Reactions of partially solvated Grignard reagents with a ketone

Article abstract of DOI:10.1016/S0022-328X(99)00254-5

Ratios of the yields of addition and reduction products for the reactions of n-butylmagnesium chloride and bromide with diisopropyl ketone in toluene were determined at different THF, diethyl ether and methyl tertbutyl ether (MTBE) contents in the Grignard reagent. The reduction reaction yield is a maximum at the molar ratio 0.1 of THF or diethyl ether to the Grignard reagent. The addition reaction has a maximum in the region of 0.3-0.4 for the same ethers and about 1.5 for MTBE. The ratio Add/Red for conventional Grignard reagents is lower than that for partially solvated reagents. The results were discussed in terms of the solvation of the species in the reaction mixture. The decisive role of the steric requirements of the reagents over their intrinsic acid-base properties was demonstrated. Partially solvated Grignard reagents can serve as tools for the investigation of solvent effects in the Grignard reaction.

Full text of DOI:10.1016/S0022-328X(99)00254-5

www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 586 (1999) 145–149
Reactions of partially solvated Grignard reagents with a ketone
Ants Tuulmets *, Meeri Sassian
Institute of Organic Chemistry, Uni6ersity of Tartu, Tartu 50090, Estonia
Received 3 March 1999; received in revised form 20 April 1999
Abstract
Ratios of the yields of addition and reduction products for the reactions of n-butylmagnesium chloride and bromide with
diisopropyl ketone in toluene were determined at different THF, diethyl ether and methyl tertbutyl ether (MTBE) contents in the
Grignard reagent. The reduction reaction yield is a maximum at the molar ratio 0.1 of THF or diethyl ether to the Grignard
reagent. The addition reaction has a maximum in the region of 0.3–0.4 for the same ethers and about 1.5 for MTBE. The ratio
Add/Red for conventional Grignard reagents is lower than that for partially solvated reagents. The results were discussed in terms
of the solvation of the species in the reaction mixture. The decisive role of the steric requirements of the reagents over their
intrinsic acid-base properties was demonstrated. Partially solvated Grignard reagents can serve as tools for the investigation of
solvent effects in the Grignard reaction. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Grignard reaction; Grignard reagents; Solvation effects
free ethers are replaced by toluene. The reactions of
ketones with alkylmagnesium bromides solvated with
one equivalent of diethyl ether or THF in benzene or
toluene give higher yields of addition products in com-
parison with those in ethers [10]. In our previous work
[11] we determined the ratios of the yields of reduction
and addition products for the reaction of n-butylmag-
nesium chloride with diisopropyl ketone in toluene–di-
ethyl ether mixtures, scanning the donor content in the
Grignard reagent from zero addition up to the reagent
bisolvated on the average. The obtained dependence
appeared to be unexpectedly complicated having ex-
treme points.
1. Introduction
Organomagnesium compounds can be prepared not
only in conventional ethers but also in hydrocarbon
media with or even without additions of donor solvents
[1,2].
Synthesis of unsolvated organomagnesium halides is
limited to primary alkyl and aryl compounds, but in the
presence of one molar equivalent of the complexing
agents, e.g. ethers and tertiary amines, several organo-
magnesium compounds have been obtained in hydro-
carbon media [1,2]. Primary, secondary and tertiary
alkylmagnesium bromide and chloride reagents in
toluene containing less than one equivalent of organic
base have been prepared recently [3–6]. Whereas the
Grignard reagents in donor solvents are solvated by at
least two solvent molecules per atom of magnesium,
those obtained in the presence of smaller amounts of
donor substances are partially sol6ated.
In this work the investigation was extended to ethers
of different solvating ability and it also involved n-
butylmagnesium bromide reagents. This enabled us to
comprehend the observed dependences on the basis of
solvation effects.
Although partially solvated Grignard reagents have
also been used in large-scale industrial processes [4,7],
their properties have been little investigated. The rate of
the reaction of the Grignard reagent with ethylethoxy-
silanes [8] and hydrazones [9] is greatly increased when
2. Experimental
Commercial reagents were carefully purified. The
reagents and solutions were operated on under dry
argon, and transferred by use of syringes. n-Butylmag-
nesium chloride and n-butylmagnesium bromide were
* Corresponding author. Fax: +372-7-465264.
0022-328X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(99)00254-5

146
A. Tuulmets, M. Sassian / Journal of Organometallic Chemistry 586 (1999) 145–149
prepared in toluene by using iodine-activated magne-
sium turnings and n-butylchloride or n-butylbromide in
the presence of a small amount (about 0.01 mol of ether
per mole of the halide) of diethyl ether, THF or methyl
tertbutyl ether (MTBE). The obtained heterogeneous
systems usually contained about 1.6 moles of the Grig-
nard reagent per litre of toluene.
The basic magnesium content in the reagent was
determined by quenching an aliquot with the standard
sulphuric acid. The excess acid was back-titrated
against aqueous sodium hydroxide. The chloride and
bromide ion concentrations were determined in the
same solution by the Mohr method after the acidimetric
analysis. The ratio Mg–X/R–Mg (X=Cl, Br) was
calculated.
From the vigorously stirred reaction mixture 5 ml
aliquots of the suspension were withdrawn and trans-
ferred to vials sealed with serum caps. Calculated
amounts of the appropriate ether were added and the
reagents were left for at least 6 h or overnight. Grig-
nard reagents in pure ethers were prepared routinely
and analyzed as described above.
Then diisopropyl ketone in the molar ratio 1:2 dis-
solved in toluene or in the appropriate ether was slowly
added at 0°C to the reagents prepared as described
above, and the mixtures were left overnight. The ketone
solutions also contained n-nonane or n-decane, i.e. the
internal standard for GLC analyses.
after the addition of the ether revealed the same reactiv-
ity. Furthermore, a seasoning of the mixtures for less
than 4–6 h brought about irreproducible results in
determining the product composition of the reaction
with the ketone. Obviously, the fairly good solubility of
the partially solvated Grignard reagents in toluene
[3,5,6] favours the relatively rapid achievement of solva-
tion equilibria. In this way, the Grignard reagents
containing very small amounts of ethers were obtained
that could not have been achieved by direct syntheses
(see, e.g. Refs. [5,6]).
Grignard reagents with different molar ratios of
ethers were further allowed to react with 0.5 molar
equivalent of diisopropyl ketone. The reaction products
were quantitatively determined by means of GLC. The
enolization reaction occurred to a low extent, not ex-
ceeding 1–2%. No ketolization was observed. A pre-
cautionary quenching of the reaction mixture enabled
us to avoid the dehydration of the addition product.
Thus, we could directly use molar ratios 2-methyl-3-iso-
propylheptane-3-ol (addition product) to 2,4-
dimethylpentane-3-ol (reduction product) from the
GLC analysis as reactivity characteristics for the Grig-
nard reagents with different molar contents of the
ethers (Fig. 1). The use of internal standards in GLC
analysis made feasible calculation of the material bal-
ance of the reaction. The sum of yields of addition and
reduction products and of recovered ketone (the eno-
lization product, never exceeding 2%) was always 96–
102%.
All the experiments including the synthesis of n-
butylmagnesium halide were repeated at least two to
three times. In Fig. 1 the points indicate the mean
values obtained from several experiments. The results
of parallel experiments agreed within 10% or less.
The ratio Mg–X/R–Mg indicates the extent of side
reactions (mainly the Wurtz reaction) during the Grig-
nard reagent formation. The ratio also indicates the
excess of magnesium halide in the Grignard reagent. It
is known that an increased content of magnesium
halide in the Grignard reagent favours the addition
reaction with ketones in case of alkylmagnesium bro-
mides and iodides, whereas in case of chlorides the
influence is the opposite (see Ref. [11] and references
therein). In our experiments the ratio ranged from 1.10
to 1.15 for n-butylmagnesium chloride reagents and
from 1.25 to 1.40 for n-butylmagnesium bromide
Grignards.
Experimental results presented in Fig. 1 and in Table
1 are somewhat astonishing, since such complicated
dependences of the ratio Add/Red on the ether molar
content in the reagent could not be expected. At a very
low ether content the reduction reaction is favoured,
having a maximum in the region of 0.1 molar ratio of
diethyl ether or THF to the organomagnesium com-
pound. With an increasing ether content the addition
The reaction mixtures were slowly quenched at 0°C
by the dropwise addition of 10 ml of the 20% aqueous
solution of NH4Cl. The organic layer was separated
and analyzed on a Chrom-5 gas chromatograph with a
flame ionization detector. The column was packed with
20% Carbowax 20 M on Chromosorb W AW-DMCS.
3. Results
We studied the compositions of products from the
reaction of diisopropyl ketone with n-butylmagnesium
chloride and bromide in toluene in the presence of
diethyl ether, THF, or methyl tertbutyl ether (MTBE).
Primary alkylmagnesium halides can be prepared in
toluene in the absence of complexing agents. However,
an easy initiation of the reaction and a small contribu-
tion of the Wurtz coupling were poorly reproducible,
therefore, we preferred to initiate the reaction with a
catalytic addition of the ether (about 0.01 mol per mole
of the halide) that led to more consistent results.
By the addition of appropriate amounts of ethers to
the obtained suspensions, Grignard reagents with dif-
ferent molar ratios of ethers were prepared. It is re-
markable that the distribution of ether additions
between the components of heterogeneous Grignard
solutions arrived at completion within hours, since the
reagents kept for 6 h or overnight (or for 1 week [11])

A. Tuulmets, M. Sassian / Journal of Organometallic Chemistry 586 (1999) 145–149
147
reaction prevails over reduction, but the ratio Add/Red
2RMgX X R2Mg+MgX2
(1)
passes a maximum (or even two in the case of THF),
largely exceeding the value for the reagent in pure ether
(Table 1), e.g. for the reagent nBuMgBr·0.4Et2O the
yield of the addition product was 79% while the same
for n-butylmagnesium bromide in pure diethyl ether
was about 53%. MTBE reveals a flat maximum only at
greater additions of the ether.
Both organomagnesium species are highly reactive
toward ketones but diorganyl-magnesiums react at least
ten times faster [15]. The primary reaction products,
alcoholates R%OMgX and RMgOR%, are able to com-
plex with other species in the solution. Alkylmagnesium
alcoxides are capable of alkyl addition to the carbonyl
bond, but more by-products of enolization and reduc-
tion have been reported [16]. Alkylmagnesium alcoxides
do not disproportionate with a recovery of dialkylmag-
nesiums in hydrocarbon solutions, however, magnesium
bromide can catalyze the exchange reaction [17,18].
A decisive role of specific solvation in organomagne-
sium chemistry has been long recognized [1,2]. Later it
was found that the steric effect of the donor solvent
considerably controlled its solvating ability [19–22].
Moreover, it was shown quantitatively [23] that the
effective basicity (solvating power) of a base in respect
to a Lewis acid (to an organomagnesium compound) is
greatly determined by the steric requirements of the
base and by the effective (Lewis) acidity of the acid, the
latter also being strongly dependent on the steric de-
mands of the acid. In further discussion of experimental
results the importance of both the specific solvation and
the steric effects of the reagents will be stressed.
4. Discussion
General features of the Grignard reaction with ke-
tones are well understood now [1,2]. The coordination
of ketone with magnesium is essential, and in donor
solvents occurs by replacement of a solvent molecule at
the magnesium atom. In partially solvated reagents the
replacement is probably not necessary. Thus, a solvent
molecule initially coordinated with magnesium is
present in the complex influencing its further behaviour.
Synthetically desirable Grignard addition providing
tertiary alcohols is frequently accompanied by the re-
duction and enolization of ketone. Although all three
are competitive reactions, the resulting magnesium al-
coholates favour reduction. For this reason the contri-
bution of the reduction reaction increases during the
process, particularly under preparative conditions,
when a little or no excess of the Grignard reagent is
used [12–14].
Grignard reagent solutions usually contain an equi-
librium mixture of a variety of species. Apart from the
association equilibria the Schlenk equilibrium (Eq. (1))
is essential.
Fig. 1. The ratios of yields of addition and reduction products (Add/Red) vs. the molar ratio of ether to Grignard reagent in toluene.

148
A. Tuulmets, M. Sassian / Journal of Organometallic Chemistry 586 (1999) 145–149
Table 1
The ratios of yields of addition and reduction products for the reaction with diisopropyl ketone
Reagent
Base
Add/Red for the partially
Add/Red in pure ether
solvated reagent a
n-BuMgBr
THF
Et2O
MTBE
3.1 (0.3)
4.0 (0.4)
3.5
0.80
1.2
1.3
n-BuMgCl
THF
Et2O
MTBE
2.5 (0.25)
2.5 (0.4)
2.8 (1.4)
1.2
1.3
1.1
a The maximum value. In parentheses the molar ratio of the ether to the Grignard reagent is given for the maximum point.
The heterolytic Grignard addition proceeds through
a four-centre transition state (I), while a cyclic six-cen-
tre transition state (II) is necessary for the reduction
reaction [2].
the reaction mixture. The R%OMgR species enter the
dismutation equilibria (Eqs. (2) and (3)), thus recover-
ing the more reactive species.
R%OMgR+RMgX X R2Mg+R%OMgX
R%OMgR+MgX2 X RMgX+R%OMgX
(2)
(3)
It is obvious that the nucleophilic solvation of the
magnesium polarizes the carbon–magnesium bond in-
creasing the nucleophilicity of the carbon and thus
favouring the addition and enolization reactions. Re-
duction comprises a b-hydrogen transfer, less influenced
by the donor at the magnesium centre. In addition to
this, the nucleophilic solvation of magnesium can sup-
press the electrophilicity of the carbonyl group to some
extent, thereby enhancing the selectivity of the reaction
centre. Consequently, an increase in the solvating abil-
ity of the donor should bring about an increase in the
addition reaction yield as well as in the extent of
enolization. This conclusion is well supported by the
experimental data (Ref. [24] and references therein).
Although these have been considered in terms of the
prevalence of enolization, an increase in the addition to
the reduction ratio with an increasing effective basicity
of the donors is evident.
Note that the reverse reactions of the equilibria (Eqs.
(2) and (3)) involve product alcoholates R%OMgX and
produce less reactive species. It is obvious that stronger
solvation shifts the equilibria to the left similarly with
the Schlenk equilibrium (see, e.g. the discussion in Ref.
[6]). On the other hand, all these dismutation reactions
as well as the Schlenk equilibrium (Eq. (1)) evidently
proceed through cyclic transition states, the formation
of which is favoured by the electrophilicity of magne-
sium centers. Thus, an increase in the solvating power
of the solvent increasingly retards the exchange reac-
tions as it has been observed for the Schlenk equi-
librium [2]. Consequently, a stronger solvation of the
Grignard reagent suppresses the dismutation of
R%OMgR species, ultimately favouring the reduction
reaction.
It is also obvious that an increase in the steric
hindrance causes a decrease in the solvating ability of
the donor regardless of its Brønsted basicity. Likewise,
the increasing bulkiness of the groups bound to the
magnesium centre hinders complexing between the
donor and the substrate. Consequently, the following
sequence of effective acidity can be envisaged for spe-
cies comprising a Grignard reaction mixture: MgX2\
RMgX\R%OMgX\R2Mg\R%OMgR.
On the basis of the above reasoning one can conclude
that very bulky alkoxy groups in magnesium alcoho-
lates resulting from Grignard addition reactions consid-
erably hinder complexation with donors, thus
suppressing the nucleophilicity of the organyl moiety.
The consequence of this is the remarkable bias of
R%OMgR species towards the reduction mentioned
above.
Our experimental results, presented in the forms of
curves in Fig. 1, can be interpreted now. The nature of
the halogen in the Grignard reagent seems to be of
minor importance since the shapes of the plots are
rather similar for the chloride and bromide. However,
the maximum Add/Red ratio is significantly higher in
each case for the bromide (Table 1), and this may be of
importance in synthetic application of the reagents.
Variation of the donor reveals a strong effect of solva-
tion. The ethers employed in this work are of very close
Brønsted basicity, however, their effective basicities dif-
fer largely, decreasing in the order THF\Et2O\
MTBE as it was shown also in our previous paper [6].
The ratio Add/Red is a minimum at small additions
of the ethers. In this region only a minor proportion of
the species are solvated thus largely favouring the re-
duction of ketone. In addition, poor solvation shifts the
Schlenk equilibrium to RMgX species which produce
R%OMgX and via equilibrium (Eq. (3)) R%OMgR spe-
The effectiveness of the solvation of the species is
also important for the exchange reactions occurring in

A. Tuulmets, M. Sassian / Journal of Organometallic Chemistry 586 (1999) 145–149
149
cies, in this way still enhancing the contribution of the
reduction reaction.
The practical implication of the results obtained in
this work is that partially solvated Grignard reagents
can be used to improve the yield of the Grignard
addition reaction. Presumably MTBE Grignards may
be the reagents for choice since they provide a good
Add/Red ratio in an approximately ‘monosolvated’
form which is easily attainable by direct synthesis [6].
An increase in nucleophilic solvation of the reagent
raises the yield of the addition reaction at the expense
of reduction as discussed above. This part of the curve
is expectedly steeper for more effective donors. How-
ever, growing solvation involves shifts in all the equi-
libria as well as a slow down of the dismutation
reaction, thus favouring again the reduction of the
ketone. As a result, the ratio Add/Red passes a maxi-
mum, expectedly located at greater additions of weaker
donors. A further increase in the molar ratio of base to
the Grignard reagent leads to the diminishing of the
Add/Red ratio down to the value for the conventional
reagent (Table 1), this value being considerably lower
than that for the ‘monosolvated’ or somewhat less
solvated Grignard reagents.
The observed dependences undoubtedly reflect an
integral effect of numerous interactions occurring in the
systems. Therefore the assignment of minor details of a
curve should be done cautiously. However, we suppose
that the second, weaker maximum in the case of THF
can be related to the Schlenk equilibrium, which unlike
the other two ethers, is shifted further to the right both
in pure THF and in the partially solvated primary alkyl
reagents [2,6]. As to the short descending part of curves
for extremely small additions of THF and diethyl ether,
the first points of the curves correspond to reagents
partially solvated with the ketone at the beginning of
the reaction and complexed with magnesiumalcoholates
by the completion of the reaction. Further donor addi-
tions are only sufficient for the solvating of some
portion of the strongest acid, MgX2, thus causing shifts
of equilibria favourable for reduction. From a certain
molar ratio of base to the Grignard reagent, effects
fostering the addition reaction prevail and give rise to
the curves discussed above.
Acknowledgements
The authors thank the Estonian Science Foundation
for financial support of this work.
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