Table 2 Yield of addition product in the reaction of Grignard reagents
those obtained with the non-deuterated acids. The ultrafast
reactions most likely have early transition states in which case
the kH/kD will be close to 1.0.
with carbonyl compounds containing a hydroxyl group†
Yielda-
In conclusion, we have shown that the rate of carbonyl addition
may compare with the rate of protonation for two highly reactive
Grignard reagents. When the Grignard reagents are added to
an excess of two competing substrates of which one has a
carbonyl group and the other a hydroxy group rather high
yields of the addition products may be obtained (intermolecular
competition). This is seen especially with allylmagnesium bromide,
but also to some extent with benzylmagnesium chloride while
butylmagnesium bromide does not undergo carbonyl addition in
the presence of protic reagents. The phenomenon is caused to
some degree by a scavenging effect from electrophilic magnesium
compounds which remove water or other hydroxy compounds
by complexation and leave the carbonyl compound free to react
with the alkylmagnesium reagent. When the competition is carried
out in an intramolecular fashion with substrates containing both a
carbonyl group and a hydroxy group the scavenging effect is absent
and only allylmagnesium bromide is able to form the addition
product in low to moderate yield.
Entry Grignard Reagent
Bifunctional Compd
(%)
=
1
2
3
4
5
6
7
8
0.16 M CH2 CHCH2MgBr 0.3 M p-HOC6H4CHO
5
30
0
=
0.16 M CH2 CHCH2MgBr 0.3 M m-HOC6H4CHO
=
0.16 M CH2 CHCH2MgBr 0.3 M o-HOC6H4CHO
=
0.16 M CH2 CHCH2MgBr 0.3 M p-HOC6H4COCH3 13
=
0.16 M CH2 CHCH2MgBr 0.3 M p-HOC6H4COOCH3
2
0
0
0
18
9
0
0.1 M C6H5CH2MgCl
0.1 M C6H5CH2MgCl
0.1 M C6H5CH2MgCl
=
0.4 M p-HOC6H4CHO
0.4 M m-HOC6H4CHO
0.4 M p-HOC6H4COCH3
9
10
11
0.2 M CH2 CHCH2MgBr 0.4 M C6H5COOH
=
0.1 M CH2 CHCH2MgBr 0.25 M CH3(CH2)6COOH
0.1 M C6H5CH2MgCl
0.2 M C6H5COOH
a GC yield.
From the table it is clear that the intramolecular competition
gives results that are different from the results in the intermolecular
competition. With both allylmagnesium bromide and benzylmag-
nesium chloride a higher degree of protonation is observed in the
intramolecular competition. When allylmagnesium bromide was
reacted with a mixture of p-methoxybenzaldehyde and phenol, the
addition/protonation ratio was 35 : 65 (Table 1, entry 15). How-
ever, when the same reagent was added to p-hydroxybenzaldehyde
the ratio was 5 : 95 (Table 2, entry 1). Similar allyl Grignard
reactions with other hydroxy carbonyl compounds (entries 2–5)
also gave lower yields of the addition product than in Table 1.
When benzylmagnesium chloride was reacted with a mixture of
p-methoxybenzaldehyde and phenol, the addition/protonation
ratio was 18 : 82 (Table 1, entry 22). With p-hydroxybenzaldehyde
as the substrate the ratio was zero (Table 2, entry 6) indicating
that the rate of protonation of benzylmagnesium chloride by
the hydroxy group is more than hundred times faster than the
addition to the aldehyde. The higher degree of protonation in
these intramolecular competition experiments confirm that the
protic reagent in the intermolecular competition experiments is
scavenged to some degree by the magnesium salts.
Similar results are obtained with benzoic acid and octanoic
acid, which can also be considered as bifunctional substrates
with both a hydroxy group and a carbonyl group (entries 9–11).
With allylmagnesium bromide only double addition was observed
to afford the tertiary alcohol and the intermediate ketone was
not detected. Since the oxygen–hydrogen bond is broken in the
protonation reaction a primary deuterium isotope effect might be
expected. Experiments with the reaction between allylmagnesium
bromide and deuterated benzoic and octanoic acid, however,
showed no significant changes in the product distributions from
Notes and references
† General procedure for competition experiments: Allylmagnesium bromide
and benzylmagnesium chloride were prepared under argon in diethyl
ether (distilled from benzophenone ketyl) from reagent grade magnesium
by slow addition (6 h) of distilled allyl bromide and benzyl chloride.
Solutions of the Grignard reagent (10 mL) and the substrates (10 mL)
were prepared separately in 20 mL syringes which were connected with
a polyethylene capillary tube. The Grignard solution contained 1 mol of
octane per mol of Grignard reagent as an internal standard. The Grignard
reagent was pressed into the syringe with the substrate solution within
2–3 s. The heterogeneous reaction mixture was shaken with saturated
ammonium chloride solution and the organic layer isolated. The solution
was analysed by quantitative GC and the peaks for the products were
measured relative to the peak for octane. To obtain complete conversion
the Grignard solution was reacted with an excess of the substrate mixture.
Each experiment was repeated twice and the average yield reported in
Tables 1 and 2.
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Marcel Dekker, New York, 1996; (b) Grignard Reagents – New Develop-
ments, ed. H. G. Richey, Jr., John Wiley & Sons, Chichester, 2000.
2 L. W. Chung, T. H. Chan and Y.-D. Wu, Organometallics, 2005, 24,
1598–1607.
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4 T. Holm, J. Org. Chem., 2000, 65, 1188–1192.
5 W.-C. Zhang and C.-J. Li, J. Org. Chem., 1999, 64, 3230–3236.
6 J. H. Dam, P. Fristrup and R. Madsen, J. Org. Chem., 2008, 73, 3228–
3235.
7 T. Holm, Acta Chem. Scand., Ser. B, 1983, 37b, 567–584.
8 T. Holm, Tetrahedron Lett., 1966, 7, 3329–3336.
9 A. W. Francis, J. Am. Chem. Soc., 1926, 48, 655–672.
3404 | Org. Biomol. Chem., 2010, 8, 3402–3404
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