Six- vs seven-membered ring formation from the 1- bicyclo[4.1.0]heptanylmethyl radical: Synthetic and ab initio studies

Article abstract of DOI:10.1021/jo981708n

The viability of utilizing 1-bicyclo[4.1.0]heptanylmethyl radical (3) to serve as a progenitor of seven-membered carbocycles was examined. Rate constants for the rearrangement of this radical to 3-methylenecycloheptyl radical (4) and 2-methylenecyclohexyl-1-methyl radical (6) were measured using the competition method of 3 with thiophenol over the temperature range of -75 to 59 °C. Arrhenius functions were calculated for the conversions of 3 to 4 and 3 to 6 and found to be log(k/s^-1) = (12.38 ± 0.20) - (5.63 ± 0.23)/θ and log(k/s^-1) = (11.54 ± 0.32) - (5.26 ± 0.37)/θ, respectively. The rate constants for these conversions at 25 °C are 1.86 x 10⁸ s^-1 and 5.11 x 10⁷ s^-1, respectively. Hence, the seven-membered ring-expanded carbocycle is formed 3.6 times faster at 25 °C than the nonexpanded species. This suggests that the 1-bicyclo[4.1.0]heptanylmethyl radical system may be synthetically useful in seven-membered ring-forming methodology. Preliminary theoretical examination of this radical system qualitatively predicted the experimentally determined energies of activation: PMP4/6-31G*//HF/6-31G*ΔE(a) (3 → 6 - 3 → 4) = 3.0 kcal/mol with zero point energy correction. The HF/6-31G* optimized reaction coordinate stationary points suggest cyclopropyl substituent eclipsing interactions play an important role in determining the kinetic outcome of these rearrangements.

Full text of DOI:10.1021/jo981708n

570
J . Org. Chem. 1999, 64, 570-580
Six- vs Seven -Mem ber ed Rin g F or m a tion fr om th e
1-Bicyclo[4.1.0]h ep ta n ylm eth yl Ra d ica l: Syn th etic a n d a b In itio
Stu d ies†
Eric J . Kantorowski, Shawn W. E. Eisenberg,‡ William H. Fink,* and Mark J . Kurth*
Department of Chemistry, University of California, Davis, California 95616
Received August 21, 1998
The viability of utilizing 1-bicyclo[4.1.0]heptanylmethyl radical (3) to serve as a progenitor of seven-
membered carbocycles was examined. Rate constants for the rearrangement of this radical to
3-methylenecycloheptyl radical (4) and 2-methylenecyclohexyl-1-methyl radical (6) were measured
using the competition method of 3 with thiophenol over the temperature range of -75 to 59 °C.
Arrhenius functions were calculated for the conversions of 3 to 4 and 3 to 6 and found to be log-
(k/s-1) ) (12.38 ( 0.20) - (5.63 ( 0.23)/θ and log(k/s-1) ) (11.54 ( 0.32) - (5.26 ( 0.37)/θ,
respectively. The rate constants for these conversions at 25 °C are 1.86 × 108 s-1 and 5.11 × 107
s-1, respectively. Hence, the seven-membered ring-expanded carbocycle is formed 3.6 times faster
at 25 °C than the nonexpanded species. This suggests that the 1-bicyclo[4.1.0]heptanylmethyl radical
system may be synthetically useful in seven-membered ring-forming methodology. Preliminary
theoretical examination of this radical system qualitatively predicted the experimentally determined
energies of activation: PMP4/6-31G*//HF/6-31G* ∆Ea (3 f 6 - 3 f 4) ) 3.0 kcal/mol with zero
point energy correction. The HF/6-31G* optimized reaction coordinate stationary points suggest
cyclopropyl substituent eclipsing interactions play an important role in determining the kinetic
outcome of these rearrangements.
In tr od u ction
to assist in predicting energies associated with the
modified archetypal system.6 As information on these
systems increases, their viability as synthetic tools also
advances.7
Rearrangement of cyclopropylcarbinyl radical systems
to the corresponding 3-butenyl radicals has received
much attention both in synthetic and theoretical set-
tings.1 The kinetics of the prototypical system have been
thoroughly studied by many research groups employing
techniques such as ESR, NMR, and product analysis.2
Once kinetic data is established3 for a distinct radical
rearrangement, it may be applied as a radical “clock”
against other radical reactions thereby providing a tool
for mechanistic investigation.4 Making substitutions to
the parent system significantly affects the rate of bond
rupture, and consequently a diverse range of radical
clocks may be developed.5 Additionally, there is great
interest in the application of molecular modeling analysis
We were interested in employing radical 3 as part of a
larger methodology for the preparation of seven-mem-
bered rings (Scheme 1). In this strategy, radical precursor
2 would be accessed via cyclopropanation of Diels-Alder-
derived cyclohexene 1. This cycloaddition reaction, which
can set up to four contiguous stereocenters, could then
be elaborated to 5 by the route shown. When the
cyclopropane ring is substituted, this methodology would
allow for introduction of a fifth stereocenter where
neighboring stereocenters could influence the facial ap-
proach of the reducing agent to the singly occupied
molecular orbital (SOMO). In addition to the ease of
preparing cyclohexenyl systems, carbon-centered radicals
are tolerant of hydroxyl and amine functionalities, thereby
allowing a synthetic plan to forego the use of protecting
groups which might otherwise be required for an ionic
ring-forming process.
† Dedicated to Professor R. Bryan Miller, deceased October 29, 1998.
‡ Current address: AMGEN, One Amgen Center Drive, Thousand
Oaks, CA 91320-1789.
(1) (a) Montgomery, L. K.; Matt, J . W.; Webster, J . R. J . Am. Chem.
Soc. 1967, 89, 923-934. (b) Montgomery, L. K.; Matt, J . W. J . Am.
Chem. Soc. 1967, 89, 934-941. (c) Mariano, P. S.; Bay, E. J . Org. Chem.
1980, 45, 1763-1769. (d) Kochi, J . K.; Krusic, P. J .; Eaton, D. R. J .
Am. Chem. Soc. 1969, 91, 1877-1879.
(2) (a) Newcomb, M.; Glenn, A. G.; Williams, W. G. J . Org. Chem.
1989, 54, 2675-2681. (b) Beckwith, A. L. J .; Bowry, V. W. J . Org.
Chem. 1989, 54, 2681-2688. (c) Newcomb, M.; Tanaka, N.; Bouvier,
A.; Tronche, C.; Horner, J . H.; Musa, O. M.; Martinez, F. N. J . Am.
Chem. Soc. 1996, 118, 8505-8506.
(3) For an excellent introduction to kinetic analysis of such systems
see: Newcomb, M. Tetrahedron 1993, 49, 1151-1176.
(4) (a) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317-323.
(b) Engel, P. S.; Wu, A. J . Org. Chem. 1994, 59, 3969-3974. (c)
Beckwith, A. L. J .; Bowry, V. W. J . Am. Chem. Soc. 1994, 116, 2710-
2716. (d) Caldwell, R. A.; Zhou, L. J . Am. Chem. Soc. 1994, 116, 2271-
2275.
(5) (a) Tadic-Biadatti, M.-H. L.; Newcomb, M. J . Chem. Soc., Perkin
Trans. 2 1996, 1467-1473. (b) Choi, S.-Y.; Newcomb, M. Tetrahedron
1995, 51, 657-664. (c) Martin-Esker, A. A.; J ohnson, C. C.; Horner, J .
H.; Newcomb, M. J . Am. Chem. Soc. 1994, 116, 9174-9181. (d)
Newcomb, M.; Choi, S.-Y. Tetrahedron Lett. 1993, 34, 6363-6364.
Central to the application of radicals in a synthetic
setting is the need to have well-established rate data for
all of the significant reaction pathways involved. The
ability to predict the outcome is critical for any synthetic
endeavor whose success depends on a tandem radical
process.8,9 Beyond this first criterion, there is a funda-
(6) (a) Martinez, F. N.; Schlegel, H. B.; Newcomb, M. J . Org. Chem.
1998, 63, 3618-3623. (b) Martinez, F. N.; Schlegel, H. B.; Newcomb,
M. J . Org. Chem. 1996, 61, 8547-8550.
(7) Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091-2115.
(8) (a) Beckwith, A. L. J . Chem. Soc. Rev. 1993, 143-151. (b) Curran,
D. P. Radical Cyclizations and Sequential Radical Reactions. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Permagon; Oxford,
1991; Vol. 4, Chapter 4.2, pp 779-831. (c) Giese, B. Radicals In Organic
Synthesis: Formation of Carbon-Carbon Bonds; Permagon Press:
Oxford, 1986.
10.1021/jo981708n CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/29/1998

Ring Formation from 1-Bicyclo[4.1.0]heptanylmethyl Radical
J . Org. Chem., Vol. 64, No. 2, 1999 571
Sch em e 1
cyclopropylcarbinyl radical 3. The incipient primary vs
secondary radical character, the build-up of ring strain
in the respective transition states, the relief of cyclopropyl
substituent bond eclipsing interactions, and any inherent
preference in the orientation of the SOMO of the initial
radical 3 all constitute factors which may influence the
outcome. Indeed, some of these variables have contradic-
tory effects making a priori product distribution difficult
to predict. A more thorough discussion of these factors
is presented in the computational section of this paper.
Our previous studies15 of radical 3 and other structural
analogues indicated that seven-membered ring formation
could be controlled to some extent by increasing the
concentration of the reducing agent (an indication of
kinetic control). As discussed in greater detail later in
this paper, MP4/6-31G*//HF/6-31G* calculations indi-
cated that ring expansion (ultimately providing methyl-
enecycloheptane 5) was kinetically favored over the
nonexpansion route (leading to 7) by 3.4 kcal/mol. On the
basis of these insights we decided to pursue synthetic
studies aimed at developing this novel methodology.
Sch em e 2
Syn th esis a n d Kin etic An a lysis. In initial studies,
we employed the S-methylthiocarbonate (xanthate ester)
derivative of the cyclopropyl alcohol as the radical
precursor (2, X ) OC(dS)SCH3).15 Regrettably, genera-
tion of the radical with this substrate called for forcing
conditions (PhH, 135 °C, sealed tube reactor). This
requirement precluded kinetic analysis over a conven-
tional temperature range, and therefore a more versatile
radical precursor was sought. In this regard, Barton’s
N-hydroxypyridine-2-(1H)-thione (PTOC, from pyridine-
2-thione-N-oxycarbonyl) ester was an attractive alterna-
tive in that it proves capable of generating radicals across
a wide range of temperatures.16
PTOC ester 12 was prepared in five steps as outlined
in Scheme 3. Application of the Wadsworth-Emmons
procedure17 to cyclohexanone with triethylphosphonoac-
etate (NaH, THF) provided the unsaturated esters 9a /
9b in 73% yield as a 52:48 mixture of the â,γ:R,â isomers
(capillary GC). The desired â,γ-unsaturated ester 9b
could be prepared quantitatively from the crude mixture
by kinetic trapping of the extended enolate (LDA, THF)
with saturated aqueous NH4Cl at -78 °C. Cyclopropa-
nation with diethyl zinc/diiodomethane in either THF or
Et2O consistently failed to consume all of the alkene
which complicated purification as the starting material
and the cyclopropanated product have identical Rf values
on TLC. When dichloromethane was employed, however,
mental need to understand how stereoelectronic effects
guide the outcome of radical reactions.
The cyclopropylcarbinyl f homoallyl radical transfor-
mation, when incorporated into a ring system (e.g., 3,
Scheme 2) has received far less attention than the acyclic
analogues. In cases where the radical center of the
cyclopropylcarbinyl moiety is embedded in the bicyclo-
[n.1.0] system, there tends to be a strong stereoelectronic
preference for exocyclic ring opening.10-12 The situation
is quite different when the radical center is exo to the
bicyclic ring system (e.g., 3). Here increased conforma-
tional mobility of the radical-bearing center allows SOMO
overlap with either of the â-cyclopropyl bonds; conse-
quently, both homoallylic radicals 4 and 6 are acces-
sible.13,14
Several factors come into play when attempting to
predict which homoallylic radical will be formed from
(9) For a recent example see: J ung, M. E.; Rayle, H. L. J . Org. Chem.
1997, 62, 4601-4609.
(10) For examples, see (a) Batey, R. A.; Grice, P.; Harling, J . D.;
Motherwell, W. B.; Rzepa, H. S. J . Chem. Soc., Chem. Commun. 1992,
942-944. (b) Clive, D. L. J .; Daigneault, S. J . Org. Chem. 1991, 56,
3801-3814. (c) Friedrich, E. C.; Holmstead, R. L. J . Org. Chem. 1972,
37, 2546-2550. (d) Friedrich, E. C.; Holmstead, R. L. J . Org. Chem.
1972, 37, 2550-2554. (e) Batey, R. A.; Harling, J . D.; Motherwell, W.
B. Tetrahedron 1992, 48, 8031-8052. (f) Harling, J . D.; Motherwell,
W. B. J . Chem. Soc., Chem. Commun. 1988, 1380-1382. (g) Davies,
A. G.; Muggleton, B.; Godet, J .-Y.; Pereyre, M.; Pommier, J .-C. J . Chem.
Soc., Perk. Trans. 2 1976, 1719-1724. (h) Boikess, R. S.; Mackay, M.;
Blithe, D. Tetrahedron Lett. 1971, 401-404. (i) Clive, D. L. J .;
Daigneault, S. J . Org. Chem. 1991, 56, 5285-5289. (j) For an example
of a nine-membered ring, see Thies, R. W.; McRitchie, D. D. J . Org.
Chem. 1973, 38, 112-116. (k) For an example where SmI2 is used to
generate a ketyl radical adjacent to a cyclopropyl ring, see Batey, R.
A.; Motherwell, W. B. Tetrahedron Lett. 1991, 32, 6649-6652.
(11) Ingold, K. U.; Walton, J . C. Acc. Chem. Res. 1986, 19, 72-77.
(12) The yield of the ring-expanded product typically is 0-10% in
these cases; however, exceptions have been reported: see refs 10a and
13c.
(14) A system similar to 3 has been reported: Dauben, W. G.;
Shaffer, G. W.; Deviny, E. J . J . Am. Chem. Soc. 1970, 92, 6273-6281.
Here, photoexcitation of I led to the ring-expanded 1-acetylcycloheptene
(II), but under the conditions of the experiment, the product isolated
was primarily the dimerized material.
(15) Kantorowski, E. J .; Borhan, B.; Nazarian, S.; Kurth, M. J .
Tetrahedron Lett. 1998, 39, 2483-2486.
(13) For cyclopentyl analogues, see (a) Beckwith, A. L. J .; O’Shea,
D. M. Tetrahedron Lett. 1986, 27, 4525-4528. (b) Stork, G.; Mook, R.,
J r. Tetrahedron Lett. 1986, 27, 4529-4532. (c) Green, S. P.; Whiting,
D. A. J . Chem. Soc., Chem. Commun. 1992, 1754-1755. (d) Beckwith,
A. L. J .; Phillipou, G. Chem. Commun. 1971, 658-659. (e) Cristol, S.
J .; Barbour, R. V. J . Am. Chem. Soc. 1968, 90, 2832-2838. (f) Destabel,
C.; Kilburn, J . D. J . Chem. Soc., Chem. Commun. 1992, 596-598.
(16) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron
1985, 41, 3901-3924.
(17) Wadsworth, W. S., J r.; Emmons, W. D. Org. Syntheses; Wiley:
New York, 1963; Vol. IV, pp 547-549.
(18) (a) Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S.
Tetrahedron Lett. 1992, 33, 2575-2578. (b) McDonald, W. S.; Verbicky,
C. A.; Zercher, C. K. J . Org. Chem. 1997, 62, 1215-1222.

572 J . Org. Chem., Vol. 64, No. 2, 1999
Kantorowski et al.
Sch em e 3
Ta ble 1. P r od u ct Distr ibu tion fr om Red u ction of 12 in
th e P r esen ce of P h SH
ester 10 was produced in 86-92% yield with no evidence
of 9b.18 Saponification of ester 10 in KOH/EtOH followed
by subsequent acidification afforded the cyclopropyl acid
11 in 92% yield. Radical precursor 12 was then prepared
by DCC coupling of acid 11 with 2-mercaptopyridine
N-oxide. This PTOC ester, isolated as a yellow solid, is
stable for weeks in air if protected from light, but slowly
decomposes when left as a solution in THF or CDCl3.
Radical 3 is generated from PTOC ester 12 in THF by
irradiation with visible light in the presence of either
tributylstannane or thiophenol. The reaction is facile
(typically under 60 s) and, for the stannane reactions,
can be readily visualized by the loss of solution color
(yellow f colorless).19 The reaction products were ana-
lyzed by capillary GC, and yields were determined using
a hydrocarbon internal standard. Authentic reaction
products 5 and 7 were prepared by Wittig olefination of
the corresponding ketones. 1-Methylbicyclo[4.1.0]heptane
(8) was prepared by dehydration of 1-methylcyclohexanol
followed by cyclopropanation (Et2Zn, CH2I2, CH2Cl2).
The cyclopropylcarbinyl radical 3 was analyzed across
a temperature range of -75 °C to 59 °C. Both thiophenol
and tri-n-butylstannane were used in >10 equiv for all
reactions in order to apply pseudo-first-order approxima-
tions for kinetic analyses. Thiophenol concentration
varied between 0.4 and 1.25 M; tri-n-butylstannane
concentration varied between 0.2 and 0.8 M. In all cases,
lower temperatures and higher concentrations of reduc-
ing agent favored the ring-expanded product 5 over the
nonexpanded product 7. The combined yields (GC; inter-
nal hydrocarbon standard) of 5, 7, and 8 ranged between
96 and 98% when thiophenol was employed and 94-98%
with tri-n-butylstannane. The chromatogram traces of
the reactions were exceptionally clean for both of these
reducing agents.
relative % yield
a
b,c
d,e
T (°C) [PhSH]m
5
8
7
log k34
log k36
59
23
14
2
2
2
1.00
1.00
1.00
0.40
0.85
1.00
1.25
1.00
1.00
1.00
63.2 17.1 19.7
48.8 37.2 14.0
42.1 46.5 11.5
54.5 31.3 14.1
41.8 47.1 11.1
39.1 50.1 10.8
35.7 53.7 10.9
8.82
8.23
8.03
7.86
7.89
7.91
7.93
7.33
7.01
6.28
8.32
7.69
7.47
7.27
7.32
7.36
7.42
6.77
6.48
5.94
2
-22
-42
-75
20.6 73.7
14.6 81.0
5.2 92.5
5.7
4.3
2.4
a
b
A stock solution of 0.02 M 12 was used for all runs. From eq
1. c The value for kH(sec) was taken from reference 20 and equals
the rate of the reaction between PhSH and isopropyl radical: log(k/
(M-1s-1)) ) 9.26 - 1.70/θ, θ ) 2.303RT in kcal/mol. From eq 2.
d
e The value for kH(prim) was taken from reference 20 and equals
the rate of the reaction between PhSH and n-butyl radical: log(k/
(M-1 s-1)) ) 9.40 - 1.74/θ.
These are reasonable assumptions to make as the rate
constants for the reactions between thiophenol and
simple alkyl radicals are only slightly affected by the
structure of the radical.21 It has been shown that tin,
sulfur, selenium, phosphorus, silicon, germanium, and
carbon-centered radicals all participate in the chain
process with PTOC esters. The rate at which any of the
carbon-centered radicals formed in this process are
intercepted by the starting ester is too slow to be of
consequence when employing PhSH.22 The rate for rear-
rangement of 3 f 4 is shown in eq 1, the rate for 3 f 6
in eq 2; where 5/8 and 7/8 represent the ratio of products
(determined by GC), and [PhSH]m is the average concen-
tration during the course of the reaction.
In general, thiols are excellent agents for trapping alkyl
radicals with kH approximately 1 order of magnitude
faster than n-Bu3SnH. Thiophenol, being especially fast,
was used to establish the rates of ring opening of radical
3 for the two reaction pathways. The rate constant for
the reaction between primary radicals 3 or 6 and thiophe-
nol (kH(prim) in Scheme 2) was taken to be equal to the
rate for the reduction of n-butyl radical by thiophenol (log
kH(prim)/(M-1s-1) ) 9.40-1.74/θ, θ ) 2.303RT).20 The rate
constant for the reaction between secondary radical 4 and
thiophenol (kH(sec)) was taken to be equal to the rate for
k34 ) kH(sec)[PhSH]m5/8
k36 ) kH(prim)[PhSH]m7/8
(1)
(2)
The results for PhSH reduction are shown in Table 1
and displayed graphically in Figure 1. The rate expres-
sions derived from the Arrhenius plot are log(k34/(s-1)) )
(12.38 ( 0.20) - (5.63 ( 0.23)/θ and log(k36/(s-1)) ) (11.54
( 0.32) - (5.26 ( 0.37)/θ. At 298 K the rates for the
unimolecular rearrangements of 3 f 4 and 3 f 6 are
1.78 × 108 s-1 and 4.90 × 107 s-1, respectively. Thus, at
the reduction of isopropyl radical by thiophenol (log kH(sec)
/
(M-1s-1) ) 9.26-1.70/θ). At 25 °C this corresponds to
reaction rates of 1.33 × 108 and 1.03 × 108, respectively.
(21) The cyclopropylcarbinyl radical substructure of 3, due to a
resonance component which provides additional stabilization, may not
react at a rate equal to that of n-butyl radical. For a commentary, see
footnote 12 in Newcomb, M.; Glenn, A. G. J . Am. Chem. Soc. 1989,
111, 275-277.
(19) Also confirmed by TLC analysis.
(20) Franz, J . A.; Bushaw, B. A.; Alnajjar, M. S. J . Am. Chem. Soc.
1989, 111, 268-275.
(22) Newcomb, M.; Kaplan, J . Tetrahedron Lett. 1987, 28, 1615-
1618.

Ring Formation from 1-Bicyclo[4.1.0]heptanylmethyl Radical
J . Org. Chem., Vol. 64, No. 2, 1999 573
products 5 and 7 as expressed in eq 3. The terms kH(prim)
and kH(sec) refer to the rate of reduction by Bu3SnH of a
primary and secondary alkyl radical, respectively. The
reported values are log(kH(prim)/(M-1 s-1)) ) 9.1 - 3.7/θ
for the reaction between Bu3SnH and n-butyl radical; log-
(kH(sec)/(M-1 s-1)) ) 8.7 - 3.5/θ for the reaction between
Bu3SnH and isopropyl radical.23 At 25 °C kH(prim) ) 2.4 ×
106 M-1 s-1 and kH(sec) ) 1.4 × 106 M-1 s-1. Furthermore,
k36 and k34 are available from the thiophenol experiments.
kH(sec)k34
k63 + kH(prim)[Bu3SnH]m
k43 + kH(sec)[Bu3SnH]m
5
7
)
×
(3)
kH(prim)k36
In the event that both of the reverse reactions (i.e., 6
f 3 and 4 f 3) are fast with respect to the rate of
quenching (i.e., k63 . kH (prim)[Bu3SnH]m and k43 . kH
(sec)[Bu3SnH]m) then eq 3 simplifies to eq 4. Hence, the
product distribution is proportional to the ratio of the rate
constants for the reverse processes. This analysis, how-
ever, does not directly reveal whether the initial assump-
tion of the reverse processes being rapid was correct. To
ascertain this information, we start by allowing only one
of the reverse processes to be fast relative to trapping by
the reducing agent. Starting with the assumption that
k43 . kH (sec)[Bu3SnH]m, eq 3 becomes eq 5 which can be
rearranged to the linear form as eq 6.
F igu r e 1. Arrhenius plots for the rearrangement of 3 f 4
(O) and 3 f 6 (4).
Ta ble 2. P r od u ct Distr ibu tion fr om Red u ction of 12
w ith Bu 3Sn H
T (°C)
[Bu3SnH]m
5/7
T (°C)
[Bu3SnH]m
5/7
2
2
2
0.80
0.60
0.40
0.20
0.60
0.40
0.20
4.09
3.98
3.91
3.64
3.88
3.67
3.59
38
38
38
58
58
58
58
0.60
0.40
0.20
0.80
0.60
0.40
0.20
3.40
3.25
3.04
3.37
3.18
3.01
2.72
2
23
23
23
kH(sec)k34
k63
5
7
)
×
(4)
(5)
(6)
kH(prim)k36 k43
kH(sec)k34
k63 + kH(prim)[Bu3SnH]m
5
7
)
×
kH(prim)k36
k43
k
H(sec)k34k63
k34kH(sec)
k36k43
5
7
)
+
[Bu3SnH]m
kH(prim)k36k43
The slope contains the rate of production of radical 3
from 4, and the ratio of the intercept to the slope provides
information about the rate of the production of radical 3
from 6. Thus, each isotherm generated values for the rate
of k43 and k63. Using eq 6, the rate constants k43 and k63
o
were calculated at 25 C and found to be 6.03 × 106 s-1
and 9.55 × 106s-1, respectively. These values are of
similar magnitude to kH[Bu3SnH]m which implies that
simplification of eq 3 to eq 5 is not valid. Therefore
extraction of good values of k43 and k63 is not possible
with this simple analysis. We therefore conclude that the
rates of reverse reactions k43 and k63 are on the same
order or slower than the reaction between Bu3SnH and
simple alkyl radicals (∼106).
F igu r e 2. Product distribution of 5 and 7 using Bu3SnH.
298 K the seven-membered ring radical 4 is formed 3.64
times faster than the nonexpanded radical 6.
We postulated that by employing a slower trapping
agent it would be possible to allow radicals 3, 4, and 6 to
partially equilibrate and thereby permit calculations
relating to the reverse process of the cyclopropyl frag-
mentation. Hence, tri-n-butyltin hydride (which has rate
constants on the order of 106 for simple aliphatic radicals)
was used across various concentrations and temperatures
to study the product distribution under equilibrating
conditions. The fragmentation of the cyclopropylcarbinyl
radical 3 is sufficiently fast (vide supra) that trapping
by Bu3SnH is a rare event, and, hence, alkenes 5 and 7
are primary products. The product ratios of 5 vs 7 are
presented in Table 2. Figure 2 displays the results for
the four isothermal reductions of radical precursor 12 at
various concentrations of Bu3SnH.
As a secondary approach to analyzing the thermoki-
netics of this system, we decided to prepare PTOC ester
16 which would allow for direct generation of radical 6.
The commercially available methyl 1-cyclohexene-1-car-
boxylate was reduced with diisobutylaluminum hydride24
in THF to afford the known25 allylic alcohol 13 in 68%
yield (Scheme 4). Acylation with acetic anhydride gave
ester 14 in 84%, and subsequent Ireland-Claisen rear-
rangement26 of the TMS ketene acetal of 14 provided
(23) J ohnston, L. J .; Lusztyk, J .; Wayner, D. D. M.; Abeywickreyma,
A. N.; Beckwith, A. L. J .; Scaiano, J . C.; Ingold, K. U. J . Am. Chem.
Soc. 1985, 107, 4594-4596.
(24) Yoon, N. M.; Gyoung, Y. S. J . Org. Chem. 1985, 50, 2443-2450.
(25) Majetich, G.; Song, J .-S.; Ringold, C.; Nemeth, G. A.; Newton,
M. G. J . Org. Chem. 1991, 56, 3973-3988.
Subjecting Scheme 2 to kinetic steady-state analysis
gives the product distribution of the two rearrangement

574 J . Org. Chem., Vol. 64, No. 2, 1999
Kantorowski et al.
Sch em e 4
F igu r e 3. Newmann projection of cyclopropylcarbinyl radical.
As briefly mentioned earlier, a stereoelectronic predic-
tion of the outcome of the cyclopropyl bond fragmentation
in radical 3 is not easily derived from simple criteria. It
is unclear which cyclopropyl bond will have best overlap
with the radical p-orbital. Singly occupied p-orbitals in
cyclopropylcarbinyl radicals generally orient themselves
to best overlap with both vicinal cyclopropyl σ-bonds
(Figure 3).27,28 This is readily explained when one consid-
ers that a significant portion of the electron density for
a cyclopropyl bond is displaced outside the internuclear
axis. This extension of the bonding orbitals beyond the
skeletal confines of the ring places them in good position
to overlap with the radical p-orbital, thereby allowing a
degree of delocalization of the radical into the cyclopro-
pane ring.29 This electronically favored orientation of the
p-orbital offers no stereoelectronic differentiation between
the two cyclopropyl σ-bonds.30
In the absence of definitive stereoelectronic differentia-
tion, it was hoped that radical stability would influence
the product distribution in our system. The process of 3
f 4 yields a thermodynamically more stable secondary
radical from a primary radical (primary f secondary);
whereas 3 f 6 yields a primary radical and no net
stabilization of the radical center (primary f primary).
The stability of the radical in the products could be
expected to influence the thermodynamic product distri-
bution. Additionally, it was hoped that the nascent
secondary radical would help stabilize the transition state
leading to the ring-expanded intermediate 4.31
carboxylic acid 15 in 70%. In the absence of TMSCl, this
rearrangement fails. Heating the reaction is also critical
since, when conducted at room temperature, the product
isolated is mainly the TMS ketene acetal. DCC coupling
of carboxylic acid 15 and 2-mercaptopyridine N-oxide
provided the PTOC ester 16 in 82% yield.
Radical generation from PTOC ester 16 was carried
out with [Bu3SnH] e 0.10 M at 0, 23, and 53 °C. In all
cases, no evidence of seven-membered ring product was
detected (capillary GC). These results can be understood
in terms of the origin of the radical precursor. The radical
formed from 16 is not in the same conformation as the
radical formed from rearrangement of 3. Along the
reaction coordinate for the rearrangement of 3 f 6, the
cyclohexane ring maintains a twist boat conformation as
shown later in the computational section. This effect
would not manifest itself for the cyclopentyl analogue of
radical 3. Stork,13b having generated the bicyclo[3.1.0]-
hexanylcarbinyl radical from the corresponding bromide,
observed a 4:1 ratio of the ring-expanded product over
the nonexpanded product. Hence, as would be expected,
the five-membered ring does not suffer the same confor-
mational nuances that are associated with the cyclohex-
ane-based system. The radical generated from 16, which
would generally occupy a chair conformation, must first
adopt a twist boat conformation before cyclopropane 3
can be formed. Since this is energetically unfavorable,
radical 6 (derived from 16) fails to rearrange and is
quenched, providing 7.
Opposing the potential stabilizing effect of the second-
ary radical is the increased ring strain of seven-
membered ring 4 as opposed to six-membered ring 6. This
could favor product 6 thermodynamically. The degree to
which strain energies could have a significant kinetic
effect would depend on whether the transition state is
product- or reactant-like; the former would be influenced
more strongly by ring strain. It was evident to us from
the preceding analysis that the question of kinetic and
thermodynamic product distribution was not readily
predicted. Hence, at the outset of developing this meth-
Com p u ta tion a l An a lysis
By virtue of the relative insensitivity of radical pro-
cesses to solvent effects, we thought these systems ideal
for theoretical study. In support of this viewpoint are the
papers by Schlegel and Newcomb,6 wherein computa-
tional studies of several substituted cyclopropylcarbinyl
radicals were performed. They determined that good
structural data can be attained by using a UHF/6-31G*
optimization. Higher level single point calculations were
used to achieve acceptable agreement with experimental
kinetic parameters, though the PMP2/6-31G*//UHF/6-
31G* level of theory provided adequate descriptions of
relative rate constants in their study.
(27) (a) Cremer, D.; Kraka, E. J . Am. Chem. Soc. 1985, 107, 3800-
3801. (b) de Meijere, A. Angew. Chem., Int. Ed. Engl. 1979, 18, 8, 809-
826. (c) Danen, W. C. J . Am. Chem. Soc. 1972, 14, 4835-4845.
(28) Although the term σ-bond will generally be used in this
discussion in reference to the cyclopropyl skeletal bonds, it is generally
acknowledged that these bonds actually incorporate p- as well as
s-character.
(29) An alternative view presents itself in the realization that the
orbitals which combine to form the cyclopropane σ-bonds have a high
degree of p-character, thereby affording good p-p overlap with the
radical p-orbital.
(30) Other factors, assuredly, can modify this ideal situation.
(31) Though it has been previously suggested for relatively simple
systems that build-up of negative charge at the forming radical center
in the transition state kinetically favors the primary radical product
over the secondary (see ref 2b), our calculations indicate a partial
positive charge on the incipient secondary radical center on TS4 which,
regardless of steric effects discussed later, should be stabilized by its
secondary nature.
(26) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J . Am. Chem. Soc.
1976, 98, 2868-2877.

Ring Formation from 1-Bicyclo[4.1.0]heptanylmethyl Radical
J . Org. Chem., Vol. 64, No. 2, 1999 575
F igu r e 4. Numbering scheme for intermediates 3, 4, and 6.
The same numbering scheme is used for TS4 and TS6.
F igu r e 6. Stereo representation of the carbinyl geometry in
3; the view is along the C8-C5 bond (cf. Figure 3). The
majority of the cyclohexane ring atoms have been removed for
clarity. The unsubstituted carbon atoms correspond to C4
(bottom) and C1 (top right).
Ta ble 3. Electr on Over la p Den sity (e-)a
atoms
4
TS4
3
TS6
6
1,2
2,3
3,4
4,5
5,6
1,6
6,7
5,7
5,8
0.337
0.325
0.334
0.355
-
0.340
0.332
0.336
0.665
0.346
0.335
0.339
0.343
0.0678
0.313
0.228
0.290
0.471
0.342
0.338
0.347
0.364
0.280
0.320
0.194
0.243
0.356
0.338
0.338
0.344
0.351
0.330
0.329
0.258
0.00668
0.477
0.329
0.331
0.337
0.356
0.359
0.355
0.324
-
F igu r e 5. Stereo representation of the UHF/6-31G*-optimized
geometry for the cyclopropylcarbinyl radical 3; note the sym-
metry of the cyclopropane ring.
odology, we undertook a theoretical investigation in
parallel with our experimental studies.
0.669
Com p u ta tion a l Resu lts a n d Discu ssion
a
Italic type indicates bond order modification in the transition
state. Bold type indicates sites of significant bond order modifica-
tion in equilibrium structures.
Initial starting guess geometries were generated using
both Biosysm’s Insight II Builder32 module and Spartan33
software. Preliminary semiempirical and HF/3-21G op-
timizations were conducted with Spartan software. All
higher level optimizations and single point calculations
were undertaken using Gaussian 92 and Gaussian 94
software packages.34 All HF/6-31G* equilibrium and
transition structures35 were subjected to vibrational
analysis to verify their natures and to acquire zero point
vibrational data.36 Figure 4 indicates the numbering
scheme used in this discussion.
We first examined cyclopropyl radical 3 since it is the
common starting point leading to both the expanded
seven-membered carbocycle 4 as well as cyclopropyl-
opened intermediate 6. Scrutinizing Figure 5, one notes
the near equilateral triangle of the cyclopropane ring.
Figure 6 shows the very slight pyramidization of radical
center C8. Contrary to the geometry expected from the
prototypical system (Figure 3), we note the geometry of
the carbinyl group provides better overlap with the â C5-
C6 bond (Figure 6), though the reason for this geometric
preference is not obvious. The relatively small enhance-
ment of the overlap density between C5-C6 (0.280 e-)
vs C5-C7 (0.243 e-) (Table 3) does not seem to indicate
Ta ble 4. Selected F er m i Con ta ct An a lysis Da ta (a tom ic
u n its) MP 3/6-31G*//UHF /6-31G*a
atoms
4
TS4
3
TS6
6
1
2
3
4
5
6
7
8
-0.0501
0.0525
-0.0060
0.0079
-0.0286
0.0027
0.0020
0.0045
0.0195
0.0277
0.0001 -0.0017
-0.0028 0.0046
0.0249 -0.0093
-0.1074 0.0467
-0.0017 -0.0571
0.1579 0.2339
0.1747 -0.0350
-0.0110 -0.0021
0.0240 0.0079
-0.1135 -0.0669
0.1753
-0.0001
0.1755
0.0091
0.2412
-0.0373
0.0405
0.0602
0.0245
0.2166
a
Bold type indicates predominantly localized radical center.
Italic type indicates delocalization in the transition state.
sufficient additional electron density to account for this
geometry, nor does the potential torsional interaction
between the rather undemanding C8-Hꢀ and C4-C5
σ-bonds. Though an explanation for the geometry of the
carbinyl radical center is not readily at hand, its effects
are apparent in the form of hyperconjugation as ex-
pressed as a function of spin distribution.
Using Fermi contact analysis data as a gauge of the
molecular spin distribution (Table 4), it is apparent that
the predominant expression of the radical character for
3 is on C8, with an unpaired spin value of 0.2166 au.
The hyperconjugation of the radical into adjacent cyclo-
propane σ-bonds is evident in the magnitude of the
unpaired spin on the nuclei of C5, C6, and C7, the atoms
encompassing the vicinal cyclopropyl bonds. The values
of -0.0669, 0.0602, and 0.0245 au, respectively, show a
degree of radical character unmatched by other carbon
nuclei in the molecule. The reduced radical character on
C7 indicates the relatively poor overlap of the singly
occupied p-orbital with the C5-C7 σ bond. It is also of
interest to note that only a modest enhancement of the
unpaired spin on nucleus C4 is exhibited, affirming that
bond C4-C5 is not in proper orientation to attain good
overlap with the singly occupied p-orbital on C8.
(32) InsightII ver 3.2.0 Biosym Technologies Inc. 9685 Scranton Rd.,
San Diego, CA 92121-2777.
(33) Spartan SGI version 3.1.2 G Wave function Inc. 18401 Von
Karman Suite 370, Irvine, CA 92715
(34) (a) Frisch, M. J .; Trucks, G. W.; Head-Gordon, M.; Gill, P. M.
W.; Wong, M. W.; Foresman, J . B.; J ohnson, B. G.; Schlegel, H. B.;
Robb, M. A.; Replogle, E. S.; Gomperts, R.; Andres, J . L.; Raghavachari,
K.; Binkley, J . S.; Gonzalez, C.; Martin, R. L.; Fox, D. J .; Defrees, D.
J .; Baker, J .; Stewart, J . J . P.; Pople, J . A. Gaussian 92, Revision A.
Gaussian, Inc., Pittsburgh, PA, 1992. (b) Frisch, M. J .; Trucks, G. W.;
Schlegel, H. B.; Gill, P. M. W.; J ohnson, B.; Montgomery, J . A.;
Raghavachari, K.; Al-Laham, M. A.; Zakrzewski, V. G.; Challacombe,
M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.;
Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.;
Defrees, D. J .; Baker, J .; Stewart, J . P.; Head-Gordon, M.; Gonzalez,
C.; Pople, J . A. Gaussian 94. Gaussian, Inc. Pittsburgh, PA, 1995.
(35) HF/6-31G*//HF/6-31G* imaginary frequencies for TS4
)
-709.9289 cm-1, for TS6 ) -716.2755 cm-1
.
(36) All zero point energies used in calculating the reported zero
point corrected energy values have been subjected to the standard 0.89
frequency scaling factor.
From cyclopropyl radical 3, two paths present them-
selves with the kinetically favored path leading to

576 J . Org. Chem., Vol. 64, No. 2, 1999
Kantorowski et al.
Ta ble 7. Selected Dih ed r a l An gles (d eg)
atoms
4
TS4
3
TS6
4.2
-52.6
-22.0
6
Hδ,8,5,6
Hδ,8,5,7
1,6,5,4
-
3.7
-4.4
53.9
-3.8
0.30
44.6
-23.1
-0.08
-1.7
-
-26.0
F igu r e 7. Stereo representation of the UHF/6-31G*-optimized
geometry for TS4; note C5-C6 bond extension.
Ta ble 5. C-C Bon d Len gth s (Å) UHF /6-31G*a
atoms
4
TS4
3
TS6
6
1,2
2,3
3,4
4,5
5,6
1,6
6,7
5,7
5,8
1.541
1.536
1.539
1.520
2.477
1.502
1.509
1.519
1.325
1.534
1.528
1.535
1.520
1.871
1.511
1.484
1.490
1.407
1.532
1.528
1.531
1.525
1.525
1.529
1.496
1.504
1.480
1.533
1.527
1.532
1.524
1.500
1.537
1.444
1.889
1.403
1.542
1.543
1.531
1.517
1.527
1.537
1.509
2.515
1.322
F igu r e 8. Stereo representation of the UHF/6-31G*-optimized
geometry for TS6; note extension of the C5-C7 bond.
dominantly localized on C8 in 3, has delocalized in TS4
(Table 4, italics). The unpaired spin density in TS4 is
spread evenly among C5 (-0.1135 au), C8 (0.1755 au),
and C6 (0.1753 au) indicating the transfer of the radical
from C8 to C6. In carbocyclic intermediate 4, the radical
has relocalized on C6 (0.2412 au) as expected. The total
overlap population between any two atoms provides a
measure of bond strength (or bond order). The bold face
entries in Table 3 highlight regions of bond reorganiza-
tion in TS4. The small C5-C6 value of 0.0678 e-
indicates the breaking of the cyclopropyl bond in concert
with the strengthening of the C5-C8 bond (0.471 e-)
toward the double bond in 4 (0.665 e-); compare with
0.356 e- for the single bond in 3. The transformation of
the bent bonds of the cyclopropane to the standard
σ-bonds is also apparent in the overlap data: C5-C7
(0.243 e- in 3) f (0.290 e- in TS4) f (0.336 e- in 4) as
well as C6-C7 (0.194 e- in 3) f (0.228 e- in TS4) f
(0.332 e- in 4).
Traveling along the other branch of the reaction
coordinate, TS6 stands as counterpoint to TS4. The C5-
C7 bond is in the process of breaking in TS6 with an
increased interatomic distance of 1.889 Å (Table 5).
Figure 8 clearly shows this extension as a deviation from
the symmetry of the cyclopropane ring in 3 (Figure 5).
There are important electronic structure changes that
occur with the accompanying geometric changes along
the reaction pathway leading to TS6 and product that
parallel or contrast with the changes along the other
reaction pathway. In the interest of manuscript brevity,
however, we suppress discussion of these. They can be
discerned in the data of Tables 3, 5, and 6 and Figure 8.
Much has already been said about the stationary points
corresponding to 4 and 6, in the preceding paragraphs.
However, a brief discussion of their geometries is needed.
These geometries represent the conformation achieved
as the structures arrive along the reaction coordinate
from their respective transition states, not necessarily
the lowest energy conformations available for these
structures. It is in this light that one should regard the
conformations of these structures. The seven membered
carbocyclic radical 4 is in an energetically favored chair-
boat conformation (Figure 9), but the primary radical 6
is in a relatively high energy twist-boat conformation
(Figure 10). To assess the thermodynamics of the reaction
we have optimized the relaxed chair form of the radical,
but it is of interest that the initial geometry coming off
the reaction coordinate is a higher energy conformer.
The original ab initio calculations were undertaken
using the 3-21G basis set, though as resources became
a
Bold type indicates breaking bonds. Italic type indicates
nonbonded C-C distances.
Ta ble 6. Selected Bon d An gles (d eg) UHF /6-31G*
atoms
4
TS4
3
TS6
6
1,6,7
1,6,HR
5,6,7
120.9
117.9
-
109.8
110.4
107.0
109.8
-
118.1
-
122.6
118.4
51.2
120.6
114.5
59.7
118.7
111.8
78.6
111.6
107.8
111.9
-
119.6
117.7
120.2
115.6
-
-
-
5,7,6
77.9
61.1
51.1
Hâ,7,6
Hâ,7,Hø
Hø,7,6
4,5,6
4,5,7
6,5,7
116.2
111.1
116.4
112.1
119.7
50.9
120.6
121.2
117.3
121.0
117.8
113.6
118.6
118.2
119.1
59.2
117.2
120.4
117.6
120.4
120.8
117.8
120.1
119.4
111.6
50.3
114.0
121.4
117.3
120.9
7,5,8
121.0
121.8
116.4
121.8
Hδ,8,5
Hδ,8,Hꢀ
Hꢀ,8,5
121.8
116.4
121.8
expanded radical 4, as discussed below. The reaction
coordinate leading to 4 passes through transition state
TS4 (Figure 7). A comparison of Figure 5 with Figure 7
immediately shows extension of the breaking bond from
1.525 Å in cyclopropyl radical 3 to 1.871 Å in TS4.
Obscure in Figure 7, but manifest in Table 5, is the
contraction of bond C5-C8, having progressed nearly
50% of the way from the 1.480 Å of the single bond of 3
to the double bond of 4 (1.325 Å). Most bond angles in
stationary points 3, TS4, and 4 offer little to describe
progress along the reaction coordinate owing to the
general lack of rehybridization37 of the centers involved
with bond making and breaking. The main exception to
this is the C5-C7-C6 bond angle which shows the
release of ring strain as the cyclopropane ring opens
(Table 6). In TS4, bond angle C5-C7-C6 has progressed
34% along its 48.7° reorganization from 61.1° of the sp5
orbital in 3 to 109.8° of the rehybridized sp3 orbital in 4.
Progress toward 4 is also evident in the Hδ-C8-C5-C7
dihedral angle (Table 7) which is increasingly flattened
in going from -23.1° in radical 3 to -3.8° in TS4 and
finally crossing over to 3.7° of the π bond in 4.
As the gross structural reorganization is occurring (3
f 4) there are dramatic changes occurring in the
electronic structure of the molecule. The radical, pre-
(37) C8 maintains its essential sp2 character from radical in 3 to
π-bond participant in 4. Both C5 and C6 have sp2-like character in
the cyclopropane ring and are sp2 hybridized in the product.

Ring Formation from 1-Bicyclo[4.1.0]heptanylmethyl Radical
J . Org. Chem., Vol. 64, No. 2, 1999 577
3, and therefore the calculated reaction barrier heights
can be compared without regard to conformational analy-
sis. In this light, scrutiny of Table 9 shows a kinetic bias
of 3.0 kcal/mol for the formation of secondary cycloheptyl
radical 4 as calculated via zero-point energy corrected
PMP4/6-31G*//HF/6-31G* single point data. We focus on
the PMP4 results because they are the highest level of
correlation we have considered, and the spin projection
removes contamination from higher multiplets and the
artifacts they may contribute to the transition state
energies. The spin contamination of the UHF calculations
was very modest for the structures corresponding to
potential surface minima. The S2 values differed from
the expected doublet value of 0.75 by at most 0.04. The
contamination was almost entirely due to quartets, as
removal of their contribution by projection reduced the
maximum difference to 0.0009. As is common, the spin
contamination for the two transition states was greater
than that for the equilibrium structures. S2 was 0.9418,
0.9578 for TS4 and TS6, respectively. The transition
state spin contamination was also dominated by quartets,
for after they were removed by projection, S2 reduced
to 0.7567 and 0.7574, respectively. Removal of still higher
spin states in preparation for the PMP energy calcula-
tions reduced S2 to 0.75000 in all cases. Absolute barrier
heights for the rearrangements 3 f 4 and 3 f 6 were
calculated (PMP4/6-31G*//HF/6-31G* (Z)) to be 6.0 and
9.1 kcal/mol, respectively.38 These data are in qualitative
agreement with the experimentally determined reaction
rates.
F igu r e 9. Stereo representation of the UHF/6-31G*-optimized
geometry for 4; note chair-boat conformation.
F igu r e 10. Stereo representation of the UHF/6-31G*-
optimized geometry for 6; note twist-boat conformation.
available, the structures were reoptimized using the
6-31G* basis set at the Hartree-Fock level of theory with
a resulting moderate change in geometry and significant
change in reaction parameters. All total energies calcu-
lated at levels of theory from UHF/3-21G through PMP4/
6-31G* are reported in the supplemental data along with
atomic spin densities and S2 before and after projection
of quartet contributions. Also included in the supplemen-
tal data are reaction energies along both reaction path-
ways and the differences of those parameters between
the two pathways. We present here the more salient of
these results (Tables 8, 9). It has been demonstrated6a
that HF/6-31G*-optimized cyclopropylcarbinyl radical
structures compared favorably with those optimized
using the QCISD/6-31G* level of theory. This result lends
credence to our choice of HF/6-31G* optimized structures
for this study.
Single point calculations using second, third, and
fourth order projected Møller-Plesset perturbation theory
were conducted on HF/6-31G*-optimized structures to
account for electron correlation. Theory appears to have
converged at the MP2/6-31G*//HF/6-31G* level for rela-
tive reaction barriers with differences ranging to 0.4 kcal/
mol (Table 9). Specific reaction parameters do not show
so tight a convergence, with variations between levels of
theory greater than 1 kcal/mol being common (Table 8).
This is expected because spin contamination will have a
greater effect on the elongated bonds of transition state
structures.
Inspection of the Erxn (3 f 4) - Erxn (3 f 6) entries in
Table 9 shows seven-membered carbocycle 4 to be both
kinetically and thermodynamically favored regardless of
level of theory or basis set. The zero-point energy cor-
rected values for the energies of reaction show expanded
radical intermediate 4 to be favored over cyclopropane-
opened intermediate 6 by 1-2 kcal/mol. Yet these figures
can be misleading. As noted above and evident in Figure
10 the optimized structure for radical 6 lies in a twist-
boat conformation as dictated by the geometry of TS6.
This is by no means the lowest energy conformer for such
structures. For this reason we undertook a conforma-
tional search yielding the low energy chair conformation
6′ shown in Figure 11. As can be seen in Table 9, now
the six-membered radical intermediate is unambiguously
the thermodynamic product at all levels of theory, favored
by 2.1 kcal/mol for the PMP4/6-31G*//HF/6-31G* calcula-
tion.
Several hypotheses have been suggested to account for
kinetic regiochemistry observed in radical ring opening
reactions of substituted cyclopropylcarbinyl radicals.31,39
Of these, that championed by Schlegel and Newcomb6
prove most aptly applied to carbinyl radical 3. They
explored the ring opening of a variety of methyl- and
dimethyl-substituted cyclopropyl carbinyl radicals using
ab initio techniques. They concluded that the rate and
consequently the regiochemistry of ring opening was
dramatically influenced by eclipsing interactions between
the carbinyl group and a vicinal methyl group (Figure
12). Even though cyclopropylcarbinyl 3 does not offer
such a steric interaction between the carbinyl group and
a vicinal C-C bond, it does have an analogous eclipsing
interaction between the two vicinal C-C bonds of the
fused cyclohexane ring (C4-C5-C6-C1 dihedral )
-0.80° (Table 7). Adjustments to minimize these eclipsing
interactions are evident in both TS4 (Figure 7) and TS6
(Figure 8). In TS4 the bonds are still essentially eclipsed
(C4-C5-C6-C1 dihedral ) 0.30°); nevertheless, the
destabilizing effect of the eclipsed bonds is lessened by
the increased distance between those bonds afforded by
the lengthening of the C5-C6 cyclopropyl σ-bond (1.871
Å, Table 5). TS6 exhibits a significant degree of torsional
flexing from the near coplanar disposition of C4-C5-
C6-C1 in 3. The C4-C5-C6-C1 dihedral angle has
opened to -22.0° in TS6 allowing some relief from the
eclipsing inherent in 3. Yet the -22.0° dihedral of TS6
or even the -26.0° dihedral of the twist-boat conformer
of stationary point 6 is remote from the ideal gauche
(38) Ab initio calculation results in other cyclopropylcarbinyl radical
systems indicate that though these calculations prove quite useful for
relative barrier height comparisons, absolute barrier heights should
be viewed with some caution (see ref 6a).
The geometries of the transition structures TS6 and
TS4 are dictated by that of cyclopropylcarbinyl radical
(39) Mariano, P. S.; Bay, E. J . Org. Chem. 1980, 45, 1763-1769.

578 J . Org. Chem., Vol. 64, No. 2, 1999
Ta ble 8. Rea ction P a r a m eter s (k ca l/m ol)
Kantorowski et al.
calculation level
Ea 3 f 4
Ea 3 f 6
Ea 4 f 3
Ea 6 f 3
Erxn 3 f 4
Erxn 3 f 6
Erxn 3 f 6′
HF/6-31G*
10.5
9.7
11.1
6.0
13.5
12.2
14.6
9.1
16.1
15.0
12.6
8.2
15.7
15.2
14.4
9.5
-5.5
-5.3
-1.5
-2.2
-2.3
-3.0
0.2
-7.8
-8.3
-4.9
-5.1
HF/6-31G* (Z)a
MP4/6-31G*//HF/6-31G* (Z)a
PMP4/6-31G*//HF/6-31G* (Z)a
-0.4
a
Zero-point energy-corrected values. Zero-point energies taken from HF/6-31G*-optimized structures and scaled by 0.89.
Ta ble 9. Rela tive Rea ction Ba r r ier a n d En er gy of Rea ction Com p a r ison s (k ca l/m ol)
calculation level
Ea(3 f 6) - Ea(3 f 4)
Erxn(3 f 4) - Erxn(3 f 6)
Erxn(3 f 4) - Erxn(3 f 6′)
HF/6-31G*
2.9
2.4
3.4
3.0
-3.3
-2.3
-1.7
-1.8
2.3
3.0
3.4
2.8
HF/6-31yG* (Z)a
MP4/6-31G*//HF/6-31G* (Z)a
PMP4/6-31G*//HF/6-31G* (Z)a
a
Zero-point energy-corrected values. Zero-point energies taken from HF/6-31G*-optimized structures and scaled by 0.89.
exceed a few kcal/mol for energy of activation. The
computations indicate that the activation barriers for
formation of both products are very close, the experi-
mental difference being less than a kcal/mol. Within the
accuracy we can expect for this level of theory, there is
consonance between the experimental activation energies
and those calculated theoretically. We believe the quali-
tative aspects of the transition state structures to be the
more important contribution from theory to our under-
standing of this reaction.
F igu r e 11. Stereo representation of the PMP4/6-31G*//HF/
6-31G*, optimized geometry for 6′.
The quantitative aspects of the theoretical calculation
of the change in entropy to the transition state are even
less reliable than are the energetics. Still some enheart-
ening aspects emerge. Kinetic and theoretical data
provides ∆Sq (3 f 4) as -3.67 eu and -1.842 eu,
respectively. Likewise, ∆Sq (3 f 6) is found to be -7.47
eu and -0.943 eu. A decrease in entropy is to be expected
for both of these processes since the freely rotating
methyl radical in 3 must adopt an orientation which
allows for proper overlap with one of the cyclopropyl σ
bonds. Progress along either pathway necessitates that
the initial •CH2 ultimately become locked into the fixed
geometry of the resulting CdC bond. This ordering will
certainly outweigh any additional degrees of freedom
gained by the carbocycle as a result of loss of the fused
cyclopropyl group.
F igu r e 12. Reaction barriers for ring opening PMP2/6-31G*//
HF/6-31G*, zeropoint corrected.6a
angle of 60.0°.40 Breaking the C5-C6 bond in TS4
appears to offer greater relief from the destabilizing
eclipsing interactions than the partial bond rotation
observed in TS6. Apparently, reduction of the eclipsing
interaction in conjunction with the stabilizing effect of
the incipient secondary radical in large part account for
the PMP4/6-31G*//HF/6-31G* (Z) result (Table 9) indicat-
ing path 3 f 4 is kinetically favored by 3.0 kcal/ mol over
3 f 6.
Cyclohexyl radical 6′ is calculated to be 2.1 kcal/mol
more stable than cycloheptyl radical 4; this can be
rationalized on the grounds of ring strain and radical
stability. Based purely on the ring strain of cyclohexanes
vs cycloheptanes,41 one would expect 6 to be favored by
6.3 kcal/mol. However, 6 is a primary radical while 4 is
a secondary radical; this should stabilize 4 by roughly
3.5 kcal/mol42 relative to 6. Combining these opposing
effects places 6 roughly 2.8 kcal/mol lower in energy than
4. This rationalization gives a surprisingly good quanti-
tative estimate in comparison with the calculated and
experimental results.
In the kinetic analysis, Ea values taken from the
Arrhenius expression suggests the two pathways are
comparable (5.63 vs 5.26 kcal/mol). Taking the error bars
into account reveals that 3 f 4 could be favored at one
extreme by 0.23 kcal/mol and 3 f 6 at the other by 0.97
kcal/mol. This apparent ambiguity between which path-
way is favored is resolved when one considers that the
preexponential factor dominates for transformation 3 f
4 (12.38 vs 11.54). It is unrealistic to expect the accuracy
of the theoretical methods employed in this study to
Con clu sion
Calculations and experimentation indicated that the
rearrangement of radical 3 could be manipulated to favor
two different products depending on three reaction
parameters: temperature, concentration, and choice of
the reducing agent. The more rigorous kinetic study
presented in this paper showed that indeed radical 3 can
be induced to give predominantly expanded product 5.
A general methodology coupling this radical ring expan-
sion with the Diels-Alder cyclization will prove a potent
synthetic tool.
Exp er im en ta l Section
Gen er a l P r oced u r es. Solvents were purified as follows:
tetrahydrofuran (THF) was distilled from sodium/benzophe-
none ketyl; methylene chloride (CH2Cl2) was distilled from
CaH2; benzene was distilled from potassium. All reactions,
unless otherwise noted, were conducted under an inert atmo-
(40) One should not discount the destabilizing effect on TS6 of the
partial adoption of the twist-boat conformation.
(41) Liebman, J . F.; Greenberg, A. Chem. Rev. 1976, 76, 311-353.
(42) From bond dissociation energies: Benson, S. W. J . Chem. Educ.
1965, 42, 502-518.
1
sphere (N2 or Ar). H and 13C NMR spectra were measured in
CDCl3 at 300 and 75 MHz, respectively, and chemical shifts
are reported in ppm downfield from internal tetramethylsilane.
Thin-layer chromatography (TLC) was performed on silica gel

Ring Formation from 1-Bicyclo[4.1.0]heptanylmethyl Radical
J . Org. Chem., Vol. 64, No. 2, 1999 579
plates, and components were visualized by UV light, iodine,
or by heating the plates after treatment with a phosphomo-
lybdic acid reagent (1:1 in EtOH). CC, RC, and PC refer to
column, radial, and planar chromatography on silica gel,
respectively. For CC and RC the eluent indicated refers to the
starting mixture of stepwise elution. Elemental analyses were
performed at the MidWest Microlab, Indianapolis, IN.
Un sa tu r a ted Ester s (9a /9b). The procedure described by
Emmons was followed.17 Vacuum distillation (62.0 °C at 1.0
mmHg) afforded a 52:48 mixture (per capillary GC) of the â,γ:
R,â isomers (20.3 g; 73.1%; lit. yield 67-77%).
1.97 (m, 3H), 2.51 (d, 1H, J ) 16.6 Hz), 2.66 (d, 1H, J ) 16.6
Hz), 6.61 (td, 1H, J ) 6.9, 1.6 Hz), 7.17 (ddd, 1H, J ) 8.8, 6.9,
1.4 Hz), 7.54 (dd, 1H, J ) 6.9, 1.4 Hz), 7.63 (dd, 1H, J ) 8.8,
1.6 Hz). 13C NMR δ 15.71, 16.94, 17.76, 20.71, 21.31, 23.48,
28.55, 43.36, 112.45, 133.38, 137.18, 137.66, 167.86, 175.71.
Anal. Calcd for C14H17NO2S: C, 63.85; H, 6.51; N, 5.32.
Found: C, 63.78; H, 6.51; N, 5.42.
1-Cycloh exen ylm eth yl Aceta te (14). To a 0 °C solution
of 1-cyclohexenemethanol (13) (0.492 g, 4.39 mmol) and acetic
anhydride (1.365 g, 13.16 mmol) in CH2Cl2 (15 mL) was added
Et3N (1.791 g, 17.70 mmol) and DMAP (59 mg, 0.48 mmol).
The ice bath was removed, and the reaction was stirred at
ambient temperature for 1.5 h. Methanol (5 mL) was added
to quench the excess Ac2O and, after a further 30 min at
ambient temperature, the reaction was diluted with H2O and
extracted with CH2Cl2 (3 × 20 mL). The combined organics
were dried (Na2SO4), filtered, and concentrated. CC (20%
EtOAc in hexanes) afforded the allylic acetate 14 as a colorless
Eth yl 2-(1-Cycloh exen yl)a ceta te (9b). To a 0 °C solution
of diisopropylamine (1.092 g, 10.79 mmol) in THF (40 mL) was
slowly added n-butyllithium (7.1 mL, 1.48 M in hexanes). The
solution was stirred for 20 min and then cooled to -78 °C.
The mixture of esters 9a /9b (1.68 g, 9.99 mmol) in THF (8
mL) was added dropwise over 10 min and allowed to stir for
an additional 10 min. Saturated aqueous NH4Cl (9 mL) was
added dropwise over 10 min, and the quenched reaction was
allowed to warm to ambient temperature, poured into H2O (75
mL), and extracted with Et2O (3 × 30 mL). The extracts were
dried (Na2SO4), filtered, and concentrated to afford 1.68 g (9.99
mmol, 100%) of the â,γ-unsaturated ester 9b as a colorless
liquid. Capillary GC analysis showed no evidence of conjugated
liquid (0.569 g, 84.0%). FTIR (thin film) 1739, 1229, 1024 cm-1
.
1H NMR δ 1.54-1.69 (m, 4H), 1.98-2.07 (m, 4H), 2.06 (s, 3H),
4.43 (s, 2H), 5.73 (br s, 1H). 13C NMR δ 20.79, 21.97, 22.22,
24.85, 25.72, 68.77, 126.16, 132.74, 170.78.
2-(2-Meth ylen ecycloh exyl)a cetic Acid (15). To a 0 °C
solution of diisopropylamine (0.187 g, 1.84 mmol, freshly
distilled from NaOH) in THF (7 mL) was added slowly via
syringe n-BuLi (1.19 mL, 1.44 M in hexanes). The solution was
allowed to stir at 0 °C for 10 min and then cooled to -78 °C.
A solution of the allylic acetate 14 (0.238 g, 1.54 mmol) in THF
(2 mL) was added via syringe and then followed immediately
by addition of TMSCl (0.21 mL, 1.65 mmol). The reaction was
allowed to warm to room temperature and then refluxed for
12 h. After the reaction was cooled to room temperature, CH3-
OH (5 mL) was added, the solution was stirred for 2 h, and
the solution was diluted with Et2O and extracted with aqueous
2 M NaOH (2 × 40 mL). The combined aqueous extracts were
acidified with aqueous 2 M HCl and extracted with Et2O (2 ×
25 mL). The organic solution was washed with H2O, dried (Na2-
SO4), filtered, and concentrated. CC (30% EtOAc in hexanes)
afforded the pure acid 15 as a colorless liquid (0.165 g, 70%).
1
ester 9a . FTIR (thin film) 3060 (weak), 1735 cm-1. H NMR δ
1.23 (t, 3H, J ) 7.1 Hz), 1.52-1.65 (m, 4H), 1.97-1.99 (m, 4H),
2.90 (s, 2H), 4.10 (q, 2H, J ) 7.1 Hz), 5.53 (s, 1H).
Eth yl 2-Bicyclo[4.1.0]h ep tyla ceta te (10). To a -5 °C
solution of Et2Zn (13.7 mL, 1.0 M in hexanes) in CH2Cl2 (50
mL) was added dropwise CH2I2 (7.37 g, 27.5 mmol) over 10
min. A white precipitate formed when the addition was
approximately half complete. After an additional 10 min, ester
9b (1.465 g, 8.71 mmol) in CH2Cl2 (8 mL) was added in one
portion, and the reaction was allowed to stir at room temper-
ature for 9 h during which time most of the white precipitate
had dissolved. The reaction was poured into saturated aqueous
NH4Cl (200 mL) and extracted with Et2O (2 × 150 mL). The
combined organics were dried (Na2SO4), filtered, and concen-
trated. The crude material could be used without further
purification. CC (5% EtOAc/hexanes) afforded the pure ester
10 as a colorless liquid (1.381 g, 87%). FTIR (thin film) 1736
1
FTIR (thin film) 2940 (br), 1708, 1646 cm-1. H NMR δ 1.14-
1.27 (m, 1H), 1.32-1.56 (m, 2H), 1.68-1.77 (m, 2H), 1.80-
1.88 (m, 1H), 2.01-2.09 (m, 1H), 2.26-2.32 (m, 1H), 2.35 (dd,
1H, J ) 14.5, 7.1 Hz), 2.50-2.59 (m, 1H), 2.65 (dd, 1H, J )
14.5, 6.7 Hz), 4.55 (s, 1H), 4.69 (s, 1H), 10.8 (br s, 1H). 13C δ
25.08, 28.42, 34.05, 35.58, 37.77, 39.54, 105.44, 151.21, 179.23.
Anal. Calcd for C9H14O2: C, 70.10; H, 9.15. Found: C, 70.07;
H, 9.03.
cm-1 1H NMR δ 0.25 (t, 1H, J ) 5.0 Hz), 0.47 (dd, 1H, J )
.
9.2, 5.0 Hz), 0.78-0.86 (m, 1H), 1.06-1.33 (m, 4H), 1.24 (t,
3H, J ) 7.1 Hz), 1.51-1.59 (m, 1H), 1.63-1.78 (m, 2H), 1.84-
1.95 (m, 1H), 2.10 (d, 1H, J ) 15.0 Hz), 2.22 (d, 1H, J ) 15.0
Hz), 4.11 (q, 2H, J ) 7.1 Hz). 13C NMR δ 14.29, 16.56, 16.86,
17.66, 21.07, 21.52, 23.79, 28.72, 46.24, 59.91, 172.63.
2-Bicyclo[4.1.0]h ep tyla cetic Acid (11). Ester 10 (0.554
g, 3.04 mmol) in basic EtOH (1.93 g KOH in 25 mL 95% EtOH)
was heated at reflux for 2 h. The reaction was diluted with
Et2O and extracted with aqueous NaOH (2 M; 2 × 40 mL).
The combined extracts were acidified with aqueous HCl and
extracted with Et2O (3 × 40 mL). The combined organics were
dried (Na2SO4), filtered, and concentrated to give an orange
liquid. CC (30% EtOAc/hexanes) afforded the pure acid 11 as
a colorless liquid (0.431 g, 92%). FTIR (thin film) 2930 (br),
1-[2-(2-Meth ylen ecycloh exyl)a cetoxy]-2(1H)-p yr id in e-
th ion e (16). Carboxylic acid 15 (0.103 g, 0.67 mmol), 2-mer-
captopyridine N-oxide (0.085 g, 0.67 mmol), and DMAP (7.80
mg, 0.06 mmol) were dissolved in CH2Cl2 (10 mL). The reaction
flask was covered with foil to protect it from light, and DCC
(0.151 g, 0.73 mmol) in CH2Cl2 (5 mL) was added dropwise
over 20 min. The bright yellow reaction mixture was allowed
to stir for 16 h at ambient temperature. The dicyclohexylurea
was filtered off, and the yellow filtrate was concentrated. PC
(35% EtOAc in hexanes) provided the pure PTOC ester 16 as
a viscous yellow oil (0.144 g, 82%). FTIR (KBr) 1807, 1607,
1
1706 cm-1. H NMR δ 0.29 (t, 1H, J ) 5.0 Hz), 0.51 (dd, 1H,
J ) 9.2, 5.0 Hz), 0.80-0.88 (m, 1H), 1.09-1.34 (m, 4H), 1.52-
1.60 (m, 1H), 1.66-1.84 (m, 2H), 1.86-1.97 (m, 1H), 2.22 (s,
2H), 11.90 (br s, 1H). 13C NMR δ 16.31, 16.85, 17.73, 21.00,
21.44, 23.72, 28.65, 46.08, 179.53.
1
1526, 1447, 1422, 1133, 1056. H NMR δ 1.23-1.79 (m, 5H),
1.92-2.01 (m, 1H), 2.06-2.14 (m, 1H), 2.29-2.37 (m, 1H),
2.70-2.76 (m, 1H), 2.75 (dd, 1H, J ) 18.2, 7.3 Hz), 3.01 (dd,
1H, J ) 18.2, 9.5 Hz), 4.64 (s, 1H), 4.76 (s, 1H), 6.62 (td, 1H,
J ) 6.9, 1.7 Hz), 7.20 (ddd, 1H, J ) 8.8, 6.9, 1.4 Hz), 7.53 (dd,
1H, J ) 6.9, 1.4 Hz), 7.69 (dd, 1H, J ) 8.8, 1.7 Hz). 13C NMR
δ 24.75, 28.28, 34.00, 35.10, 35.30, 39.38, 105.92, 112.52,
133.48, 137.39, 137.68, 150.73, 168.24, 175.92.
1-[2-(Bicyclo[4.1.0]h e p t yl)a ce t oxy]-2(1H )-p yr id in e -
th ion e (12). Carboxylic acid 11 (0.598 g, 3.88 mmol), 2-mer-
captopyridine-N-oxide (0.494 g, 3.88 mmol), and DMAP (46.9
mg, 0.38 mmol) were dissolved in CH2Cl2 (50 mL). The reaction
flask was covered with foil to protect it from light, and DCC
(0.886 g, 4.29 mmol) in CH2Cl2 (15 mL) was added dropwise
over 20 min. The bright yellow reaction mixture was allowed
to stir for 10 h at ambient temperature. The dicyclohexylurea
was filtered off, and the yellow filtrate was concentrated. CC
(30% EtOAc in hexanes) provided 0.812 g (3.08 mmol, 79%) of
the pure PTOC ester 12 as a yellow solid. mp ) 106.0-107.0
Kin etic Exp er im en ts. A stock solution of the PTOC ester
(0.02 M in THF) containing a hydrocarbon standard was
prepared. A 2.0 mL aliquot was taken and placed in a
N2-flushed test tube and capped with a rubber septum. With
stirring, the solution was equilibrated to the desired temper-
ature, and the hydride agent was added via syringe. A 200 W
tungsten bulb was placed within 0.5 m of the tube, and the
reaction was stirred until no PTOC ester was present per TLC
(TLC taken ∼60 s after the reaction was initiated). When
1
°C. FTIR (KBr) 1804, 1531, 1136, 1062, 750 cm-1. H NMR δ
0.36 (t, 1H, J ) 5.1 Hz), 0.59 (dd, 1H, J ) 9.3, 5.1 Hz), 0.90-
0.98 (m, 1H), 1.11-1.39 (m, 4H), 1.52-1.61 (m, 1H), 1.79-

580 J . Org. Chem., Vol. 64, No. 2, 1999
Kantorowski et al.
tributylstannane is used as the hydride source, the completion
of the reaction may be judged by the loss of the yellow color of
the solution (also confirmed by TLC). Isothermal experiments
were conducted simultaneously. The reactions were analyzed
immediately afterward by capillary gas chromatography.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR,
and FTIR spectra for compound 12, Cartesian coordinates for
HF/6-31G* optimized structures, atomic spin densities, total
electronic energies, reaction parameters, and relative barriers
(12 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
Ack n ow led gm en t. This work was supported by
NSF. We thank Dr. Babak Borhan for his help at the
initial stages of the modeling work.
J O981708N