Solvation effects in the Grignard reaction with carbonyl compounds

Article abstract of DOI:10.1002/hlca.200390021

Ratios of the yields of addition and reduction products for the reactions of butylmagnesium chloride with diisopropyl ketone, methyl 2-methylpropanoate, and isopropyl 2-methylpropanoate in toluene were determined at different THF, diethyl ether, and tert-

Full text of DOI:10.1002/hlca.200390021

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Solvation Effects in the Grignard Reaction with Carbonyl Compounds
by Meeri Sassian and Ants Tuulmets*
Institute of Organic and Bioorganic Chemistry, University of Tartu, Tartu 51014, Estonia
(tel.: ‡3727375238; fax: ‡3727375245; e-mail: tuulmets@chem.ut.ee)
Ratios of the yields of addition and reduction products for the reactions of butylmagnesium chloride with
diisopropyl ketone, methyl 2-methylpropanoate, and isopropyl 2-methylpropanoate in toluene were determined
at different THF, diethylether, and tert-butylmethylether contents in the Grignard reagent. Replacement of the
alkoxy group in the ester leads to strikingly different results for very small additions of donors. The results are
discussed in terms of the solvation of the species in the reaction mixture.
Introduction. The most important reactions of Grignard reagents are those with
carbonyl compounds. Formation of a tertiary or secondary alcohol is frequently
accompanied by the reduction and enolization reactions lowering the yield of the target
compound. It has been reported that reactions of ketones with alkylmagnesium
bromides solvated with 1 equiv. of Et2O or THF in benzene or toluene solution afford
higher yields of addition products in comparison with those obtained in ethers as
solvents [1].
Above all, the replacement of readily flammable ethers by solvents of high boiling
point is important for large-scale organomagnesium syntheses. However, the use of
hydrocarbon solvents offers additional advantages, since they are cheap and non-
hygroscopic. In the presence of complexing agents, e.g., ethers and tertiary amines, a
great variety of organomagnesium compounds can be obtained in hydrocarbon media
[2 7]. Primary, secondary, and tertiary alkylmagnesium chlorides in toluene solutions,
which contain less than 1 equiv. of organic base, have been prepared recently [5 7].
Whereas the Grignard reagents in donor solvents are solvated by at least two
solvent molecules per Mg-atom, those obtained in the presence of smaller molar
amounts of donors are stoichiometrically only −partially× solvated. Toluene proved to be
a particularly suitable solvent for partially solvated Grignard reagents. While their
solubility in alkanes is extremely low, one can obtain rather concentrated (1m and
higher) solutions in toluene [4][6][7].
Although partially solvated Grignard reagents have also been used in large-scale
industrial processes [5][8], their properties have been little investigated. One can
expect severalfeatures different from those of conventional Grignard reagents.
Recently, we determined the ratios of the yields of reduction and addition products
for the reaction of BuMgBr and BuMgClwith diisopropylketone ((i-Pr) 2CO) in
various toluene/ether mixtures, scanning the donor content in the Grignard reagent
from almost zero addition up to the partially solvated reagents [9][10]. The observed
dependencies appeared to be complicated, including extreme points, the ratio addition/
reduction (Add/Red) for conventional Grignard reagents being lower than that for

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partially solvated reagents. The results were discussed in terms of the solvation of the
reagents [10]. It became evident that partially solvated Grignard reagents can serve as
tools for the investigation of the solvent effects in Grignard reactions.
In this work, the investigation was extended to alkyl esters. The main purpose of the
work was a wider examination of solvation effects of donors to get insight into the
mechanism of the controlover formation of Grignard products governed by the
solvation of the reactive species in Grignard solutions. Revised and complemented data
for the reaction of (i-Pr)2CO from our previous work [10] are also included and
discussed more conclusively in this report.
Results. We determined the yields of products from the reaction of BuMgCl in
toluene with (i-Pr)2CO, methyl 2-methylpropanoate and isopropyl 2-methylpropa-
noate in the presence of Et2O, THF, or t-BuOMe.
The Grignard reagent, BuMgCl, was prepared in toluene with a catalytic amount of
the ether (ca. 0.01 mole per mole of the halide). By addition of appropriate amounts of
ethers to the obtained suspensions, Grignard reagents with different molar ratios of
ethers were prepared. Previously, it was found [9][10] that the distribution of ether
additions between the components of heterogeneous Grignard solutions arrived at
completion within hours. Obviously, the fairly good solubility of the partially solvated
Grignard reagents in toluene [6][7] favors the relatively rapid achievement of solvation
equilibrium. In this way, the Grignard reagents containing very small amounts of ethers
were obtained that could not have been achieved by direct synthesis [6][7].
Grignard reagents with different molar ratios of ethers were further allowed to
react with the ketone in a molar ratio 1:2 (ketone to Grignard reagent), or with an
ester in the molar ratio 1:3. The reaction products were quantitatively determined by
means of GLC. The enolization process recovering the ketone or yielding a ketone (in
the case of esters) was a minor side reaction, not exceeding 1 3%, except for a few
points for methyl 2-methylpropanoate with the yields close to 6%. No ketolization was
observed. Cautious quenching of the reaction mixture enabled us to prevent
dehydration of the addition products.
The use of internal standards in GLC analysis allowed calculation of the material
balance of the reaction. The sum of yields of addition and reduction products and of
ketone (the enolization product) was always within the range of 97 102%.
Results of the experiments are presented in Figs. 1 3. The addition product of
(i-Pr)2CO is 2-methyl-3-isopropylheptan-3-ol and the corresponding reduction product
is 2,4-dimethylpentan-3-ol (Scheme 1). For the esters, the recovered ketone is 2-
methylheptan-3-one, and the addition and reduction products are 5-isopropylnonan-
5-ol and 2-methylheptan-3-ol, respectively (Scheme 2).
All experiments, including the synthesis of BuMgCl, were repeated at least two to
three times. In Figs. 1 3, the points indicate the mean values obtained from several
experiments. The results of parallel experiments agreed within Æ 5%.
As will be discussed below, the nucleophilic solvation of the Mg-atom favors both
the addition and enolization, being less effective for the reduction reaction. Therefore,
we use the molar ratios of the sum of addition and enolization products to the reduction
product from the GLC analysis as reactivity characteristics for the Grignard reagents
with different molar contents of the ethers.

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Fig. 1. The ratios of yields of addition and reduction products (Add/Red) of (i-Pr)2CO vs. the molar ratio of ether
to Grignard reagent (MTBE ˆ t-BuOMe)
Fig. 2. The ratios of yields of addition and reduction products (Add/Red) of isopropyl 2-methylpropanoate vs.
the molar ratio of ether to Grignard reagent (MTBE ˆ t-BuOMe)
Discussion. Grignard-reagent solutions usually contain an equilibrium mixture of
variety of species. Apart from the association equilibria, the Schlenk equilibrium is
essential:
2 RMgX > R2Mg ‡ MgX2
Both organomagnesium species are highly reactive toward ketones, but diorganyl-
magnesium species react faster [11]. The primary reaction products, alkoxymagnesium
species R'OMgX and RMgOR', are able to complex other species in solution.
Alkylmagnesium alkoxides are capable of alkyl addition to the carbonyl compound,
but more by-products of enolization and reduction have been reported [12].
Alkylmagnesium alkoxides do not disproportionate with recovery of dialkylmagnesium

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Fig. 3. The ratios of yields of addition and reduction products (Add/Red) of methyl 2-methylpropanoate vs. the
molar ratio of ether to Grignard reagent (MTBE ˆ t-BuOMe)
Scheme 1
Scheme 2
species in hydrocarbon solution, however, but MgBr2 catalyzes the exchange reaction
[13][14].
The generalfeatures of the Grignard reaction with ketones are well-understood
now [15 17]. The coordination of the ketone with the Mg-atom is essential, and occurs
by replacement of a donor molecule at the Mg-atom. Thus, one solvent molecule initially
coordinated with the Mg-atom is present in the coordination complex, influencing its
reactivity.

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The heterolytic Grignard addition proceeds through a four-center transition state I,
while a cyclic six-center transition state II is necessary for the reduction reaction [16].
It is obvious that the nucleophilic solvation of the Mg-atom polarizes the CÀMg
bond, increasing the nucleophilicity of the C-atom and, thus, favoring the addition and
enolization reactions. Reduction involves a b-H transfer, less influenced by the donor at
the Mg-center. Consequently, an increase in the solvating ability 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 (cf. [18] and
refs. cit. therein). An increase in the addition or enolization to the reduction ratio with
an increasing effective basicity of the donors is evident.
It is also obvious that an increase in steric hindrance causes a decrease in solvating
ability of the donor regardless of its Br˘nsted basicity. Likewise, the increasing
bulkiness of the groups bound to the Mg-center hinders complexing between the donor
and the substrate. One can conclude that very bulky alkoxy groups in magnesium
alcoholates resulting from Grignard addition reactions considerably hinder complex-
ation with donors, thus supressing the nucleophilicity of the organyl moiety. The
consequence of this is the remarkable bias of R'OMgR species towards the reduction
mentioned above. For this reason, the contribution of the reduction reaction increases
during the process, particularly under preparative conditions, when a little or no excess
of the Grignard reagent is used [19][20] (cf. Scheme 3).
Effectiveness of the solvation of the species is also important for the exchange
reactions occurring in the reaction mixture. The primary products from the Grignard
species RMgX and R2Mg, and R'OMgX and R'OMgR, respectively, enter the
dismutation equilibria 2 and 3 in Scheme 3. It is obvious that stronger solvation shifts
equilibrium 2 towards the formation of MgX2 species, similar to the Schlenk
equilibrium [16][17], and equilibrium 3 towards RMgX formation. Thus, an increase
in the solvating ability of the solvent increasingly produces R'OMgR species prone to
reduce the carbonylcompound. It appears that a stronger sovlation of the Grignard
reagent in parallel to enhancement of the addition reaction can also favor the reduction
reaction.
On the basis of the reasoning above, one can predict the course of the Add/Red
ratio with increasing content of the donor in the Grignard reagent (Scheme 4).
The ratio Add/Red is minimal for small additions of the ethers. In this region, only a
minor proportion of the species are solvated, thus largely favoring the reduction of
ketone. 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

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Scheme 3
Scheme 4
is expectedly steeper for more effective donors. However, growing solvation involves
shifts in all equilibria, thus favoring, again, reduction of the ketone. As a result, the ratio
Add/Red passes a maximum, 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.
Our experimentalresutls presented in the form of curves in Fig. 1 are in good
agreement with the predictions above.
The first points of the curves correspond to reagents partially solvated with the
ketone at the beginning of the reaction and complexed with magnesium alcoholates by
the completion of the reaction. Further donor additions are sufficient for solvation of
only some portions of the strongest acid, MgCl2, thus causing shifts of equilibria
favorable for reduction. From a certain molar ratio of base to the Grignard reagent,
effects fostering the addition reaction prevailand give rise to the curves discussed
above.
Variation of the donor reveals a strong effect of solvation. The ethers employed in
this work are of very similar Br˘nsted basicities; however, their effective basicities

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differ largely, decreasing in the order THF > Et2O > t-BuOMe, as it was shown also in
our previous publication [7].
The addition reaction prevails over reduction, but the ratio Add/Red passes a
maximum (or even two in the case of THF), exceeding the value for the reagent in pure
ether (see [10]). t-BuOMe reveals a flat maximum only at greater amounts of the ether.
It was attractive to apply the conclusions drawn from reactions with ketone to those
with esters. A characteristic feature of the reaction with esters consists in interim
formation of a ketone and magnesium alcoholate. The ketone further reacts with
another molecule of the Grignard reagent producing the addition or reduction products
(Scheme 5). Magnesium alcoholates form stable complexes with Grignard reagents
[15][16]. Obviously, the stabilities of the complexes strongly depend on the steric
requirements of the alkoxy groups.
Scheme 5
As shown in Scheme 5, the reaction of the ketone can proceed via at least three
pathways, i) with the ordinary Grignard reagent, ii) with the alkylalkoxymagnesium
from the reaction with the ester, and iii) with the Grignard-alcoholate complex. The
proportion of the alcoholate complexes gradually increases during the reaction. Thus,
the determined Add/Red ratio is a critic value.
In Figs. 2 and 3, a significantly higher Add/Red ratio is seen for esters in comparison
with the ketone. This is clearly due to the lower steric requirements of the intermediate
ketone. Although the contribution of ROMgBu depends on relative reactivities of
BuMgCland Bu 2Mg towards the ester, its presence cannot be excluded, and it
supposedly leads to an addition reaction of considerably greater extent than that with
the species R'OMgBu (cf. Scheme 3).
The most impressive result of the experiment with esters is a dramatic diversity of
patterns for the Add/Red ratio vs. molar ratio of ether to Grignard reagent. The only
structuraldifference between the esters concerns the alkoxy moiety being either a MeO
or an i-PrO group. The same moieties build up the alkoxymagnesium chlorides and
their complexes with the initial Grignard reagent. Consequently, steric requirements of
the alkoxy groups play a crucial role in the complexing equilibrium and in further
reactions of the resulting complex.
For the isopropylester, the features of the pol ts Add/Red vs. molar ratios of the
ethers (Fig. 2) are similar to those for diisopropyl ketone. This points to the interaction
of the intermediate ketone with the Grignard reagent as a prevailing process in the

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reaction mixture. The interpretation of the experimentaldata for diisopropylketone
seems to be relevant also in this case. However, the maxima of the curves are shifted
slightly to higher relative contents of Et2O and THF, and to a smaller one of t-BuOMe.
Most probably the levelling effect is related to a contribution of the reaction with the
Grignard-alkoxymagnesium complex (see below).
On the contrary, plots for the methyl ester (Fig. 3) exhibit no distinct maxima. In
addition, the ratio Add/Red is similar for all ethers and only slightly increases in the
region up to the molar ratio of ca. 1.3. Greater ether contents differentiate the bases,
THF being the most favorable for the addition reaction. This exceptional behavior of
the methyl ester should be attributed to the strong donating ability of MeOMgCl.
Obviously, the Grignard reagent is largely tied up to the alkoxide, and the reaction
essentially proceeds with participation of the complex at lower molar ratios of an ether.
Only greater additions of ethers can compete with the alkoxide, shifting the equilibria
towards liberation of the Grignard reagent and, in this way, giving rise to a distribution
of the products approaching but not identicalto that for the isopropylester. Expectedly,
THF as the most effective donor exerts the greatest influence on the equilibria.
The reason for the position of t-BuOMe relative to Et2O is not clear, because, on the
grounds of previous experimentaldata [7][10], t-BuOMe is reputedly a weaker base.
Similarly, a bias of the alkoxide complex towards the reduction reaction is also a matter
of speculation. As a possible explanation, different rigidities of the transition states of
addition and reduction reactions should be considered (Scheme 6).
Scheme 6
Simultaneous occurrence of two four-membered rings at a Mg-atom seems to be
energetically less favorable than formation of a more-flexible six-membered transition
state for the reduction reaction.
As an important conclusion, one can infer from the results for esters that their
reactions, at least in the region of insufficient solvation, are strongly governed by the
nature of the alkoxy group. Susceptibility of the process to steric effects is unexpectedly
high. The key step of the reaction appears to be complexation between a Grignard
reagent and the alkoxymagnesium compound. Replacement of Me group by slightly
bulkier i-Pr group makes complexation unfavorable and switches the reaction to
another pathway. It can also be concluded that sterically hindered alkoxy compounds
resulting from reactions of ketones (Scheme 3) probably do not form stable complexes
with the Grignard species in the presence of donor solvents.
The authors thank the Estonian Science Foundation for financialsupport of this work (ESF Grant No.
4630). The authors are also greatful to Dr. V. M‰emets for the NMR spectra and to Dr. I. Leito and Mr. I.
Kaljurand for their help in obtaining chromatomass spectra.

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Experimental Part
Commercial reagents were carefully purified. The reagents and solns. were operated on under dry Ar, and
transferred by use of syringes. BuMgClwas prepared in toluene by using I 2-activated Mg turnings and BuClin
the presence of a small amount (ca. 0.01 mole of ether per mole of Mg) of Et2O, THF, or t-BuOMe. The
heterogeneous systems obtained usually contained ca. 1.5 molof the Grignard reagent per lof toul ene.
The basic Mg content in the reagent was determined by quenching an aliquot with the standard H2SO4. The
excess acid was back-titrated against aq. NaOH. From the vigorously stirred mixture, 5-ml aliquots of the
suspension were withdrawn and transferred to vials sealed with septa. Calculated amounts of the appropriate
ether were added, and the reagents were left for a few hours or overnight. Then, (i-Pr)2CO in the molar ratio 1 :2
(ketone to Grignard reagent) or an ester in the molar ratio 1:3 dissolved in toluene was slowly added at À 158 to
the reagents prepared as described above, and the mixtures were left overnight at r.t. The solns. also contained
nonane or decane, i.e., the internalstandard for GLC anayl ses.
Reaction mixtures were slowly quenched at À 158 by the dropwise addition of 10 mlof the 20% aq. soln. of
NH4Cl. The org. layer was separated and analyzed on a Varian 3700 gas chromatograph with a cap. column SGE
BP 10 (0.3 mm  24 m) and a flame-ionization detector. The reaction products were identified by their spectra.
The 1H- and 13C-NMR spectra were acquired on a Bruker AC-200 P spectrometer in CDCl3 with TMS as internal
standard. The mass spectra were recorded on a GC/MS Varian Star 3400 gas chromatograph with a cap. column
Alltech ECONO-CAP EC-5 (SE-54; 0.25 mm  30 m) connected to an ion trap MS detector Finnigan MAT
Magnum.
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Received July 10, 2002