Hammett ρ of reactions of MeLi with benzophenones

Article abstract of DOI:10.1021/jo0111762

Relative rates of reactions of MeLi with benzophenones in diethyl ether at 0 °C that furnish methyldiaryl-methanols were determined using slow addition of a MeLi solution to solutions containing an excess of two benzophenones. The additions exhibit a Hammett p of 0.94.

Full text of DOI:10.1021/jo0111762

4370
J . Org. Chem. 2002, 67, 4370-4371
0.2-0.3 for four additions5,8,9 of methyllithium, butyl-
Ha m m ett G of Rea ction s of MeLi w ith
lithium, and phenyllithium to benzaldehydes or benzo-
phenones.
Ben zop h en on es
Keith M. Maclin and Herman G. Richey, J r.*
Department of Chemistry, The Pennsylvania State
University, University Park, Pennsylvania l6802
hgr@chem.psu.edu
Received December 22, 2001
Abstr a ct: Relative rates of reactions of MeLi with benzo-
phenones in diethyl ether at 0 °C that furnish methyldiaryl-
methanols were determined using slow addition of a MeLi
solution to solutions containing an excess of two benzo-
phenones. The additions exhibit a Hammett F of 0.94.
We wondered if mixing problems similar to those we
encountered might have influenced other results obtained
by competition reactions, a possibility more likely for
additions of organolithium reagents than of the less
reactive Grignard reagents.10 A brief study11 (data in
Table 1) of ethyllithium and benzophenones (eq 1, R )
Et) in hexane at 5 °C, a system not previously studied,
found a F of 1.16, prompting an examination of a
previously studied system.
We chose to investigate reactions of methyllithium and
benzophenones (eq 1, R ) Me), for which a F of 0.27 was
reported.5 The solvent (diethyl ether) and temperature
(0 °C) were those used previously. Rather than the 1:1:1
portions of methyllithium, benzophenone, and substi-
tuted benzophenone (initial concentrations of ca. 0.10 M)
used before, however, 1:5:5 portions (initial ketone con-
centrations of ca. 0.15 M) were used. In the previous
work, methyllithium had been added with a hypodermic
syringe at an unspecified rate; in this work, methyl-
lithium was added slowly with a syringe pump and
through a needle that reached below the surface of the
rapidly stirred solution of ketones so that addition was
continuous rather than in drops. The only product found
from each benzophenone had the same GC retention time
as an authentic sample of the corresponding 2. The
observed rates relative to that of unsubstituted benzo-
phenone are listed in Table 1. A Hammett plot12 (Figure
1) gives a F of 0.94 (r2 ) 0.983), a value in the range
observed with Grignard reagents.
After toluene solutions of Et3ZnLi were found to rapidly
form products of addition to the carbonyl groups of
several aldehydes and ketones,1,2 we tried to determine
rates of such reactions with a series of substituted
acetophenones to obtain substituent effects. The rates,
however, proved to be too fast to determine by the
conventional procedure of taking and analyzing aliquots.
A competition procedure, adding Et3ZnLi to an excess of
a pair of acetophenones, was used instead. After a
reaction is quenched, an analysis of the mixture of two
addition products should provide the relative reactivities
of the acetophenones. Initial results suggested that
substituent effects were small, but these results were not
reproducible. Results that were reproducible and indi-
cated substituent effects to be significant finally were
obtained by using a lower temperature and slow addition
of Et3ZnLi to the solution of acetophenones. Apparently,
the rates are so fast that addition competed with mixing
of the reagents in the initial studies: the less reactive
acetophenone seemed more reactive than it really was
because its reaction with Et3ZnLi was faster than the
mixing that ideally would lead to Et3ZnLi always en-
countering a constant ratio of the two acetophenones.
The large Hammett F of 2.78 for Et3ZnLi reactions with
acetophenones is similar in magnitude to the F of 3.0
observed3 for additions of t-BuMgCl to benzophenones,
reactions in which electron transfer from the organome-
tallic reactant to the ketone generally is considered to
be rate determining.4 Except for a F of 1.96 for addition5
of “Me2CuLi” to benzophenones, additions of other polar
organometallic reagents to aryl carbonyl compounds have
much smaller F values: for example, 0.4-1.4 for seven
additions3,6-8 of methyl, butyl, and phenyl Grignard
reagents to acetophenones or benzophenones and only
Factors that might influence the relative reactivities
must change as the ratio of ketone to organolithium
reagent is increased; both the extent to which the
organolithium compound is coordinated by the ketone
and the amount of uncoordinated ketone, for example,
must be greater when the ketone is in considerable
excess. In fact, reactions with 1:1:1 methyllithium, 2a ,
and 2f (initial concentrations of 0.03 M, where a correc-
tion for depletion of the ketones was made) gave a
* To whom correspondence should be addressed. Fax: 814 865-3314.
(1) Musser, C. A.; Richey, H. G., J r. J . Org. Chem. 2000, 65, 7750.
(2) Also see: Maclin K. M.; Richey, H. G., J r. J . Org. Chem., in press.
(3) Holm, T.; Crossland, I. Acta Chem. Scand. l971, 25, 59.
(4) A review of mechanisms of Grignard reagent reactions: Holm,
T., Crossland, I. In Grignard Reagents: New Developments; Richey,
H. G., J r., Ed.; Wiley: Chichester, 2000; Chapter 1.
(5) Yamataka, H.; Fujimura, N.; Kawafuji, Y.; Hanafusa, T. J . Am.
Chem. Soc. l987, 109, 4305.
(6) Lewis, R. N.; Wright, J . R. J . Am. Chem. Soc. l952, 74, 1257.
Anteunis, M.; Van Schoote, J . Bull. Soc. Chim. Belg. l963, 72, 776.
(7) Yamataka, H.; Matsuyama, T.; Hanafusa, T. J . Am. Chem. Soc.
l989, 111, 4912.
(8) Yamataka, H.; Miyano, N.; Hanafusa, T. J . Org. Chem. l991,
56, 2573.
(9) Yamataka, H.; Kawafuji, Y.; Nagareda, K.; Miyano, N.; Hana-
fusa, T. J . Org. Chem. l989, 54, 4706.
(10) In fact, actual rates were determined for two of the Grignard
reagent addition series using a thermochemical method;4 therefore,
the relative rates of the reactions of these series are not susceptible to
the problems associated with using a competition procedure.
(11) Experiments were performed by Curtis A. Musser.
(12) Hammett σ values taken from: Hansch, C.; Leo, A.; Taft, R.
W. Chem. Rev. l991, 91, 165.
10.1021/jo0111762 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/22/2002

Notes
Ta ble 1. Rela tive Ra tes of Ad d ition of Alk yllith iu m
J . Org. Chem., Vol. 67, No. 12, 2002 4371
however, an alternate explanation considers both ketones
to react by the same rate-determining step; mixing is
slower than addition to benzophenone, masking inherent
rate differences between the isotopomers, but faster than
addition to very hindered 2,4,6-trimethylbenzophenone.
Com p ou n d s to Su bstitu ted Ben zop h en on es a n d σ Va lu es
of Su bstitu en ts
substituent
σ a
relative rate
3-CF3
3-Cl
4-Cl
4-Cl
4-F
none
3-Me
4-OMe
4-OMe
0.43
0.37
0.23
0.23
0.06
2.82b
2.47b
1.72b
1.81c
1.19b
(1.00)b,c
0.84b
0.67b
0.48c
Exp er im en ta l Section
Procedures involving organometallic compounds were per-
formed under a nitrogen atmosphere in a glovebox. Glassware
was dried in an oven at 180 °C. Diethyl ether and THF were
distilled over sodium benzophenone ketyl immediately prior to
use. Hexane was washed with a 50/50 solution of concentrated
sulfuric and nitric acids, concentrated sulfuric acid, water, 10%
aqueous sodium carbonate, and water; it then was dried (MgSO4)
and distilled from Na. Methyllithium (1.4 M in diethyl ether),
the benzophenones, and 1,3-diphenyl-2-propanone p-tosylhy-
drazone were commercial samples. Ethyllithium was prepared
following a literature procedure except that the solvent was
hexane instead of toluene.1 Samples of the addition products (2)
were synthesized by routine reactions of the benzophenones (1)
with methyllithium or ethyllithium.
0
-0.06
-0.27
-0.27
a
b
Values from ref 12. Methyllithium in diethyl ether at 0 °C.
c Ethyllithium in hexane at 5 °C.
R ea ct ion s of Or ga n olit h iu m Com p ou n d s a n d Ben zo-
p h en on es. Methyllithium solutions were prepared by diluting
the purchased solution with diethyl ether. Concentration was
determined by adding a portion to a standard solution of 1,3-
diphenyl-2-propanone tosylhydrazone in THF until an orange
color persisted;15 the concentration used was the average of three
determinations. Benzophenone solutions were prepared by
weighing benzophenone and the substituted benzophenone into
a volumetric flask and diluting with diethyl ether. In a glovebox,
samples of benzophenone solution (1.5 mL, 0.15 M in each
ketone) were measured into three small reaction vials, each
containing a magnetic stirring bar, which then were sealed with
septa. A 1 mL gastight syringe with a 12 in., 20 gauge needle
was filled with methyllithium solution (usually ca. 0.15 M). The
end of the needle was sealed temporarily by pressing it into a
septum. A vial and the syringe were removed from the glovebox.
A nitrogen line with a needle on the end was inserted into the
septum of the vial to maintain a positive pressure of nitrogen,
and the vial was placed in a stirred ice bath. The syringe was
mounted on the syringe pump in a horizontal orientation. The
syringe needle, which had a 90° bend, was inserted into the
septum of the vial until the tip of the needle was below the liquid
surface. The methyllithium solution (0.3 mL) was pumped slowly
(usually 1.04 × 10-5 mol/min) into the vial whose contents were
rapidly stirred. This pumping rate was chosen, as described
previously,1 after finding that somewhat higher rates led to the
same results with the more reactive ketones. The nitrogen and
syringe needles were then transferred to the next vial, and the
addition was repeated. A reaction was quenched by addition of
water (2 mL) and xylene (2 mL). The water was removed, and
the organic layer was dried (Na2SO4) and filtered in preparation
for GC analysis. Similar procedures were used for the reactions
with ethyllithium in hexane (the bath temperature was 5 °C).
F igu r e 1. Plot against Hammett σ values of the logarithm of
relative rates of addition of methyllithium to substituted
benzophenones. Reactions are in diethyl ether at 0 °C.
relative rate that was 20% greater than that observed
when the ketones were in larger excess.
Under at least some circumstances, therefore, F for
addition of an organolithium reactant to an aryl ketone
is greater than previously reported. A kinetic isotope
effect was reported to be absent (12k/14k ) 1.000 ( 0.002)
in addition of MeLi to benzophenone isotopically substi-
tuted at the carbonyl carbon but significant (12k/14k )
1.023 (0.004)in a similar experiment with 2,4,6-trimethyl-
benzophenone.5,13,14 The very different isotope effects
were attributed to different rate-determining steps for
the additions to benzophenone and 2,4,6-trimethyl-
benzophenone. Since these isotope effects were deter-
mined by a competition between the two isotopomers,
Ack n ow led gm en t. We thank the National Science
Foundation for supporting this work and Curtis A.
Musser for preliminary experiments.
(13) Negligible 12k/14k kinetic isotope effects also were reported
for additions of phenyllithium to benzophenone and benzaldehyde
isotopically substituted at the carbonyl carbon.9
Su p p or tin g In for m a tion Ava ila ble: Description of the
GC analyses. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Significant 12k/14k isotope effects were observed in reactions of
MeMgBr and MeMgI with benzophenones isotopically substituted at
the carbonyl group.7 A negligible isotope effect was noted with
t-BuMgCl,7 but a more recent investigation suggests that finding to
be erroneous [Holm, T. J . Am. Chem. Soc. l993, 115, 916]. Reactions
of benzophenone with t-BuMgCl are faster than with MeMgBr;4
perhaps the rate of mixing was slow compared to rates of addition of
methyl Grignard reagents but not of t-BuMgCl.
J O0111762
(15) Lipton, M. F.; Sorenson, C. M.; Sadler, A. C.; Shapiro, R. H. J .
Organomet. Chem. l980, 186, 155.