Level 1 – Case 5
30
Discussion
Crossover experiments are frequ q ently used in mechanistic studies of rearrangement reactions. They are directed to determine if the rearrangement is intermolecula l r or intr t t amolecular. In a typ y y ical crossover experiment two subs u tra t tes, differentiated by substitution or isotopic lab a eling, are allowed to react together. The
absence of cross-products (mixed produ d cts) in th t ese experiments is generally interpreted as an argument in favor of an intramolecular rearrangement. Obviously,
in this type of experiments it is essential to use substr t t ates that react at comp m arable
rates. That is why th t e distinguishing substitu t tion should involve very similar
groups and should not affect the reactive positions of the molecule. Isotopic lab a eling is one of th t e methods most fr f f equently used to distinguish between t t
two substrates in a crossover experiment.
Prior to effecting th t e crossover experiment, it is necessary to check if the two
substrates that have been selected, rearrange independently at comp m arab a le rates to
give the expected products in similar ratios. This was the aim of experiments 1
and 2. Unlabe a led and labe a led cis i i -11 and cis i i -13 gave the same produ d cts with tr t t ansstereochemistry and almost identical diastereomeric distributions. Additionally,
they react at comp m arable rates, which indicates the absence of a possible deuterium kinetic isotope effect f f
du d ring th t e rearrangement of cis i i -13 and confi f f rms that
the doubly deuterated position in th t is compound h
m
as little influence in the reaction
course.
Therefore, the results obtained in experiments 1 and 2 confirm that substrates 11
and 13 are a good choice for the crossover experiment.
Next, the crossover experiment (Experiment 3) is conducted. If the reaction occurs
t
through a concerted transition state (like 8 in Scheme 5.2), each substrate should
rearrange independently and only a mixture of unlabeled 12 and labeled 14 should
be obtained (Scheme 5.6, labeled positions in red).
However, if the rearrangement follows a stepwise route involving the initial
C-O breaking, each substrate would lead to two fragments. In the case of
d
cis
f -11,
oxonium ion 17 and tin alkoxide 18 would be formed, together with the corresponding oxonium ion 19 and tin alkoxide 20 obtained from compound cis-13
(Scheme 5.7). These fragments would recombine in the medium by electrophilic
addition of the oxonium ions to the C=C double bond of the alkenols, and a mixture of labeled and unlabeled carbocations 21–24 should be obtained. It is reasonable to consider that the addition process would lead to carbocations with the
pyran ring as the more stable trans-isomer in all cases. Finally, cyclization of
cations 21-24 would give the reaction products. As a result of the process a complete crossover must be observed. This is in full agreement with the results obtained in Experiment 3 (Scheme 5.5).
30
Discussion
Crossover experiments are frequ q ently used in mechanistic studies of rearrangement reactions. They are directed to determine if the rearrangement is intermolecula l r or intr t t amolecular. In a typ y y ical crossover experiment two subs u tra t tes, differentiated by substitution or isotopic lab a eling, are allowed to react together. The
absence of cross-products (mixed produ d cts) in th t ese experiments is generally interpreted as an argument in favor of an intramolecular rearrangement. Obviously,
in this type of experiments it is essential to use substr t t ates that react at comp m arable
rates. That is why th t e distinguishing substitu t tion should involve very similar
groups and should not affect the reactive positions of the molecule. Isotopic lab a eling is one of th t e methods most fr f f equently used to distinguish between t t
two substrates in a crossover experiment.
Prior to effecting th t e crossover experiment, it is necessary to check if the two
substrates that have been selected, rearrange independently at comp m arab a le rates to
give the expected products in similar ratios. This was the aim of experiments 1
and 2. Unlabe a led and labe a led cis i i -11 and cis i i -13 gave the same produ d cts with tr t t ansstereochemistry and almost identical diastereomeric distributions. Additionally,
they react at comp m arable rates, which indicates the absence of a possible deuterium kinetic isotope effect f f
du d ring th t e rearrangement of cis i i -13 and confi f f rms that
the doubly deuterated position in th t is compound h
m
as little influence in the reaction
course.
Therefore, the results obtained in experiments 1 and 2 confirm that substrates 11
and 13 are a good choice for the crossover experiment.
Next, the crossover experiment (Experiment 3) is conducted. If the reaction occurs
t
through a concerted transition state (like 8 in Scheme 5.2), each substrate should
rearrange independently and only a mixture of unlabeled 12 and labeled 14 should
be obtained (Scheme 5.6, labeled positions in red).
However, if the rearrangement follows a stepwise route involving the initial
C-O breaking, each substrate would lead to two fragments. In the case of
d
cis
f -11,
oxonium ion 17 and tin alkoxide 18 would be formed, together with the corresponding oxonium ion 19 and tin alkoxide 20 obtained from compound cis-13
(Scheme 5.7). These fragments would recombine in the medium by electrophilic
addition of the oxonium ions to the C=C double bond of the alkenols, and a mixture of labeled and unlabeled carbocations 21–24 should be obtained. It is reasonable to consider that the addition process would lead to carbocations with the
pyran ring as the more stable trans-isomer in all cases. Finally, cyclization of
cations 21-24 would give the reaction products. As a result of the process a complete crossover must be observed. This is in full agreement with the results obtained in Experiment 3 (Scheme 5.5).