Organic Letters
Letter
δ positions of 7. The ratio of 13C in the β versus δ positions
defines an intramolecular kinetic isotope effect (KIE), and we
have previously found that this KIE varies depending on how 6
was formed.1 Reactions that provide a high amount of energy
to 6 on formation exhibit a low KIE in the subsequent ring
opening, while reactions that afford 6 with little excess energy
exhibit a much higher KIE in the ring opening. In this way, the
distribution of 13C between the β and δ positions in the
product derived from 7 could be associated both qualitatively
and quantitatively with the mechanism of the step forming 6.
Our hypothesis was that the energy read-out from the KIE
could be used to assign the mechanism.
analogy, when a bus collides with a person, it is the person that
is most accelerated and damaged.
Calculations support this qualitative expectation. In the case
of transition structure 9‡ for the HAT from 5 to 3 (Figure 1),
The conversion of 5 to 5-bromo-2-pentanone (8) was
carried out under the Shi PPO/Bu4N+Br−/blue LED
conditions at 25 °C. The formation of 8 is not quantitative,
as a number of trace byproducts were observed in the baseline
of an NMR of the crude product, but 8 appeared to be ∼90%
of the material formed. The relative 13C content at the β versus
δ positions of purified samples of 8 was determined at natural
abundance by NMR methodology.12 From the ratio of 13C in
these two positions in 12 analyses on two independent
samples, a KIE of 1.048 with a 95% confidence range of 0.001
Figure 1. HAT between 5 and 3 would pass through a transition state
9‡ involving predominantly hydrogen atom motion, with little
vibrational energy imbued to the product alkoxy radical.
the motion of the hydrogen atom is 15 times greater than that
of any other atom in the transition vector. To analyze the
energy in 6 on formation, structure 9‡ was used as the starting
point for our modified version of the classical single-trajectory
approximation of Hase.14,15 A series of trajectories were started
from 9‡ with no zero-point energy for the real modes and a
Boltzmann-random energy in the transition vector. The
trajectories were integrated forward in time, and the average
translational, rotational, and vibrational components of the
energy in 6 and 4 were determined as the molecules separated.
Only 0.5 kcal/mol of extra vibrational energy is predicted to be
formed in 6. At this energy, half of the molecules of 6 are
formed with insufficient energy to overcome the ring-opening
barrier. This means that ∼1/2 of the reaction at a minimum
should be governed by a thermal KIE of 1.063. Allowing for
this, the predicted minimum KIE is 1.060. This is not
consistent with the experimental observation.
From the general logic above, the large initial excess energy
in 6 suggested to us that a heavy atom is being transferred in
the mechanistic step forming 6. This led us to consider a
hypobromite radical chain process as the source of the ω-
bromoketones. The corresponding ring-opening reaction of
cycloalkyl hypochlorites are well-known and mechanistically
well studied, since the hypochlorites are often sufficiently
stable for full characterization.16 By comparison, alkyl
hypobromites are less stable, generally only at low temper-
atures in the dark. Most have been characterized solely by
titrimetric and UV−visible spectrophotometric methods.17,18
Ring-opening reactions of putative hypobromites have afforded
products analogous to 2 or 8.19
If 6 were thermally equilibrated before undergoing ring
opening, the expected KIE would be 1.063.1 The lower
observed KIE is then indicative of excess energy in 6 on
formation. Using RRKM theory and a tunneling correction as
previously described,1 it was calculated that an excess energy of
3.5 0.2 kcal/mol would give rise to the observed KIE.
We now consider whether this energy fits with the proposed
HAT by phthalate radical anion 3 as in eq 2. The vibrational
energy that arises initially in 6, or in any molecular fragment
expelled during a reaction, may be qualitatively thought of as
arising from two components. The first component is the
change in the fragment’s geometry as it morphs into the
product geometry. A large geometry change could in principle
lead to a large excess of vibrational energy in a fragment, but
here the changes from 5 to 6 are minor (the largest change is a
shortening of the C−O bond by 0.08 Å).
The second component of the initial vibrational energy in a
leaving molecular fragment arises from the impulse provided by
the repulsive energy surface after the transition state.13 As a
hydrogen atom is transferred away from 5, the oxygen atom of
5 is pushed away by the hydrogen, and this impulse provides
energy to 6. However, the hydrogen atom is much lighter than
the oxygen atom, so it is mainly the hydrogen atom that moves.
This is reflected in the motion in the transition vector, and any
HAT involves a transition vector that is dominated by the
motion of the hydrogen atom. The HAT then puts vibrational
energy into the new bond to hydrogen, but little impulse is
provided to the fragment giving up a hydrogen atom. As an
In a hypobromite chain mechanism, a bromine atom would
be abstracted from the hypobromite 10 by 7 to afford the
product 8 and alkoxy radical 6. The α-cleavage/ring opening of
6 then gives 7 which feeds back into the chain. The initial
radicals to start the chain could be readily formed from the
blue LED irradiation. The computational study of the key
bromine-atom abstraction step was carried out in M06-2X/6-
31+G** calculations using the ethyl radical as a model for 7.
The abstraction step is highly exergonic (by 28.0 kcal/mol),
and no potential energy barrier could be located. However, an
approximate variational transition state 11‡ was located by a
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Org. Lett. 2021, 23, 2174−2177