Theoretical elucidation of kinetic and thermodynamic control of radical addition regioselectivity

Article abstract of DOI:10.1021/ja029342q

The cyclizations of two structurally similar 2-oxo-5-hexenyl-type radicals have been investigated by ab initio and density functional (UB3LYP/6-31+G**//UHF/6-31G* and UB3LYP/6-31G*//UB3LYP/6-31G*) calculations. The origin of apparently contradictory reports of 6-endo and 5-exo cyclizations is determined. Kinetic control favors 6-endo cyclization, while thermodynamic control gives 5-exo cyclization, and the observation of different products from different research groups arises from the difference in experimental conditions used by the two groups. The outcome of a new cyclization reaction was predicted by using these theoretical techniques. Kinetic control is predicted to yield exclusively the products of 6-endo cyclization, while thermodynamic control would lead to an approximately equal mixture of one 6-endo and one 5-exo cyclized product. Experimental studies revealed that the reaction yields only the products of 6-endo cyclization through kinetic control.

Full text of DOI:10.1021/ja029342q

Published on Web 03/14/2003
Theoretical Elucidation of Kinetic and Thermodynamic
Control of Radical Addition Regioselectivity
Andrew G. Leach, Renxiao Wang, G. Erich Wohlhieter, Saeed I. Khan,
Michael E. Jung,* and K. N. Houk*
Contribution from the Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, California 90095-1569
Received November 14, 2002; E-mail: houk@chem.ucla.edu
Abstract: The cyclizations of two structurally similar 2-oxo-5-hexenyl-type radicals have been investigated
by ab initio and density functional (UB3LYP/6-31+G**//UHF/6-31G* and UB3LYP/6-31G*//UB3LYP/6-31G*)
calculations. The origin of apparently contradictory reports of 6-endo and 5-exo cyclizations is determined.
Kinetic control favors 6-endo cyclization, while thermodynamic control gives 5-exo cyclization, and the
observation of different products from different research groups arises from the difference in experimental
conditions used by the two groups. The outcome of a new cyclization reaction was predicted by using
these theoretical techniques. Kinetic control is predicted to yield exclusively the products of 6-endo
cyclization, while thermodynamic control would lead to an approximately equal mixture of one 6-endo and
one 5-exo cyclized product. Experimental studies revealed that the reaction yields only the products of
6-endo cyclization through kinetic control.
Scheme 1. Cyclization of the 5-Hexenyl Radical3
Introduction
The intramolecular additions of radicals to carbon-carbon
double bonds to form five- or six-membered rings are of
continuing interest in synthetic organic chemistry.1,2 Generally,
5-hexenyl radicals cyclize with high regioselectivity to give five-
rather than six-membered rings (Scheme 1).3
This is a mainstay of Baldwin’s rules, which note that 5-exo
cyclization should be preferred over 6-endo for attack on a
trigonal center.4 Two force field models have been developed
which enable quantitative predictions of these regioselectivities
to be made.5 In contrast to Baldwin’s rules, the intramolecular
cyclizations of radicals adjacent to endo carbonyls (“acyl-
substituted radicals”) have been found to yield 6-endo products
(Scheme 2).6 Several factors (both electronic and steric)
contribute to this preference,7 and a force field model has been
developed which accounts for these in a quantitative fashion.8
Recently, Jung and Rayle9 and Haney and Curran2 reported
experimental intramolecular radical additions that revealed
puzzling differences in this type of regioselectivity. Although
the reactants employed are quite similar (Schemes 3 and 4),
Scheme 2. Cyclization of an Acyl-Substituted Hexenyl Radical7
strikingly different product mixtures were obtained. Haney and
Curran’s experiments, in which the reaction is initiated by the
combination of tin hydride with vinyl iodide 1, yield the 6-endo
derived products 2 and 3 in line with expectation for this type
of radical.
However, Jung and Rayle’s intramolecular radical additions,
initiated by thiyl radical addition to vinyl cyclopropane 4, gave
a preponderance of the 5-endo pathway instead (Scheme 4).
Curran and Haney suggested that the radical cyclizations might
be reversible under these conditions and that the product could
be the result of thermodynamic control.2
(1) (a) Bennasar, M.-L.; Juan, C.; Bosch, J. Chem. Commun. 2000, 2459-
2460. (b) Ellis, D. A.; Hart, D. J.; Zhao, L. Tetrahedron Lett. 2000, 41,
9357-9360. (c) Snider, B. B.; Buckman, B. O. J. Org. Chem. 1992, 57,
4883-4888.
(2) Haney, B. P.; Curran, D. P. J. Org. Chem. 2000, 65, 2007-2013.
(3) Walling, C.; Cioffari, A. J. Am. Chem. Soc. 1972, 94, 6059-6064.
(4) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-746.
(5) (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett. 1985, 26, 373-
376. (b) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-
3941. (c) Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959-
974.
To determine energetics and the nature of the transition states,
products, and intermediates for these processes, quantum
mechanical calculations have been employed. Such calculations
have been found to be a useful tool for understanding the
selectivity of radical reactions,10,11 and we have employed them
(6) Clive, D. L. J.; Cheshire, D. R. J. Chem. Soc., Chem. Commun. 1987, 1520-
1523.
(7) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989, 54, 3140-3157.
(8) Broeker, J. L.; Houk, K. N. J. Org. Chem. 1991, 56, 3651-3655.
(9) Jung, M. E.; Rayle, H. L. J. Org. Chem. 1997, 62, 4601-4609.
9
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J. AM. CHEM. SOC. 2003, 125, 4271-4278
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A R T I C L E S
Leach et al.
Scheme 3. Haney-Curran Radical Cyclization2
Scheme 4. Jung-Rayle Radical Cyclization9
Scheme 5. Model Reactions
to explain these dichotomous experimental results and to predict
the outcome of a similar reaction.
Computational Methodology
Two levels of theory have been employed. Using Hartree-Fock
geometries but evaluating energies with a method which accounts for
correlation has previously been shown to be effective for radical
reactions.5c,11 Thus, the UB3LYP/6-31+G**//UHF/6-31G* method was
used throughout. To assess this methodology, the same species were
optimized with UB3LYP/6-31G* in some cases, and the corresponding
UB3LYP/6-31G* energies were compared to those obtained with the
computationally less demanding method already described.12 All
calculations were performed using the Gaussian98 program,13 and all
stationary points were analyzed through computation of their vibrational
frequencies. Reported energies include a thermal correction to 298 K
based on the UHF (UB3LYP//UHF method) or UB3LYP (UB3LYP//
UB3LYP method) frequencies.
Results
Table 1. UB3LYP/6-31+G(d,p)//UHF/6-31G(d) Energetics of
Intramolecular Additions of Alkyl-Substituted Radicals to Alkenesa
(1) Model Reaction Study of Intramolecular Additions of
Alkyl and Acyl-Substituted Radicals. Initially, the cyclizations
of four model reactants, 5, 6, 7, and 8, were studied. These
reactions were chosen to investigate the regioselectivity for the
cyclization of alkyl radicals and the effect of introducing alkyl
substituents at C1, C5, and C6. Similarly, 9, 10, 11, and 12,
were used to study the intramolecular additions of radicals R
to carbonyls (Scheme 5).
6-endo pathway
5-exo pathway
endo/exo
(expt)
endo/exo
(calcd)
reactant chair TS boat TS chair TS boat TS
5
6
7
8
9.1
9.6
8.4
9.8
11.6
12.2
10.7
12.5
6.4
7.0
9.1
6.5
8.1
8.7
10.3
8.1
2:9814, <1:>993
1:9914
1:99
1:99
60:4014,15
75:25
<1:> 99
<1:>9916
a Energies are in kcal/mol. The reactant in the all-anti conformation is
taken as reference.
(10) (a) Houk, K. N.; Paddon-Row: M. N.; Spellmeyer, D. C.; Rondan, N. G.;
Nagase, S. J. Org. Chem. 1986, 51, 2874-2879. (b) Olivella, S.; Sole´, A.
J. Am. Chem. Soc. 2000, 122, 11416-11422.
Transition states in different conformations were identified
for each reaction. In the following sections, these transition states
will be named chair, boat, or twist-boat, after the arrangement
of C1-C2-C3-C4-C5-C6 even for species leading to five-
membered ring products.5c The results for the alkyl radical
addition reactions of 5 to 8 are summarized in Table 1, and the
results for 9 to 12 are summarized in Table 2. The kinetic
6-endo/5-exo regioselectivity in each model reaction was
assumed to depend on the relative activation energies of
cyclization in the two series and was calculated from a
Boltzmann distribution over all relevant transition states obtained
from these calculations.
(11) Wong, M. W.; Radom, L. J. Phys. Chem. 1995, 99, 8582-8588.
(12) B3LYP utilizes Becke’s three-parameter exchange functional and the Lee-
Yang-Parr correlation functional. Becke, A. D. J. Chem. Phys. 1993, 98,
5648 and Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785.
(13) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,
J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.7; Gaussian,
Inc.: Pittsburgh, PA, 1998.
9
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Control of Radical Addition Regioselectivity
A R T I C L E S
Table 2. UB3LYP/6-31+G(d,p)//UHF/6-31G(d) Energetics of
Table 3. UB3LYP/6-31+G(d,p)//UHF/6-31G(d) Energetics
(kcal/mol) for the Haney and Curran Reactionsa
Intramolecular Additions of Acyl-Substituted Radicals to Alkenesa
6-endo pathway
5-exo pathway
reaction
reactant
TS1
intermediate
TS2
product
endo/exo endo/exo
15b
16b
17b
18b
19b
20b
0.0
0.0
0.0
0.0
0.0
0.0
12.2
11.0
19.0
19.2
17.7
21.1
-2.3
-4.2
7.1
5.5
5.9
8.0
9.9
9.1
16.7
15.8
13.1
-8.9
-4.8
6-endo
reactant chair TS boat TS chair TS boat TS twist-boat TS
(expt)
(calcd)
97:37
-
98:2
95:5
>99:<1
84:16
99:1
-10.6
-0.8
9
10.0
12.6
8.6
16.5
19.1
15.2
17.2
-
13.3
15.9
15.8
12.7
18.7
12.6
14.4
14.7
12.1
18.0
14.7
16.6
16.4
14.1
-
10
11
12
13
5-exo
-
-0.9
-12.7
10.9
15.4
75:257
-
7.2
a The two favored kinetic pathways are in boldface (corresponding to
experimental results) while thermodynamically favored products are
underlined.
a Energies are presented in kcal/mol. The reactant in all-anti conformation
is taken as reference.
Table 4. UB3LYP/6-31+G(d,p)//UHF/6-31G(d) Energetics
(kcal/mol) for the Jung and Rayle Reactionsa
reaction
reactant
TS1
intermediate
TS2
product
15a
16a
17a
18a
19a
20a
0.0
0.0
0.0
0.0
0.0
0.0
13.2
12.1
16.1
14.5
14.5
16.6
-4.6
-5.2
0.0
-1.4
-2.2
0.7
4.7
7.0
7.7
8.0
7.9
4.3
-14.7
-12.0
-16.0
-10.2
-9.5
6-endo
5-exo
-17.9
a The two favored kinetic pathways are in boldface while thermodynami-
cally favored products (corresponding to experimental results) are under-
lined.
always favored, whether there is alkyl substitution at C1, C5,
or C6 (Table 2). For all of these simple system, there is excellent
agreement between the computational results and available
experimental data.
For the acyl-substituted radicals, the bond between the radical
(C1) and the carbonyl group (C2) is a partial double bond of
an oxyallyl radical (Figure 3). When a C1 substituent is present,
it can adopt an (E)- or a (Z)-geometry. To make a comparison
between E and Z conformers, the reaction of 13 was studied.
On the basis of the computational results (Table 2), the
E-configured transition state (from 13) is much higher in energy
than its Z-configured counterpart (from 10). Even in the case
of E-configuration, the 6-endo pathway is still favored.
Experimentally determined regioselectivities are available for
six model reactions, i.e., the cyclizations of 5, 6, 7, 8, 9, and
12, although the reaction corresponding to 8 has a 3-butenyl
substituent rather than a methyl substituent on the olefin.3,7
Generally speaking, these calculations reproduce the experi-
mental results very closely (Tables 1 and 2).
(2) Study of the Jung and Rayle and the Haney and
Curran Intramolecular Radical Additions. We have studied
in detail the possible pathways for the reactions examined by
Jung and Rayle and by Haney and Curran (Scheme 6). Since
such a radical addition reaction may take a 6-endo or 5-exo
pathway and C1 and C5 are potential chiral centers, there are
six possible pathways in both cases.
The reactions leading to 15-20 were studied by ab initio
and density functional calculations. The reactants, transition
states of the first step (TS1), intermediates, transition states of
the second step (TS2), and final radical products of these
reactions were determined at the UB3LYP/6-31+G(d,p)//UHF/
6-31G(d) level.
The energetics of the various reactions are listed in Tables 3
and 4. As with the model reactions, there could be chair, boat
and twist-boat conformations for each reaction, but for the sake
of convenience, only the conformation found to be lowest in
energy in the model studies was computed.
Figure 1. Transition states for the cyclization of alkyl radical 5.
For the alkyl-substituted radical intramolecular addition
reactions (5, 6, 7, and 8), chair and boat transition states were
found for the 6-endo and the 5-exo pathways. The chair
transition state is usually ∼2 kcal/mol lower in energy than its
boat counterpart (Table 1). The average length of the forming
single bond is 2.25 Å for the 6-endo pathway and 2.19 Å for
the 5-exo pathway (Figure 1). The activation energy of 6.4 kcal/
mol calculated for the cyclization of 5 is in good agreement
with the experimental value of 6.9 kcal/mol.17 Generally
speaking, the 5-exo pathway is preferred. The results for 6 and
8 indicate that alkyl substitution at C1 or C6 will not change
this preference. However, as indicated by the reaction of 7, alkyl
substitution on C5 changes the preferred site of cyclization and
favors the 6-endo product.
For the acyl-substituted radical intramolecular addition reac-
tions (9, 10, 11, and 12), chair and boat transition states were
again found for the 6-endo pathway; the chair is preferred (Table
2). The average length of the forming bond is 2.19 Å (Figure
2). For the 5-exo pathway, a twist-boat transition state was also
found; of the three possible transition states, the boat conforma-
tion is lowest in energy (Table 2). The average length of the
forming bond is 2.15 Å for the 5-exo pathway (Figure 2).
According to the computational results, the 6-endo pathway is
(14) Beckwith, A. L. J.; Blair, I. A.; Phillipou, G. Tetrahedron Lett. 1974, 15,
2251-2254.
(15) Beckwith, A. L. J.; Lawrence, T. J. Chem. Soc., Perkin Trans. 2 1979,
1535-1539.
(16) Based upon the reaction for an olefin with a 3-butenyl substituent in place
of the methyl substituent in 8, data from ref 14.
(17) Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc. 1981,
103, 7739-7742.
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A R T I C L E S
Leach et al.
Figure 2. Transition states for the cyclization of endo-carbonyl-substituted radical 9.
Scheme 6. Summary of Species Studied Theoretically
Figure 3. Substrates for the radical cyclization with an (E) or (Z)
configuration about the partial double bond between the carbonyl and the
radical center.
The data in Table 3 allow the observations of Haney and
Curran to be interpreted. The reaction is under kinetic control
with the preference being determined in the first cyclizations
each product from this cyclization can only go on to form one
product which occurs with a lower barrier than that for the first
cyclization. The activation barriers for the four 5-exo pathways
are 5-10 kcal/mol higher than the ones for the 6-endo pathways.
For the 6-endo pathways, the observed preference for product
16b (1.5 times that for 15b) corresponding to a difference in
activation energies of 0.2 kcal/mol can also be understood. There
is a 1.2 kcal/mol lower barrier calculated for 16b than for 15b
which, although a larger difference than is seen experimentally,
comprises excellent agreement considering the simplifications
introduced during the calculations. These results agree with
Curran’s interpretation and the literature on simple acyl radical
cyclizations.
Reactions performed under Haney and Curran’s conditions
are likely to be under kinetic control as the product radical must
abstract a hydrogen atom from a molecule of tin hydride to
maintain the radical chain. The reduced product thus generated
cannot participate further in the reaction. The barriers to
reversion from the product are significant, and as a result the
abstraction will be much faster than reversion. The production
of significant amounts of side products derived from hydrogen
abstraction by some of the intermediate radical species attests
to the importance of this process.
so straightforward to interpret. As indicated by the data in Table
4, the difference in the activation barrier for the 6-endo and the
5-exo reaction pathways (the first step) is smaller (2-3 kcal/
mol) than for Haney and Curran’s reaction. This is still sufficient
The results of the reaction studied by Jung and Rayle are not
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Control of Radical Addition Regioselectivity
A R T I C L E S
Scheme 7. Proposed Mechanism for the Equilibration of the
Products of the Jung-Rayle Reaction
Table 6. Calculated UB3LYP/6-31+G**//UHF/6-31G* Energetics
(kcal/mol) for the Reactions of 14ca
reaction
reactant
TS1
intermediate
TS2
product
15c
16c
17c
18c
19c
20c
0.0
0.0
0.0
0.0
0.0
0.0
11.8
10.9
19.2
17.2
17.0
19.4
-6.0
-6.7
3.4
2.5
2.4
3.2
5.3
9.8
11.9
14.3
7.4
-15.3
-12.1
-14.0
-5.4
6-endo
5-exo
Table 5. Calculated Energies of the Product Alkenes of the
Jung-Rayle Reaction (Relative to Lowest in Each Series)a
-2.3
3.8
-15.2
B3LYP/6-31+G**//
HF/6-31G*
B3LYP/6-31G*//
B3LYP/6-31G*
a The two favored kinetic pathways are in boldface while thermodynami-
cally favored products are underlined.
reaction
15a′
16a′
17a′
18a′
19a′
20a′
2.9
3.8
3.3
7.6
8.2
0.0
2.8
3.3
2.7
7.8
8.2
0.0
6-endo
5-exo
Table 7. Calculated UB3LYP/6-31G*// UB3LYP/6-31G* Energetics
(kcal/mol) for 14ca
reaction
reactant
TS1
intermediate
TS2
product
15c
16c
17c
18c
19c
20c
0.0
0.0
0.0
0.0
0.0
0.0
11.5
10.7
19.1
16.9
16.7
19.4
-8.7
-9.3
1.7
0.8
0.7
1.3
3.1
9.1
11.0
13.2
6.5
-18.6
-15.7
-17.0
-8.4
6-endo
a Thermodynamically preferred products are underlined.
5-exo
-5.7
to conclude that the 6-endo path would be observed almost
exclusively if the reaction were under kinetic control with no
steps being reversible. However, the reaction is performed under
extended irradiation over the course of a number of weeks.
Therefore, it is not unreasonable that the product is attacked by
a thiyl radical and that the intermediate radical could revert to
the acyl-substituted radical intermediate (Scheme 7).
If this were the case, the product mixture would turn over
slowly from the 6-endo product, through the reactant 14a, to
form an equilibrium mixture of the product alkenes, and the
product ratio would be determined by the energy of the products.
The alkenes corresponding to the removal of H• from 15a
through 20a (denoted 15a′-20a′) were therefore studied both
with the UB3LYP//UHF method used previously and with
UB3LYP/6-31G*//UB3LYP/6-31G*. The energies of these
alkenes are reported in Table 5.
2.0
-18.3
a The two favored kinetic pathways are in boldface (corresponding to
experimental results) while thermodynamically favored products are
underlined.
Table 8. Energies of the Product Olefins for the Cyclization of
Methyl-Substituted Olefin 14ca
UB3LYP/6-31+G**//
UHF/6-31G*
UB3LYP/6-31G*//
UB3LYP/6-31G*
reaction
15c′
16c′
17c′
18c′
19c′
20c′
0.0
2.5
2.1
9.7
13.1
0.4
0.0
2.3
1.7
10.0
12.9
0.1
6-endo
5-exo
a Thermodynamically preferred products are underlined.
Both levels of theory predict that 20a′ is the lowest-energy
product. This is in accord with the experimentally observed
major product. Both methods predict that the 6-endo product,
15a′, and the 5-exo product, 17a′, are close in energy. The
prediction based on B3LYP//B3LYP is in accord with the
experimentally observed outcome that 20a′ is obtained in 47%
yield and 17a′ is obtained in 26%. It may be that the remaining
27% contains some of the next favored product 15a′.
(3) Prediction of the Possible Outcomes of an Experimen-
tally Untried Reaction. Finally, the as-yet unreported cycliza-
tion of the methyl-substituted olefin 14c was studied. It is
known, and was confirmed by our model calculations on
compound 11, that such substitution favors the 6-endo cycliza-
tion. All of the important transition states and intermediates were
optimized as before, but alongside these calculations, the same
structures were optimized with the alternative density functional
method. The results of all of these calculations are shown in
Tables 6 and 7. The energetics obtained with both methods are
in good agreement with one another, suggesting that both
methods may be suitable for tackling these types of reactions.
This also gives us confidence that the results obtained during
the earlier studies when only one method was utilized are
realistic.
forming bond in the transition state. The 6-endo products should
be formed more rapidly than for the monosubstituted olefin 14a,
but they should also reverse more readily to regenerate reactant
14c. The difference in barrier heights between 6-endo and 5-exo
is in the range 5-9 kcal/mol, similar to the difference calculated
for the Haney and Curran reaction. Thus, were the reaction under
kinetic control, the two 6-endo products 15c and 16c should be
the major products. By contrast, if the reaction is able to
equilibrate, this will take place more slowly than for the reaction
of 4, modeled by 14a, due to the higher barriers for the 5-exo
paths. To predict the expected product mixture if this process
takes place, the product olefins were also studied, and their
energies are reported in Table 8.
Interestingly, in this case, both methods predict the same
ordering of products and lead us to expect that at equilibrium,
the major product should be the 6-endo product 15c′. The 5-exo
product 20c′ should be the next most significant and form to
almost the same extent as 15c′. The other low-energy 5-exo
product, 17c′, and the 6-endo product, 16c′, might also be
observed.
(4) Synthesis and Experimental Study of the Cyclization
of Methyl-Substituted Olefin 14c. The synthesis of the
compounds corresponding to the radical 14c begins with the
conversion of 3-methyl-3-buten-1-ol to the corresponding
bromide 22, as shown in Scheme 8. The bromide was treated
with tert-butyllithium to generate the anion which was im-
mediately coupled to the known exo-aldehyde 23.9 The resulting
As expected, the barrier for 6-endo cyclization is lowered
with the methyl substituent present, since the product of this
step is now a tertiary radical, whereas the barrier for 5-exo
cyclization is raised due to the increased crowding along the
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A R T I C L E S
Leach et al.
Scheme 8
alcohol (24) was oxidized to the ketone 25, which was
subsequently photolyzed in the presence of butyl disulfide. The
progress of the reaction was monitored by GC, and after 6 days
the reaction was complete. Characterization and assignment of
the isolated compounds (26, 27) proved to be more difficult
than originally anticipated, and after a number of IR and NMR
methods were ruled out, the dinitrophenyl hydrazones (28, 29)
were synthesized. Fortunately, the hydrazones were crystalline,
and the structures could be identified unambiguously from the
X-ray analysis, Figure 4.
Figure 4. X-ray crystal structure of the 2,4-dinitrophenylhydrazone
derivatives of the product of the reaction in which 25 is subjected to the
Jung and Rayle conditions for radical cyclization. The crystal is composed
of a mixture of two isomers, 28 and 29, represented by white and black
structures in the region where the two structures diverge.
days. This is consistent with the calculated barrier heights which
are lower for 6-endo cyclization for 14c (10.9 and 11.8 kcal/
mol) than for 14a (12.1 and 13.2 kcal/mol). The barriers for
subsequent equilibration to 5-exo products show the opposite
trend and are lower for 14a which subsequently undergoes
equilibration.
The barriers calculated for 14c are similar to those for 14b,
which had been used to model the Haney-Curran reaction of
1. The difference between barriers for 6-endo and 5-exo
cyclizations is 5-10 kcal/mol for 14b. The reaction of 1 was
performed under conditions that ensured the observation of
kinetic products. The computed energetics suggest that, if a
reaction is performed on the analogous substrate under the
Jung-Rayle conditions, the same kinetically determined prod-
ucts should be observed.
The X-ray structure clearly shows the product is a mixture
of 6-endo products. The structure in black, the cis-syn-cis
product 28 corresponding to 16c is the major isomer constituting
82% of the crystal, while the white structure, the cis-anti-cis
product 29 corresponding to 15c is the minor component found
1
in 18%. GC and H NMR data show that the ratio of major to
minor products is 1.7:1, corresponding to a ∆∆Eq of ∼0.3 kcal/
mol. This closely parallels the Haney-Curran work, wherein a
1.5 to 1 ratio of major to minor 6-endo products corresponding
to 16b and 15b was observed. Our calculations had shown that
kinetic control should yield a mixture of 16c and 15c, and
thermodynamic control, 15c and 20c. The experimental obser-
vations are consistent with kinetic control even though the same
conditions had previously provided thermodynamic control for
the cyclization of 4.
To rationalize the switch from thermodynamic to kinetic
control, the computed energetics for 14c were contrasted with
those computed for 14a, which modeled the cyclization of 4.
The difference in barrier heights between 6-endo and 5-exo
cyclizations was 1-5 kcal/mol for 14a but 5-9 kcal/mol for
14c. This significant change in relative barriers for 6-endo and
5-exo makes the 5-exo products kinetically less easily accessible.
Equilibration of 14c would be much slower than for 14a. Indeed,
degradation may become competitive with the equilibrations
this is suggested and supported by the experimental observation
that the baseline of the GC chromatogram becomes crowded
with small peaks as the photolysis progresses.
Conclusions
Ab initio and density functional calculations have been used
to rationalize and to predict the outcome of radical reactions.
The calculations mirror the outcome of simple model reactions
and are useful in interpreting the studies of more complex
systems.
In a radical cyclization reported by Haney and Curran,
calculations are consistent with a selectivity determined by
kinetic control; the difference in activation energies favors
6-endo cyclization over the alternative 5-exo cyclization by 5
to 10 kcal/mol.
A further aspect of note is the change in reaction times on
going from 4, which took 3 weeks to 25, which took just 6
The radical cyclization reported by Jung and Rayle is
explained as being reversible under the reaction conditions with
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4276 J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003

Control of Radical Addition Regioselectivity
A R T I C L E S
1
give 9.86 g (67%) of the bromide 22 as a light-sensitive, clear oil. H
the products being determined by thermodynamic stability. The
difference in activation energies still favors 6-endo cyclization,
but only by 1-5 kcal/mol.
A prediction was made for the outcome of a related reaction
which was performed under the Jung and Rayle conditions but
which experimental testing showed yielded products determined
by kinetic control. This reaction demonstrates the subtle balance
involved in the energetics determining the outcome of these
reactions. The difference in activation barriers between 6-endo
and 5-exo cyclization was 5-9 kcal/mol in this case.
NMR (CDCl3, 400 MHz) δ 4.85 (1H, d, J ) 0.7 Hz), 4.76 (1H, d, J )
0.7 Hz), 3.44 (2H, t, J ) 7.4 Hz), 2.57 (2H, t, J ) 7.4 Hz), 1.74 (3H,
s). 13C NMR (CDCl3, 100 MHz) δ 142.4, 112.7, 40.9, 30.8, 21.9.
(rRS,1R,5R,6S)-r-(3-Methyl-3-butenyl)-bicyclo[3.1.0]hex-2-ene-
6-methanol, 24. To an oven-dried round-bottomed flask charged with
a stir bar and diethyl ether (10 mL) was added tert-butyllithium (2.0
M in pentanes, 2.22 mL, 5.6 mmol), and the solution was cooled to
-90 °C. To this solution was added dropwise a solution of the bromide
22 (0.51 g, 2.8 mmol) in diethyl ether (5 mL) via syringe pump, and
the reaction was allowed to stir for 20 min. To this solution was then
added a solution of the aldehyde 23 (0.20 g, 1.85 mmol) in diethyl
ether (5 mL), and the reaction was allowed to stir until TLC indicated
completion (ca. 0.5 h). The reaction was quenched by pouring the cold
solution into water (30 mL). The organic layer was washed with
saturated sodium bicarbonate (30 mL) and brine (30 mL) before being
dried over MgSO4. After filtration, the resulting solution was reduced
in vacuo, and the oil was purified by flash chromatography (silica gel,
15% diethyl ether in pentane) to give 0.35 g (71%) of the alcohol 24
as a 1:1 mixture of diastereomers. 1H NMR (CDCl3, 500 MHz) δ 5.89
(1H, m), 5.42 (1H, m), 4.71 (2H, bs), 2.97 (1H, m), 2.58 (1H, m), 2.37
(1H, m), 2.13 (2H, m), 1.89 (1H, m), 1.74 (5H, m), 1.65 (1H, m), 1.53
(1H, m), 0.38 (1H, m). 13C NMR (CDCl3, 125 MHz) δ 145.9, 145.8,
133.5, 133.1, 129.0, 128.6, 110.0, 109.9, 74.5, 74.1, 36.6, 36.0, 35.8,
35.6, 35.0, 34.7, 34.0, 33.9, 29.3, 28.9, 22.6 (2C’s), 20.7, 20.3.
Experimental Section.
1
General. All H NMR spectra were obtained on a Bruker ARX-
400 spectrometer operating at 400.132 MHz, a Bruker ARX-500
spectrometer operating at 500.132 MHz, or a Bruker Avance-500
operating at 500.330 MHz as indicated. All 13C NMR spectra were
recorded on a Bruker ARX-400 spectrometer operating at 100.625 MHz,
a Bruker ARX-500 spectrometer operating at 125.773 MHz, or a Bruker
1
Avance-500 spectrometer operating at 125.808 MHz. All H and 13C
NMR data are reported in parts per million (δ) downfield from
tetramethylsilane. Coupling constants are reported in hertz (Hz), with
the following abbreviations used: s ) singlet, d ) doublet, t ) triplet,
q ) quartet, m ) multiplet. When appropriate, the multiplicities are
preceded with b, indicating that the signal is broad.
FTIR spectrometry was performed on a Nicolet-501 FTIR spec-
trometer using liquid films (neat) on NaCl plates, and only the most
significant absorption bands are reported in cm-1. High-resolution mass
spectra (HRMS) were recorded on a VG Analytical Autospec double-
focusing instrument using the electron impact (EI) technique. Gas
chromatographic analyses were performed using a Hewlett-Packard
5790A series chromatograph with an SE-30 cross-linked methyl silicone
gum column (12 m × 0.2 m × 0.33 mm film thickness). Photolysis
was done using a Hanovia model 73A36 550 W medium-pressure
mercury lamp at room temperature.
Thin-layer chromatography (TLC) was carried out using Baker
Si250F254 silica gel plates and visualization was facilitated by the use
of ultraviolet light, anisaldehyde stain, phosphomolybdic acid stain,
permanganate stain, vanillin stain, or iodine chamber methods. Flash
chromatography was performed using E. Merck silica gel 60 (230-
400 mesh) with compressed air as the source. All solvent mixtures
used are indicated as percentages.
The following solvents were dried and distilled from the indicated
drying agent under an argon atmosphere: tetrahydrofuran (THF) and
diethyl ether from sodium benzophenone ketyl radical; dichloromethane,
benzene, toluene, hexane, pyridine, and triethylamine from calcium
hydride; diisopropylamine from sodium hydroxide; methanol from
magnesium methoxide. All other solvents and reagents were purified
and dried before use as necessary by standard techniques.
4-Bromo-2-methyl-1-butene, 22. To an oven-dried round-bottomed
flask charged with a stir bar and dichloromethane (200 mL) was added
3-methyl-3-buten-1-ol (10.0 mL, 99.0 mmol), and the solution was
cooled to 0 °C, and triethylamine (21.0 mL, 148.6 mmol) was added.
To the stirring solution was added dropwise a solution of methane-
sulfonyl chloride (MsCl, 11.6 mL, 148.6 mmol) in dichloromethane
(50 mL) via addition funnel. The reaction was allowed to stir for 1 h
while warming to room temperature, and was then quenched by the
addition of saturated ammonium chloride (200 mL). The organic phase
was washed with saturated ammonium chloride (3 × 100 mL) and brine
(100 mL) before being dried over MgSO4. After filtration, the resulting
solution was reduced in vacuo in the dark to produce a clear oil. This
oil was dissolved in THF (125 mL), and dry lithium bromide (17.0 g,
198.1 mmol) was added. The suspension was heated at reflux for 12 h
and cooled to 25 °C, and water (100 mL) was added. The organic phase
was washed with brine (100 mL) and then dried over MgSO4. After
filtration, the resulting solution was reduced in vacuo in the dark to
1-[(1R,5R,6S)-Bicyclo[3.1.0]hex-2-en-6-yl]-4-methyl-pent-4-en-1-
one, 25. To an oven-dried round-bottomed flask charged with a stir
bar and dichloromethane (20 mL) was added trifluoroacetic anhydride
(0.48 mL, 3.4 mmol), and the reaction was cooled to -78 °C. To the
stirring solution was added dimethyl sulfoxide (DMSO, 0.48 mL, 6.7
mmol) with venting, and the reaction was allowed to stir for 0.5 h. To
the stirring solution was then added the alcohol 24 (0.20 g, 1.1 mmol)
in dichloromethane (3 mL), and the reaction was allowed to stir for 1
h. Triethylamine (1.41 mL, 10.1 mmol) was then added, and the reaction
was allowed to warm to 0 °C before the addition of saturated ammonium
chloride (30 mL). The organic layer was washed with saturated
ammonium chloride (3 × 30 mL) and brine (30 mL) before being dried
over MgSO4. After filtration, the resulting solution was then reduced
in vacuo, and the oil was purified by flash chromatography (silica gel,
20% diethyl ether in pentane) to give 0.136 g (70%) of the ketone 25
1
as a clear oil. H NMR (CDCl3, 500 MHz) δ 5.98 (1H, m), 5.62 (1H,
m), 4.77 (1H, s), 4.71 (1H, s), 2.82 (1H, m), 2.72 (2H, t, J ) 7.6 Hz),
2.49 (2H, m), 2.33 (2H, t, J ) 7.6 Hz), 2.29 (1H, m), 1.77 (3H, s),
1.34 (1H, m). 13C NMR (CDCl3, 125 MHz) δ 209.0, 144.5, 132.3,
130.6, 110.0, 41.7, 38.6, 37.2, 36.4, 31.6, 28.7, 22.5. IR (neat) 2910,
1690, 1390, 1370, 1180, 1100 cm-1
.
(3aR,4S,8R,8aS)-8-Methyl-3a,4,6,7,8,8a-hexahydro-3H-4,8-metha-
noazulen-5-one, 26, and (3aR,4R,8S,8aS)-8-Methyl-3a,4,6,7,8,8a-
hexahydro-3H-4,8-methanoazulen-5-one, 27. To an oven-dried round-
bottomed flask charged with a stir bar and benzene (5 mL) was added
the ketone 25 (91 mg, 0.52 mmol) and n-butyl disulfide (69 µL, 3.6
mmol). The solution was degassed using five freeze-pump-thaw
cycles and was then photolyzed until analysis by GC indicated all the
starting ketone had been consumed (ca. 6 d). The reaction mixture was
then reduced in volume to approximately 1 mL and directly loaded
onto a silica gel column. Flash chromatography (10% diethyl ether in
pentane) gave 75.2 mg (82%) of the ketones 26 and 27 as an inseparable
mixture. The ratio of the major product 26 to the minor product 27
was 1.7:1 (26, 52%; 27, 30%). 1H NMR (CDCl3, 500 MHz) δ 26: 5.77
(1H, m), 5.62 (1H, m), 2.97 (1H, bs), 2.75 (2H, m), 2.49 (1H, m), 2.38
(1H, d, J ) 4.4 Hz), 2.19 (1H, m), 2.03 (1H, m), 1.74 (3H, m), 1.64
(1H, m), 1.04 (3H, s). 27: 5.83 (1H, m), 5.75 (1H, m), 3.05 (2H, m),
2.76 (1H, m), 2.49 (1H, m), 2.26 (1H, bd, J ) 6.9 Hz), 2.17 (1H, m),
2.05 (1H, m), 1.87 (1H, m), 1.64 (3H, m), 1.20 (3H, s). Mixture of 26
and 27: 13C NMR (CDCl3, 125 MHz) δ 214.3 (2C’s), 132.4, 131.9,
9
J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003 4277

A R T I C L E S
Leach et al.
131.0, 130.3, 60.1, 58.9, 58.3, 55.7, 45.7, 43.8, 43.7, 42.5, 40.8, 39.9,
39.1, 36.0, 35.2, 34.1, 33.9, 27.0, 22.4, 15.3.
9.5 Hz), 5.77 (1H, m), 5.68 (1H, m), 3.14-1.24 (11H, m), 1.20 (3H,
s). Minor, cis-anti-cis, 29: 11.1 (1H, s), 9.12 (1H, d, J ) 2.5 Hz), 8.28
(1H, dd, J ) 9.5, 2.5 Hz), 7.94 (1H, d, J ) 9.5 Hz), 5.77 (1H, m), 5.62
(1H, m), 3.14-1.24 (11H, m), 1.04 (3H, s). Mixture of 28 and 29: 13C
NMR (CDCl3, 125 MHz) δ 138.2, 132.3, 131.7, 129.8, 128.2, 123.5,
116.2, 116.1, 59.6, 57.6, 52.4, 48.6, 45.9, 45.4, 45.0, 42.6, 42.2, 40.9,
39.8, 38.2, 33.5, 33.0, 27.3, 22.1, 21.6, (imine carbon not observed).
IR (neat) 3326, 3104, 3054, 2930, 2868, 1618, 1592, 1519, 1506, 1426,
1335, 1265, 739 cm-1. HRMS (EI) 356.148310 calcd for C18H20N4O4
356.148455.
IR (neat) 3050, 2930, 2861, 1713, 1460 cm-1. HRMS (EI)
175.112037 calcd for C12H16O 175.112290.
N-(2,4-Dinitrophenyl)-N′-[(3aR,4S,8R,8aS)-8-Methyl-3a,4,6,7,8,-
8a-hexahydro-3H-4,8-methanoazulen-5-ylidene]hydrazine, 28, and
N-(2,4-Dinitrophenyl)-N′-[(3aR,4R,8S,8aS)-8-Methyl-3a,4,6,7,8,8a-
hexahydro-3H-4,8-methanoazulen-5-ylidine]hydrazine, 29. To a
solution of ethanol (25 mL), water (7 mL), and sulfuric acid
(concentrated, 7 mL) was added 2,4-dinitrophenyl hydrazine (1.0 g,
5.0 mmol), and the mixture was stirred. This solution (6.6 mL) was
then added to a solution of the ketones 26 and 27 (0.10 g, 0.57 mmol)
in ethanol (2 mL) which immediately formed an orange precipitate.
The reaction was allowed to stir for 0.5 h before filtering the mixture
to give an orange solid. The solid was washed with saturated sodium
bicarbonate (3 × 50 mL) and water (3 × 50 mL) to give a crude orange
solid. The solid was dissolved in a minimum amount of diethyl ether
and purified by flash column chromatography (silica gel, 33% diethyl
ether in pentane) to give 124 mg (61%) of the hydrazones 28 and 29
as an orange powder. X-ray quality crystals were grown by the slow
Acknowledgment. We thank the National Institute of General
Medical Sciences, National Institutes of Health for financial
support, and AstraZeneca and the UK Fulbright Commission
for a fellowship (to A.G.L.). This work was partially supported
by National Computational Science Alliance.
Supporting Information Available: 1H and 13C NMR spectra
for compounds 22 and 24-27 (PDF). An X-ray crystallographic
file in CIF format. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
evaporation of a 1:1 mixture of benzene and 1,2-dichloroethane. H
NMR (CDCl3, 500 MHz) δ Major, cis-syn-cis, 28: 11.0 (1H, s), 9.12
(1H, d, J ) 2.5 Hz), 8.28 (1H, dd, J ) 9.5, 2.5 Hz), 7.97 (1H, d, J )
JA029342Q
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4278 J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003