are formed with the loss of
only the hydrogen isotope originally present at the
substitution site; in the meta case, ∼10% of the molecules
have lost a deuterium atom, possibly via hydrogen
exchange along a path leading to the most stable arenium
ion (7 f 9 (and 2-H isomer) f meta 5). The deuterium
labeling results indicating that the ortho, meta, and para
isomers are formed by similar mechanistic pathways, the
linear log % hydrocarbon yield vs log % meta yield
relationship for our data, and the yield data (Table 1)
provide evidence that the yield of the meta isomer in
benzylation is in proportion to the reactivity of the
electrophile.
provides a conceptual basis for the empirical BSR and it
may be applicable to other electrophilic substitutions that
follow that relationship, although the identity and type
of electrophile will differ from case to case.
Su p p or tin g In for m a tion Ava ila ble: Experimental details
(10 pages).
Our benzylation results, thus, are not in agreement
with a proposal that the meta isomer in alkylations
stems, to an indeterminate degree, from para (and ortho)
J O960935R
(19)
(15) In a few cases, however, b values calculated from the BSR
equation have been reported near the theoretical value of 1.3.3e,4b,c
(16) J ohnson, C. D.; Schofield, K. J . Am. Chem. Soc. 1973, 95, 270-
272.
(17) (a) University of Illinois Mass Spectrometry Laboratory (Field
Ionization used). (b) No detectible M - 1 peaks were observed for model
compounds.
(18) Putative supporting evidence was obtained for the mecha-
nism19,20 in the methylation of 2,4,6-trideuteriotoluene; no data or
details were given for the analysis of the xylene mixture produced, and
the large M - 1 MS peak for toluene renders the analysis arguable.21
Further, the observed order of arenium ion rearrangements22 is nearly
the opposite of the order cited3g in support of the rearrangement
hypothesis.
(20) The coupled hydrogen-alkyl rearrangements were addressed in
refs 3a,b,d-h.
(21) Biemann, K. Mass Spectrometry: Organic Chemical Applica-
tions; McGraw-Hill Book Company, Inc.: New York, 1962; p 209.
(22) Koptyug, V. A. Contemporary Problems in Carbonium Ion
Chemistry III: Arenium Ions-Structure and Reactivity; Springer-
Verlag: New York, 1984. (a) p 164. (b) p 159.
(23) Hedaya, A. E.; Winstein, S. J . Am. Chem. Soc. 1967, 89, 1661-
1672.
(24) Adapted from ref 3f.