Solvents for ring-closing metathesis reactions

Article abstract of DOI:10.1039/b802921k

A study of the influence of eight diverse solvents on a Grubbs II-catalysed ring-closing metathesis (RCM) reaction reveals a complex dependence of the different reaction steps on the solvent and suggests acetic acid as a useful solvent for RCM reactions. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802921k

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Solvents for ring-closing metathesis reactionsw
Claire S. Adjiman,*a Adam J. Clarke,b Gregory Cooperb and Paul C. Taylor*b
Received (in Cambridge, UK) 26th February 2008, Accepted 2nd April 2008
First published as an Advance Article on the web 28th April 2008
DOI: 10.1039/b802921k
A study of the influence of eight diverse solvents on a Grubbs II-
catalysed ring-closing metathesis (RCM) reaction reveals a
complex dependence of the different reaction steps on the solvent
and suggests acetic acid as a useful solvent for RCM reactions.
permitted), and with 0.12 M 1,3,5-trimethoxybenzene as the
internal standard,9 noting that the 1H NMR signal due to
the aromatic H-atoms of the standard in perdeutero acetic
acid is almost zero due to rapid deuterium exchange. Since we
aimed to develop a model of direct relevance to synthetic
chemists, no special precautions were taken to exclude air
or moisture. Spectra were recorded at 2 min intervals for
4 h. Spectra were examined carefully to select peaks that
would integrate cleanly, with particular care being needed
to avoid overlap with the many broad peaks due to the
catalyst species.
Olefin metathesis reactions catalysed by the 1,3-dimesityl-4,5-
dihydroimidazol-2-ylidene ruthenium complex Ru (Grubbs II
catalyst)1 continue to be of great importance2 (the 1999 paper
describing the preparation of this complex has been cited
ca. 1300 times). Despite the numerous mechanistic and com-
putational studies of these reactions,3,4 relatively few publica-
tions have focused on solvent effects, even though solvents
influence both the rate and cis/trans stereoselectivity.
A
number of reaction schemes and corresponding
kinetic models were developed, based on extensive reading
of the literature.3,4,10 The best match to the data, based on
the application of reaction progress kinetic analysis11 and
maximum likelihood estimation,12 is given in Scheme 1,
and in the kinetic model in eqns (1)–(5). The key features
are (i) a first, reversible, dissociative step to form Ru*
and tricyclohexylphosphine (PCy3), in accordance with
the literature,3,4 (ii) treatment of the entirety of the
Experimentally, studies by several groups have identified
solvent influences on both rates and turnover frequencies of
metathesis reactions.4–6 Computational studies3a support the
observation by Grubbs that more polar solvents lead to higher
initiation rates, due to their greater stabilising effect on the
complex Ru*, resulting from phosphine dissociation.
The stereoselectivity of ring-closing metathesis (RCM)
using Ru can be highly solvent-dependent. For example,
Wang and Forsyth, in a ring-closing reaction to form the
subsequent metathesis reactions as
a single, reversible
rate-determining step, (iii) an assumption that the barrier
to ethylene coordination is negligible,3d and that there
is always a sufficient amount of ethylene in solution (confirmed
by NMR spectroscopy), so that the concentration of
ethylene is not included in the rate expression for the reverse
metathesis reaction, and (iv) irreversible deactivation to form a
diruthenium species (‘‘Ru2’’ in Scheme 1). A mechanism
for deactivation from the methylidene analogue of Ru*
has been proposed.10 In our model, we have not treated the
methylidene and benzylidene species as distinct, and have
assumed that the rate of deactivation is independent of
phosphine concentration.
macrolide-containing
domain
of
phorboxazole
A,
observed almost complete selectivity for the desired cis isomer
when the reaction was carried out in hexanes, whereas a
slight predominance of the trans isomer was found in
toluene.7
In this study, we aimed first to develop a model of solvent
influences on the rates of ring-closing reactions catalysed by
Grubbs II catalyst Ru that matched kinetic data collected in a
set of diverse solvents. We then wished to use our model to
explain the chemical basis for the observed effects.
The model reaction we elected to study was the RCM of
diethyl diallylmalonate (diene) to yield the corresponding
cyclopentene (prod) and ethylene, since the starting material
is readily available and it is known that the reaction can be
followed by NMR spectroscopy.8 Eight solvents, all available
to us in perdeuterated form, were selected to include a
representative range of polarities and functional groups. The
two solvents most widely used for RCM reactions, dichloro-
methane and toluene, were included amongst them.
Kinetic data were obtained using 1H NMR spectroscopy at
298 K with 0.12 M diene and 0.0067 M Ru (where solubility
a Department of Chemical Engineering, Centre for Process Systems
Engineering, Imperial College London, London, UK SW7 2AZ.
E-mail: c.adjiman@imperial.ac.uk
b Department of Chemistry, University of Warwick, Coventry,
UK CV4 7AL. E-mail: p.c.taylor@warwick.ac.uk
w Electronic supplementary information (ESI) available: NMR spec-
tra of reaction mixtures. See DOI: 10.1039/b802921k
Scheme 1 Mes = mesityl (2,4,6-trimethylphenyl).
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Table 1 Rate constants fitted to experimental dataa for the RCM of diene
Solvent
k1/sꢂ1
k
ꢂ1/l molꢂ1 sꢂ1
k2/l molꢂ1 sꢂ1
k
ꢂ2/l molꢂ1 sꢂ1
k3/l molꢂ1 sꢂ1
Dichloromethane
Cyclohexane
Toluene
Acetic acid
Chlorobenzene
Acetone
0.0617
0.241
0.159
0.527
0.239
0.0146
0.373
0.137
0.523
0.195
1.412
0.301
1.676
0.00775
0.0123
0.0128
0.00872
0.0197
0.231
0
0
0.0363
0.0159
0.00808
0.405
0.0207
0.029
0.0344
3.000
2.434
a
All NMR data were recorded on a Bruker DRX500 at 500.13 MHz.
The evolution of the concentration of the five key species in
the reaction is given by:
edly, acetic acid clearly emerged as the best solvent for the
RCM of diene. The reaction in dichloromethane, a solvent
commonly used for RCM reactions, was significantly slower,
though it did proceed to completion. Cyclohexane was the
only other solvent of our set in which complete conversion was
predicted, but the very poor solubility of the catalyst in
cyclohexane meant that this was not achieved in practice.
Fig. 2 shows the predicted evolution of the active catalyst
Ru* during the reaction. In dichloromethane and cyclohexane
we recorded no deactivation.z Acetic acid, as well as the two
aromatic solvents, led to some deactivation, whereas in acet-
one, catalyst deactivation dominated the reaction’s progress,
limiting conversion to around 60%.
d½Ruꢁ
¼ ꢂk1½Ruꢁ þ k ½Ruꢃꢁ½PCy ꢁ
ð1Þ
ð2Þ
ð3Þ
ð4Þ
ð5Þ
ꢂ1
3
dt
d½Ruꢃꢁ
dt
2
2
¼ k1½Ruꢁ ꢂ k ½Ruꢃꢁ½PCy ꢁ ꢂ 2k3½Ruꢃꢁ
ꢂ1
3
d½PCy3ꢁ
dt
¼ k1½Ruꢁ ꢂ k ½Ruꢃꢁ½PCy ꢁ ꢂ k3½Ruꢃꢁ
ꢂ1
3
d½dieneꢁ
dt
¼ ꢂk2½dieneꢁ½Ruꢃꢁ þ k ½prodꢁ½Ruꢃꢁ
ꢂ2
Dichloromethane and acetic acid appear to represent two
strategies in terms of successful solvents for this RCM reac-
tion. First, as described by Grubbs,4 the strategy represented
by dichloromethane is to minimise catalyst deactivation. Fig. 2
shows that, of the solvents we studied, dichloromethane and
cyclohexane do not promote deactivation under these reaction
conditions. A second strategy is to maximise the rates of the
productive reactions, in which case some catalyst deactivation
can be tolerated. Table 1 shows that acetic acid has relatively
d½prodꢁ
dt
¼ k2½dieneꢁ½Ruꢃꢁ ꢂ k ½prodꢁ½Ruꢃꢁ
ꢂ2
Experimentally, there is insignificant conversion of diene in
both isopropanol and propionitrile. For isopropanol, this
appears to be due to the very low solubility of the catalyst,
whereas propionitrile is expected to coordinate Ru* and
reduce its catalytic activity.13 Values for the five rate constants
were obtained for each of the six remaining solvents by fitting
to concentration data for prod (Table 1). The catalyst is
sparingly soluble in both cyclohexane and acetic acid, and
only 0.0004 M Ru was used in these cases in order to maximise
dissolution.
high values for k1 and k2, relatively low values for kꢂ1 and k
and an intermediate value for k3, the rate constant for
,
ꢂ2
deactivation.
We note that the rate constants reported in Table 1 for the
two equilibrium processes are highly correlated. We next plan
to determine values for the equilibrium constants computa-
tionally, and thereby to adjust these data.
To facilitate a comparison of the influences of the six
solvents in which turnover occurred, we carried out simula-
tions of the kinetic data based on the observed rate constants
from Table 1.12 The normalised conditions we selected were
0.10 M diene and 0.00042 M catalyst. The simulated evolution
of the product with time is shown in Fig. 1. Most unexpect-
We developed a basic model of solvent effects to gain a
better understanding of the observed differences in rate and
yield. For each rate constant, we used the solvent data to fit
solvatochromic eqn (6), which relates the logarithm of the rate
Fig. 1 Simulated concentration of product, based on observed rate
constants, in the reaction of 0.1 M diene with 0.00042 M catalyst.
Fig. 2 Simulated concentration of active catalyst Ru* in the reaction
of 0.1 M diene with 0.00042 M catalyst.
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Table 2 Solvatochromic coefficients for the five rate constants in the
proposed kinetic model
In conclusion, our systematic investigation of solvent influ-
ences on a metathesis reaction highlights significant variation
in productivity, resulting from a fine balance between initia-
tion, catalytic turnover and catalyst deactivation. One of the
traditional solvents for metathesis, dichloromethane, is effec-
tive mainly because the rate of catalyst deactivation is negli-
gible. Surprisingly, acetic acid is revealed to be a more
productive solvent for the RCM of diethyl diallylmalonate,
due to notably faster rates of initiation and catalytic turnover;
synthetically, the RCM of diethyl diallylmalonate is efficient
with only 0.25 mol% of Grubbs II catalyst.
Rate constant co,i
cA,i
cB,i
cS,i
cd,i
cd /
H,i
MPaꢂ1
k1 (i = 1)
ꢂ16.888
ꢂ17.555
ꢂ95.272 11.196 35.701 ꢂ81.849 14.621 34.707
3.097
4.039 ꢂ15.129 2.225 6.304
k
ꢂ1
(i = ꢂ1) ꢂ0.4720 ꢂ4.237 ꢂ0.3051 4.496 ꢂ1.922 ꢂ0.5062
5.151 ꢂ15.634 1.733 6.707
(i = ꢂ2) ꢂ17.833 ꢂ0.1985 4.876 ꢂ15.372 1.188 6.570
k2 (i = 2)
2.239
k
ꢂ2
k3 (i = 3)
constant to five solvent properties:14 the solvatochromic para-
meters15 A, B and S, a polarisability correction factor, d, and
the cohesive energy density, d2H, in MPa. A is a measure of the
solvent’s hydrogen bond acidity, B of its hydrogen bond
basicity and S of its dipolarity/polarisability. The factor d is
equal to 1 for aromatic solvents, 0.5 for polyhalogenated
aliphatic solvents and 0 for other solvents. The rate constant
ki,j for reaction i in solvent j is given by:
We thank the EPSRC for a Discipline-Hopping Award to
C. S. A. and P. C. T. (EP/E000878/1).
Notes and references
z Plotting rate vs. substrate concentration at different catalyst con-
centrations11 in dichloromethane confirmed that the rate of deactiva-
tion is negligible in dichloromethane.
cd
log ki;j ¼ co;i þ cA;iAj þ cB;iBj þ cS;iSj þ cd;idj þ H ;i dH2 ;j
100
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An examination of Table 2 shows that, with the exception of
the solvatochromic coefficient for hydrogen bond acidity cA,
the rate constants for the metathesis process k2 and k are
ꢂ2
affected to the same extent by all coefficients. Therefore, the
best way to influence the productive step using the solvent
seems to be to increase its hydrogen bond acidity, taking care
not to adversely affect the rate of deactivation. Deactivation is
best suppressed by solvents that have a high polarisability, S,
which is one reason why dichloromethane is a good choice of
solvent for RCM reactions. The parameter values reported in
Table 2 were obtained using a limited set of solvents, which
results in wide confidence intervals. In a more detailed study,
we plan to expand the range of solvents used, in order to
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confirmed in synthetic studies. Diene (1.0 g) in acetic acid
(50 ml) with just 8.8 mg (0.25 mol%) Grubbs II catalyst
underwent complete conversion to the cyclopentene product
in 3 h at room temperature, as judged by TLC and NMR
spectroscopy, with a yield after aqueous work-up of 82%.
Using dichloromethane instead of acetic acid under the same
conditions, i.e. 0.25 mol% catalyst, led to only 80% conversion
after 5 h, as judged by NMR spectroscopy. Pleasingly, acetic
acid is rated highly as an environmentally favourable solvent.16
We do not yet understand how acetic acid improves the
outcome of this RCM reaction, though we note that acid
additives, including acetic acid, have been shown to suppress
isomerisation processes, probably caused by ruthenium hy-
dride intermediates, which compete with RCM.17 Nor can we
be sure that acetic acid will have the same effect on other
metathesis reactions. Hence we plan further computational,
solvent design and synthetic studies.
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