Chemistry Reference
In-Depth Information
commercially available, the remaining experiments were performed using
this buffer.
One of the most important discoveries in this study was that the rate of
deallylation was highly dependent upon TFP concentrations; optimal TFP
concentrations were in the range 70-100, 100-140 and 160-180 mM at 25, 43
and 50 1C, respectively [Figure 16.18(c)].
66
The apparent second-order kin-
etics with respect to the concentration of TFP at lower concentrations sug-
gested that two TFP molecules were involved in the rate-determining step.
It should be noted that these optimal TFP concentrations are atypical
reaction conditions in synthetic organic chemistry; in most palladium-
catalyzed organic reactions, the stoichiometry of the phosphine ligands is
less than 10 equivalents relative to palladium. In this aqueous Tsuji-Trost-
type reaction, the optimal TFP stoichiometry was in the range 13 000-19 000
equivalents, presumably because at such low palladium concentrations
excessive TFP was necessary to shift the binding equilibrium towards a
palladium-TFP complex.
The rate of deallylation of APE showed a first-order dependence at
low concentrations of NaBH
4
and a zero-order dependence for [NaBH
4
]
Z30 mM.
66
Hence the reaction exhibited saturation kinetics; the rate-
determining step was the reduction of palladium(II) to palladium(0) at low
concentrations of NaBH
4
. At higher concentrations of NaBH
4
, the rate-
determining step was presumably the reaction between a nucleophile and a
p-allylpalladium complex. The reaction proceeded even in the absence of
NaBH
4
, because TFP could, albeit slowly, reduce palladium(II) to
palladium(0). However, collaboration between Koide's group and Merck
Research Laboratories revealed that the addition of NaBH
4
could improve
the percentage signal recovery when palladium species were quantified in
the presence of drug-like compounds.
67
The molecularity of the deallylation was first order in APE,
66
indicating that
one molecule of APE was involved in the transition state of the rate-
determining step. From this and aforementioned studies, the rate-determining
step was likely the nucleophilic attack of the p-allylpalladium complex.
Under the conditions developed above ([TFP]
¼
120 mM, [NaBH
4
]
¼
1mM,
[APE]
¼
12.5 mM, 45 1C, 30 min, 1 : 9 v/v DMSO-1.25 M phosphate pH 7 buffer),
the metals shown in Figure 16.19(a) were tested at a concentration of 100 nM,
with the exception of palladium, which was tested at a concentration of
10 nM. The method was most responsive to palladium despite the lower
concentration. Interestingly, unlike the previous method with PPh
3
that
showed a moderate response with platinum, this method did so with rho-
dium. To examine further the generality of the method, palladium and each of
the metals listed in Figure 16.19(b) were mixed in a 1 : 10 ratio and used for
the deallylation reaction. Except for the mixture of palladium and rhodium,
the combination of metals did not produce false data, indicating that metal
contaminants in palladium samples do not interfere with the APE method.
Figure 16.20 shows how the APE method evolved over time. The 2010
version was 19 times more sensitive than the 2009 version. The rate
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