FULL PAPER
byproducts, limited attention has been given to the quantifi-
cation of these oligomeric products.[3a,20b] Herein, we have
separated and characterized the main oligomeric byproducts
(mostly cyclodimers) that are formed during RCM reactions
by using preparative column chromatography. In this con-
text, the intermediate substrate concentrations (8–20 mm)
were purposely used for assembling medium- and large-size
Grubbs and co-workers,[10a] the conversion reached a plateau
after 6–8 h when the reactions were performed at 50–608C
with ultralow catalyst loadings. Increasing the temperature
to 808C significantly enhanced the reaction rates without a
loss of productivity (TON). At this temperature, the RCM
of neat diene 1 reached 35% conversion within 20 min by
using 20 ppm of catalyst B. This conversion increased to
68% on the addition of a further 20 ppm of catalyst B. How-
ever, when 50 ppm of catalyst B was added in one portion,
92% conversion of diene 1 was obtained after 30 min at
808C. Under the same conditions, six-membered-ring 8 was
produced in 83% yield when 50 ppm of catalyst C was
added in one portion. Dienes 1, 3, 5, and 7 are characterized
by their very high effective molarity (EM)[25] and, therefore,
bear strong affinities for ring formation. For practical rea-
sons, it can be beneficial to perform the RCM reactions of
this type of diene without any solvent. The large-scale
(0.2 mol) syntheses of five- and six-membered rings (2, 4, 6,
and 8) were successfully performed by using 100–200 ppm of
fast-initiating catalysts B and C.
The use of RCM reactions for the synthesis of macrocyclic
targets of broad practical interest commonly requires dilu-
tion in inert solvents to achieve higher selectivities. Recent-
ly, we and several other groups have highlighted that the
identity of the solvent has a significant impact on the meta-
thesis reaction.[5s,8a,26] Aromatic hydrocarbon solvents and,
especially, fluorinated aromatic solvents were found to have
the most positive effect on the performance of the second-
generation ruthenium catalysts. Taking into account the
process costs and environmental regulations, toluene is the
solvent of choice for industrially relevant applications. In in-
itial experiments, we have observed variations in reaction
rates, depending on the toluene source and batch. To elimi-
nate this problem, we purified toluene by using recommend-
ed methods,[21] then dried it over 3 ꢁ molecular sieves,[22]
thereby lowering the moisture content to 1–2 ppm. Degass-
ing by ultrasonication minimized the potential for oxygen-
related decomposition and, hence, improved the reproduci-
bility of the kinetic curves when working with ultralow cata-
lyst loadings.
rings. The assignment of double-bond isomers (E/Z) was
3
done on the basis of vicinal J
N
Results and Discussion
The results of the catalytic runs can be rather sensitive to
impurities in the substrates when working with ultralow cat-
alyst loadings. Therefore, we carefully purified all of the
starting dienes by using repeated vacuum distillation or re-
crystallization (for details, see the Supporting Information).
It is worth noting that starting diene 11 isomerizes in the re-
frigerator at just 48C and, therefore, should be stored at
much lower temperatures. When stored in the refrigerator
at 48C for more than one month, we observed significantly
lower activities. Fractional amounts of double-bond isomers
either slow down the metathesis reaction, that is, if the allyl-
phenyl moiety isomerizes into a 1-propenylphenyl moiety
(see below), or act as a quenching reagent by forming a
Fischer alkylidene complex, that is, if the allyloxy group iso-
merizes into a 1-propenyloxy group.
Several groups have recently demonstrated that the reac-
tion of neat diethyl diallylmalonate (1) proceeds at substan-
tially higher rates than that in solution, especially when
Hoveyda-type catalysts are used.[23–24] One of the reasons for
this result is that the initiation rate of the Hoveyda-type cat-
alysts follows second-order kinetics and linearly depends on
the concentration of the substrate; therefore, the reaction
rate is accelerated in neat substrate.[24b] Another possible
reason for this result could be that the solubility of ethylene
is limited by the low total volume of the substance. This pos-
itive effect could be reinforced by purging off evolving eth-
ylene. Intensive argon sparging with fine blowhole distribu-
tion throughout the entire volume (for increasing the gas/
fluid surface) gives rise to the efficient volatilization of eth-
ylene. Practically, the reactions were carried out in round-
bottomed flasks that were fitted with an effective reflux con-
denser and placed in an oil bath. Sparging with an inert gas
was provided by a vigorous stream of argon through a long
thin needle that was introduced through a rubber septum.
Stirring at high rate gave rise to better dispersion of the gas
bubbles and, therefore, increased the speed of gas transfer.
The RCM reactions of neat diene 1 were monitored over
a range of catalyst loadings from 2 to 50 ppm and tempera-
tures from 55 to 808C. To ensure a high degree of precision
of catalyst metering, we used a stock 5 mm solution of the
catalyst that was prepared in a glovebox. To minimize the
influence of the solvent that was used for catalyst dilution,
the experiments with neat substrate were performed with
0.1–0.2 mol of the diene. Consistent with the findings of
To evaluate the catalytic performance in diluted solutions
in toluene, the RCM reactions were performed at 808C and
at concentrations from 8 to 40 mm in the presence of alkanes
(dodecane, tetradecane, and octadecane) as internal stand-
ards. The course of the reaction was monitored by GC by
removing aliquots with syringes and quenching in a solution
of ethyl vinyl ether. All of the monocyclic products were iso-
lated, carefully purified, and their GC signals were calibrat-
ed against a corresponding standard. In the case of com-
pound 12, double-bond isomerization occurred to some
extent during vacuum distillation. We also observed double-
bond isomerization products towards the end of the meta-
thesis reaction. Therefore, the calibration of the RCM prod-
ucts in that particular case was done by assuming that all of
the double-bond isomers had almost the same relative re-
sponse factor.
Chem. Eur. J. 2013, 19, 1002 – 1012
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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