Regioselectivity on electroreductive transannular reaction of 7-methylenebicyclo[3.3.1]nonan-3-one

Article abstract of DOI:10.1246/bcsj.74.339

A competitive transannular reaction occurred to give 7-methyltricyclo[3.3.1.0^3.7]nonan-3-ol (5) and 1-adamantanol (6) in the non-mediated electroreduction of 7-methylenebicyclo[3.3.1]nonan-3-one (1) in N,N-dimethylformamide. The apparent temperature dependence of the regioselectivity of the reaction may be attributed to the competitive operation of both kinetic and thermodynamic controls in the cyclization of the ketyl radical anion. The differences in the parameter of activation between the 5-exo- and 6-endocyclizations of 1,? ,ΔΔH?_{(5-exo - 6-endo)} and ΔΔS?_{(5-exo - 6-endo)}, were evaluated to be -3.1 kcal mol^-1 and -11 cal mol^-1 K^-1, respectively. Semiempirical PM3 (RHF and UHF) calculations were also carried out to elucidate the reaction mechanism.

Full text of DOI:10.1246/bcsj.74.339

© 2001 The Chemical Society of Japan
339
Bull. Chem. Soc. Jpn., 74, 339–345 (2001)
Regioselectivity on Electroreductive Transannular Reaction of
7-Methylenebicyclo[3.3.1]nonan-3-one
Hiroki Itoh,* Ichiro Kato, Kei Unoura, and Yasuhisa Senda
Department of Material and Biological Chemistry, Faculty of Science,Yamagata University,
Koshirakawa,Yamagata 990-8560
(Received July 24, 2000)
A competitive transannular reaction occurred to give 7-methyltricyclo[3.3.1.03,7]nonan-3-ol (5) and 1-adamantanol
(6) in the non-mediated electroreduction of 7-methylenebicyclo[3.3.1]nonan-3-one (1) in N,N-dimethylformamide. The
apparent temperature dependence of the regioselectivity of the reaction may be attributed to the competitive operation of
both kinetic and thermodynamic controls in the cyclization of the ketyl radical anion. The differences in the parameter of
–
‡
activation between the 5-exo- and 6-endocyclizations of 1 , ∆∆H (5-exo – 6-endo) and ∆∆S‡(5-exo – 6-endo), were evaluated to be
–3.1 kcal mol–1 and –11 cal mol–1 K–1, respectively. Semiempirical PM3 (RHF and UHF) calculations were also carried
out to elucidate the reaction mechanism.
•
a JEOL JNM α-400 instrument in the pulse Fourier mode. Infrared
spectra were obtained with a Hitachi 270-50 spectrophotometer.
Materials. The solvent, N,N-dimethylformamide, dried over
Molecular Sieves was vacuum distilled before use. All other chem-
icals used were reagent grade and were recrystallized or distilled if
necessary.
Electroreduction of δ,ε-unsaturated ketones has attracted a
great deal of interest as a useful synthetic method of trans-me-
thylcyclopentyl alcohols.1 Regioselectivity of the cyclization
of δ,ε-unsaturated ketyl radicals was derived from the kinetic
preference of the 5-exocyclization of 5-hexenyl radicals (Bald-
win’s rules).2 The stereoselectivity was controlled by the steric
and the electrostatic repulsion between the eclipsed methylene
terminal carbon having an odd electron and the negatively
charged oxygen atom.1
7-Methylenebicyclo[3.3.1]nonan-3-one (1); 7-Methylenebi-
cyclo[3.3.1]nonan-3-one (1) was prepared according to the proce-
dure of Momose and Muraoka from adamantane.7 Bromination of
adamantane (43 g, 0.32 mol) with bromine (500 g, 3.1 mol), boron
tribromide (75 g, 0.30 mol), and anhydrous aluminium tribromide
(1.0 g, 0.0037 mol) was carried out by refluxing for 4 h and gave
1,3-dibromoadamantane (79 g, 85%). Subsequent alkaline cleav-
age was carried out by heating of a 200-cm3 autoclave containing
the dibromide (10 g, 0.034 mol) in dioxane (80 cm3) and 5 wt%
aqueous sodium hydroxide (70 cm3) to 175–180 °C for 18 h. The
cooled reaction mixture was extracted with ether, and dried over
anhydrous sodium sulfate. Isolation by column chromatography
(SiO2, hexane–ethyl acetate) and recrystallization from hexane af-
forded 3.6 g (70%) of the product. Mp 160–163 °C (lit.; 161–163
°C)7; 1H NMR (CDCl3) δ 1.88–1.99 (m, 2H), 2.24–2.44 (m, 10H),
4.77 (s, 2H); 13C NMR (CDCl3) δ 30.8 (C1 and C5), 32.1 (C9),
41.4 (C6 and C8), 47.4 (C2 and C4), 114.7 (C10), 141.8 (C7),
211.0 (C3); IR (0.20 M in CCl4) νC=O 1716 cm–1.
Bicyclo[3.3.1]nonan-3-one (2); Bicyclo[3.3.1]nonan-3-one,
as a standard compound of 1, was also prepared by modifying the
procedure described by Momose and Muraoka.7 The mixture of 2-
cyclohexen-1-one (26.8 g, 0.28 mol), methyl acetoacetate (39.0 g,
0.33 mol), and sodium methoxide (17.9 g, 0.33 mol) in dry metha-
nol (400 cm3) was refluxed for 35 h to give methyl 5-hydroxy-3-
oxobicyclo[3.3.1]nonan-2-carboxylate. The product was used for
the next step without purification. Decarboxylation of the bicyclic
product was carried out by refluxing with potassium hydroxide
(33.0 g, 0.59 mol) in aqueous ethanol solution (500 cm3) for 8 h to
give 1-hydroxybicyclo[3.3.1]nonan-3-one (19.9 g, yield for 3
steps; 46%). Bromination of the hydroxy ketone (17.8 g, 0.12 mol)
by phosphoryl bromide (17.5 g, 0.065 mol) in dry benzene (60
7-Methylenebicyclo[3.3.1]nonan-3-one, (1), containing a
δ,ε-unsaturated carbonyl unit in itself, exists in the double-
chair conformation in which both π-electron moieties are on
the same plane of symmetry and face each other. The intramo-
lecular through-space interaction between two π-orbitals of 1
which was revealed in the carbon-13 NMR chemical shifts3 af-
fords characteristic reactivities in some reactions, such as the
catalytic hydrogenation,4 the chemical reduction,5 and the pho-
toreaction.6 It is quite interesting to examine the effect of such
an intramolecular through-space interaction on the electro-
chemical reduction of 1. Since the bicyclic structure of 1 – de-
•
rived from one electron reduction of 1 prevents itself from hav-
ing a staggered conformation between the methylene terminal
carbon and the negatively charged oxygen atom, it would be
expected that decrease in the efficiency of 5-exocyclization of
–
•
1
may enhance some alterative behavior such as 6-endocy-
–
•
clization and/or simple reduction of 1 . We present here a
study of the electroreduction of 7-methylenebicyclo[3.3.1]-
nonan-3-one. Effects of temperature and some additives on the
electrolysis and the parameter of activation of the reaction will
be discussed from the experimental and the quantum-mechani-
cal approaches.
Experimental
General. 13C NMR and 1H NMR spectra were obtained with

340 Bull. Chem. Soc. Jpn., 74, No. 2 (2001)
Regioselectivity on Electroreductive Reaction
cm3) at 3 °C for 5 h gave 5-bromobicyclo[3.3.1]nonan-3-one. The
product was used for the next step without purification. Hydroge-
nation of the bromide (13.3 g) was carried out over Raney Ni (14.0
g) in dry diisopropylamine (270 cm3) under ambient temperature
until the hydrogen uptake ceased. Sublimation afforded bicyc-
lo[3.3.1]nonan-3-one (1.7 g, yield for 2 steps; 11%). Mp 166–170
with saturated brine and dried over anhydrous sodium sulfate. Gpc
analysis was performed on a Shimadzu model GC-8A with a Shi-
madzu fused silica capillary column CBP2-M25-0.25 (0.25 mm ×
25 m) at an injection temperature of 250 °C and a column temper-
ature of 150 °C. Retention time of each chemical was compared
with that of the authentic sample. Finally, gpc analysis showed that
89% of 1 were consumed. The yields of 5 and 6 against the con-
sumed 1 were 34 and 20%, respectively. The gpc analysis detected
neither exo- nor endo-alcohol, 3 or 4.
1
°C (lit.; 170–176 °C)8; H NMR (CDCl3) δ 1.37–1.97 (m, 8H),
2.35–2.51 (m, 6H); 13C NMR (CDCl3) δ 18.2 (C7), 30.9 (C1 and
C5), 32.1 (C6 and C8), 32.8 (C9), 47.4 (C2 and C4), 213.5 (C3);
IR (0.20 M in CCl4) νC=O 1714 cm–1.
Current Controlled Electrolysis (Typical). The cathode com-
partment (45 cm3) was attached to a lead plate electrode (WE: 14
cm2), an SCE (RE: bridged with agar containing saturated potassi-
um chloride), an argon inlet tube, and a stirring rod. The anode
compartment (5 cm3) was attached to a platinum electrode (CE).
In the cathode compartment, 338 mg (2.3 mmol) of 1 was added to
7-Methylenebicyclo[3.3.1]nonan-3-endo- and exo-ols
(3 and
4, respectively). The reduction of 1 by NaBH4 gave a mixture of
the exo- and endo-alcohols.5
1-Adamantanol (6) was purchased from Nacalai Tesque, INC.
Cyclic Voltammetry. Cyclic voltammetry was carried out us-
ing a four-necked 10-cm3 cell system with a glassy carbon (as a
working electrode), a platinum wire (a counter electrode), an SCE
(a reference electrode), and an argon inlet tube. A Hokuto HA-310
potentiostat/galvanostat and a Hokuto HB-104 function generator
controlled the potentials. Tetraethylammonium tetrafluoroborate
–
45 cm3 of DMF containing a 200 mM of TEA+BF4 . A constant
current of 100 mA was passed until the amount of the electricity
was 1.0 F/mol to determine the distribution of the chemicals dur-
ing the early stages (up to 15%) of the reduction, except in cases in
which the difference in reactivity was very large. Quantification of
the chemicals was performed by the same method as the case of
preparative electrolysis. The temperature effect on the product dis-
tribution was studied at –18, 0, 25, and 38 °C. Electrolysis of the
cyclized product, (5 or 6; 136 mg, 0.89 mmol), was examined in-
dependently at 0 °C. It was proven that no mutual conversion oc-
curred. The effect of additives such as water, methanol, ethanol,
and 2-propanol on the electrolysis of 1 at 0 °C was also investigat-
ed under the same conditions.
–
(TEA+BF4 ; polarographic grade, 100 mM) was used as a support-
ing electrolyte without further purification. DMF solution of the
substrate (10 mM) with or without a mediator (biphenyl, 2.0 mM)
was bubbled by argon (15 min) before the measurement. The cur-
rent-voltage curve from 0.00 to –3.10 V vs. SCE was recorded on a
Rikadenki model RW-21 electric XY recorder with the scan rate of
50 mV s–1 at 25.0 0.5 °C.
Potential Controlled Electrolysis of 1.
A
preparative-scale
non-mediated electrolysis was carried out in an H-style cell sepa-
rated by glass filter at 0.0 0.5 °C. The cathode compartment (100
cm3) was attached to carbon rods (WE: diameter; 5 mm, length; 60
mm × 6), an SCE (RE: bridged with an agar containing saturated
potassium chloride), an argon inlet tube, and a stirring rod. The an-
ode compartment (50 cm3) was attached to the carbon rod (CE).
The reduction potential was controlled to be –3.00 V and the
amount of charge passed was monitored by the coulometer
(Hokuto Hf-201). In cathode compartment, 1.48 g (9.9 mmol) of 1
Quantum-Mechanical Calculations.12
Semiempirical
PM313/RHF method was used for the analysis of the neutral 1.
UHF method14 was used for the calculation of each transition-state
of the 5-exo- and 6-endocyclizations of 1 . The transition state
obtained was ascertained by “Force” calculation.
–
•
Results and Discussion
Previously, Kariv–Miller reported that the reduction poten-
tial of 6-hepten-2-one, (7), showed a relatively more positive
shift in the presence of homogeneous mediator such as biphe-
nyl than in its absence.15 Though the non-mediated electrore-
duction of 7 at –3.00 V vs. SCE gave only 6-hepten-2-ol, the
mediated reduction of 7 (2.0 mM) with biphenyl (10 mM) at
–2.725 V gave cis- and trans-1,2-dimethylcyclopentanols as
exclusive products. Passage of 1 F/mol afforded 49% of the re-
actant conversion and 48% of 1,2-dimethylcyclopentanols in
which the ratio of cis to trans was 4.0 (Fig. 1). The proposed
mechanism involved reversible cyclization of the ketyl radical
anion formed from reduction of the ketone. The cis- or trans-
cyclized radical anions can be trapped by further reduction or
by protonation to form the observed products.
Cyclic Voltammetry. Preliminary cyclic voltammetry
measurement of 1 showed an irreversible wave and the reduc-
tion peak potential, Ered, was determined to be –2.88 V vs.
SCE. Contrary to the case in 6-hepten-2-one, the Ered of 1 shift-
ed negatively to –2.96 V in the presence of biphenyl.
Bicyclo[3.3.1]nonan-3-one, (2), bearing no methylene moiety,
showed no reduction peak in the range from 0.00 to –3.10 V.
Such a result suggests that the intramolecular through-space
interaction exists in between two π-orbitals of 1. Molecular or-
bital calculation revealed that the LUMO of 1 showed appre-
ciable magnitude of eigenvectors on both π-orbitals (Fig. 4).
–
was added to 100 cm3 of DMF containing 200 mM of TEA+BF4 .
After the argon bubbling for 15 min, the solution was electrolyzed
until the amount of the electricity was 2.5 F/mol. Time dependence
of the solution was monitored by gas chromatography for each 0.5
F/mol of electricity passed. Finally, the mother solution was ex-
tracted with chloroform, washed with saturated brine, dried over
anhydrous sodium sulfate. Separation of the concentrated residue
by column chromatography (SiO2, hexane–ethyl acetate) and re-
crystallization afforded 7-methyltricyclo[3.3.1.03,7]nonan-3-ol (5,
163 mg, isolated yield; 13%) and 1-adamantanol (6, 226 mg isolat-
ed yield; 18%). Diminution of the isolated yield of 5 is due to the
difficulty of separation from the starting material.
7-Methyltricyclo[3.3.1.03,7]nonan-3-ol (5); Mp 167–168 °C,
(lit.169–170 °C)9; 1H NMR (CDCl3) δ 0.97 (s, 3H), 1.39–1.63 (m.
s, 7H), 1.76–1.83 (m., 4H), 2.14 (br. s, 1H); 13C NMR (CDCl3) δ
21.4 (CH3), 33.3 (C9), 35.0 (C1 and C5), 43.7 (C7), 50.7 (C6 and
C8), 51.0 (C2 and C4), 83.2 (C-OH); IR (KBr) νOH 3320 cm–1.
1-Adamantanol (6); 1H NMR (CDCl3) δ 1.20 (br. s., 4H)
1.50–1.80 (m., 12H), 2.15 (m., 3H)10; 13C NMR (CDCl3) δ 30.8
(C3, C5, and C7), 36.2 (C4, C6, and C10), 45.4 (C2, C8, and C9),
68.1 (C−OH); IR (KBr) νOH 3250 cm–1.11
Quantification was carried out as follows; cyclohexanol, as an
internal standard, was added to each separated mother solution (3
cm3), and the solution was extracted by three 10 cm3 portions of
hexane. The combined hexane layers were washed three times

H. Itoh et al.
Bull. Chem. Soc. Jpn., 74, No. 2 (2001) 341
Fig. 1. Electroreduction of 6-hepten-2-one (7).15
*
*
*
C=C
The perturbation of π
the energy level of π
π
with π
causes the lowering of
relevant cyclization reaction, Chen and his coworkers reported
the temperature dependence examination of the trapping prod-
uct ratio from 7-methylenebicyclo-[3.3.1]nonyl radical, (8 ),
C=O
which lies essentially lower than
C=O
•
*
C=C. Since the negative shift of Ered of 1 in the presence of
mediator was attributed to suppressing the intramolecular
through-space interaction of 1, we decided to examine the non-
mediated electroreduction of 1.
with CCl4 over the 75–126 °C range.16 The ratio of 5-exocy-
clization product (chloro(3-noradamantyl)methane) to 6-en-
docyclization product (1-chloroadamantane) appeared to
change very slowly (53.6 and 27.3, for 75 °C and 126 °C, re-
spectively). The Arrhenius plot did not produce a credible re-
sult. They also evaluated the difference in the enthalpy of acti-
vation between the 5-exo- and 6-endocyclizations,
∆∆H‡(5-exo – 6-endo), at 25 °C to be –2.8 kcal mol–1 by using mo-
lecular mechanics calculation (Table 2).
Preparative-Scale Electrolysis of 1. A quite interesting
result was obtained by the potential controlled non-mediated
reduction of 1. In addition to the observation that neither 7-me-
thylenebicyclo[3.3.1]nonan-3-endo- nor exo-ol, (3) or (4), was
formed, competitive cyclization to give 7-methyltricyclo-
[3.3.1.03,7]nonan-3-ol (5) and 1-adamantanol (6) was found
(Fig. 2). It is noteworthy that the formation of 6, derived from
the 6-endocyclization, does not obey the Baldwin’s rule. It is
well known that the 5-exocyclization of δ,ε-unsaturated radi-
cals is kinetically preferred despite the thermodynamic prefer-
ence for the 6-endo cyclization. Time dependent examination
showed the slight enhancement of the product ratio, (5/6), from
1.3 to 1.6 (Table 1, entries 1a–1e). Increase in the product ratio
seemed to be affected by decrease in the amount of electricity
with the progress of the reaction. The controlled potential elec-
trolysis afforded the low cyclization efficiency for the conver-
sion of 1. It was considered that the low cyclization efficiency
originated from the low current efficiency of the carbon rods
used as the cathode electrode. For the kinetic analysis of the
competitive cyclization of 1, the constant current electrolysis
was examined by using a lead plate electrode of which the hy-
drogen overvoltage was higher than the graphite.
After establishing the absence of any mutual conversion of
the products by the electoreduction of 5 or 6, we examined the
electroreduction of 1 at –18, 0, 25, and 38 °C. A constant cur-
rent of 100 mA was passed until the amount of the electricity
was 1.0 F/mol, to determine the distribution of the chemicals
during the early stages (up to 15%) of the reduction. The ratio
of 5 to 6 decreased moderately from 2.2 to 0.61 with increasing
the reaction temperature from –18 to 38 °C (Table 1, entries
2a–2d). This indicates that the regioselectivity of the reaction is
controlled by the competitive operation of both kinetic and
thermodynamic factors in the cyclization of the rigid ketyl rad-
ical anion. We wish to propose the mechanism for the competi-
tive cyclization on the electroreduction of 1 as depicted in the
Scheme 1. Initially formed radical anion of 1 kinetically cy-
clizes to give 5 – which contains steric and electrostatic repul-
•
sion between the eclipsed methylene terminal carbon having an
odd electron and the negatively charged oxygen atom. On the
Temperature Effect on the Product Ratio. As a closely
Fig. 2. Non-mediated electroreductive transannular reaction of 1.

342 Bull. Chem. Soc. Jpn., 74, No. 2 (2001)
Regioselectivity on Electroreductive Reaction
Table 1. Electroreductive Transannular Reaction of 7-Methylenebicyclo[3.3.1]nonan-3-one (1) in DMF1)
Entry
Additive
Temp.
Amount of
Conv. of
Product yield/%
Ratio
(concn/mM)
/◦C
charge/F mol−1
1/%
5
6
5/6
Potential controlled electrolysis2)
1a
1b
1c
1d
1e
non
non
non
non
non
0
0
0
0
0
0.5
1.0
1.5
2.0
2.5
21
41
60
77
89
9.1
20
26
7.2
14
18
1.3
1.4
1.5
1.5
1.6
27
19
30(343))
18(203))
Current controlled electrolysis4)
2a
2b
2c
2d
3a
3b
3c
3d
4
non
non
non
non
(
−18
0
25
38
0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
13
11
15
12
15
25
29
36
43
33
37
9.0
5.0
5.8
4.6
8.5
15
19
30
41
28
4.1
5.8
7.0
7.5
6.4
10
2.2
0.86
0.83
0.61
1.3
1.5
1.9
5.2
19
H2O
10)
H2O ( 100)
H2O5) ( 500)
H2O (1000)
MeOH5) (500)
EtOH5) (500)
2-PrOH5) (500)
0
0
0
0
0
0
10
5.8
2.2
4.7
9.1
5
6
6.0
3.0
27
1) 200 mM of TEA+BF4− was contained. 2) Concentration of 1; 100 mM. 3) Only the two values are yield to the consumed 1. 4) Concentration of
1; 50 mM. 5) Swains solvent polarity: H2O; 2.0, MeOH; 1.25, EtOH; 1.11, 2-PrOH; 1.04. C. G. Swain, M. S. Swain, A. L. Powell, and S. Alunni,
J. Am. Chem. Soc., 105, 502 (1983).
Table 2. Relative Heats of Formation at 298 K, in kcal mol−1 to the Ketyl Radical Anions for the 5-Exocyclized and
6-Endocyclized Radical Anions and the Corresponding Transition States
[TS]‡
ꢀ
[TS]‡
ꢀ
∆∆H‡
∆∆H
Reactant (5-Exocyclized)•−
(Ketyl radical anion)
(6-Endocyclized)•− (TS 5-exo − TS 6-endo
)
(5-Exo − 6-endo)
1
∼4.31)
4.3
0.02)
0.0
8.4 −2.1
9.7 −1.4
8.25) −20.05)
−4.1 (−3.13))
−3.4
6.4
5.0
7
3.64)
6.34)
5.45)
8•
−9.05)
0.05)
−2.85)
11.05)
1) Optimized structure was not obtained. The value was obtained as the energy minimum of the reaction coordinate. 2) The value of 1•−cOcC. 3)
The value was obtained by the temperature dependent examination. 4) The approach of the two functional groups was assumed to be in staggered
mode. 5) The values were for radicals and obtained by molecular mechanics calculation. A. M. Mueller and P. Chen, J. Org. Chem., 63, 4581
(1998).
Scheme 1. Non-mediated electroreductive transannular reaction of 1. The values in parentheses are Heats of formation at 25 ◦C
(kcal/mol) obtained by MO calculation.

H. Itoh et al.
Bull. Chem. Soc. Jpn., 74, No. 2 (2001) 343
other hand, even though the energy level of the transition state
of 6-endocyclization is higher than that of 5-exocyclization, the
kinetically preferred and that the structure is more rigid than
that of 6-endocyclization. The negative values of both
∆∆H‡(5-exo – 6-endo) and ∆∆S‡(5-exo – 6-endo) suggest a relatively large
–
•
formation of
6
is thermodynamically favored. As
magnitude of inter-orbital interaction of 1 – in the manner of 5-
•
Kariv–Miller proposed, the cyclized radical anions can be
trapped by further reduction or by protonation to form the final
products. If one supposes that 5-exocyclization and 6-endocy-
clization process are rate-determining and if the rate constants
are defined as k5 and k6, respectively, the following equation
can be derived (Eq. 1).
exocyclization. More detailed consideration will be carried out
later with the data of molecular orbital calculations. As the re-
sults, the difference in Gibbs function of activation at 0 °C,
∆∆G‡(5-exo – 6-endo), can be derived to be – 0.1 kcal mol–1.
Conformation Analysis of 1 and 1 – by MO Calculation.
•
Assuming that the difference in the heats of formation could be
regarded as the difference in the free energies, we evaluated the
ln ([product 5]/[product 6]) = ln (k5/k6)
= −{[∆H‡(5-exo) − ∆H‡(6-endo)]/R}(1/T)
ratio of the conformers of 1 or 1 – (Fig. 3). PM3/RHF calcula-
•
+[∆S ‡(5-exo) − ∆S ‡(6-endo)]/R
(1)
tion reproduces well the result that the most stable conforma-
tion of the neutral 1 exists in a chair-chair form (1cOcC, 95.5%).
As depicted in Fig. 4, the LUMO of 1cOcC shows significant
magnitude of the eigenvectors on both the functional groups
and the coincidence of the symmetry of the orbitals. It suggests
that an incorporation of an electron to the LUMO should afford
an inter-orbital interaction. On the other hand, PM3/UHF cal-
culation shows that the corresponding conformer of the anion
The logarithmic plot of the product ratio against the reciprocal
of temperature showed good Eyring correlation; the slope and
intercept were 1.57 × 103 and –5.55 (r; 0.91), respectively. The
difference in the parameter of activation between the 5-exo-
and 6-endocyclizations was defined as follows.
∆∆H‡(5-exo−6-endo) =[∆H‡(5-exo) −∆H‡(6-endo)] = −1.57 × 103 • R (2)
–
•
radical (1 cOcC) is minor (12.5%) and the most stable confor-
∆∆S ‡
= [∆S ‡(5-exo) − ∆S ‡(6-endo)] = −5.55 • R
(3)
(5-exo − 6-endo)
–
•
mation of 1 has the boat form of the methylenecyclohexane
–
–
the values of ∆∆H‡(5-exo – 6-endo) and ∆∆S‡(5-exo – 6-endo) were evalu-
ated to be –3.1 kcal mol–1 and –11 cal mol–1 K–1, respectively.
It suggests that the transition state of 5-exocyclization is
ring (1 cObC, 85.2%). For the ring inversion from 1 cOcC to
•
•
–
‡
•
1 cObC, the enthalpy of activation, ∆H calcd, was calculated to
be 0.6 kcal mol–1. Since ∆H‡calcd of the ring inversion is smaller
Fig. 3. The difference in the heats of formation (∆H298) of 1 and 1•− obtained by MO calculation. The values in parentheses are
∆H298 (kcal/mol) and percent of existence, respectively. The difference in ∆H298 between 1cOcC and 1•−cOcC is 4.4 kcal mol−1.

344 Bull. Chem. Soc. Jpn., 74, No. 2 (2001)
Regioselectivity on Electroreductive Reaction
evaluated to be –3.4 kcal mol–1. It is well reproduced that the 5-
exocyclization is the kinetically preferential process. Thermo-
dynamic preference of 6-endocyclized intermediate was re-
vealed by the difference in relative heats of formation of the
two cyclized intermediates (∆∆H(5-exo – 6-endo); 5.0 kcal mol–1).
Calculation of the cyclization of 1 – gave the unique character
•
–
•
ascribed to the rigidity of 1 . The reaction coordinate for the
5-exocyclization did not give the optimized structure as the sta-
–
•
ble intermediate of 5 , and it barely gave the transition state as
an inflection point, whereas the reaction coordinate for the 6-
endocyclization showed clear maximum and minimum corre-
sponding to the transition state and the stable intermediate of
–
•
6 . It was also proven that the energy of the transition state for
the 5-exocyclization was by far lower than that of the transition
state for the 6-endocyclization. The evaluated difference in
∆∆H‡(5-exo – 6-endo) was –4.1 kcal mol–1 (Table 2). The calculated
value was slightly more negative than that of experimental re-
Fig. 4. LUMO of 1. The values in parentheses are sig-
nificant eigenvectors of 2px and 2py, respectively.
than those of 5-exo- and 6-endocyclizations (∆H‡calcd; 4.3, 8.4
sult. The characteristic parameters of the transition states from
– are summarized in Table 3. The transition state of 5-exocy-
–1
–
•
•
kcal mol , respectively, shown in Table 2), 1 cOcC could be
1
–
•
changed to 1 cObC that should afford δ,ε-unsaturated alcohols.
The fact that no simple alcohol was formed on the electrolysis
suggested that the adsorption of 1 on the electrode prevented
any conformational exchange from 1 cOcC to 1 cObC.
Evaluation of the Parameter of Activation by MO Calcu-
lation. As a standard reaction, we examined the electroreduc-
tion of 7.15 In order to search for the transition state of 5-exocy-
clization of 7 , we postulated that the approach of the two
functional groups took place in a staggered mode that, in fact,
gave cis-1,2-dimethylcyclopentanol, as a major product. The
clization shows the effective bond order between the ketyl car-
bon and the inner methylene carbon as to be 0.218 at the dis-
tance of 235.6 pm. The transition state of 6-endocyclization
shows the effective bond order between the ketyl carbon and
the terminal methylene carbon as to be 0.116 at the distance of
249.1 pm. It suggests that the effective orbital interaction in
–
–
•
•
–
•
manner of 5-exocyclization should occur in the rigid 1 .
–
•
Though the difference of enthalpies of activation
–
–
(∆∆H‡(5-exo – 6-endo)) among 1 , 7 , and 8 was similar (Table 2),
•
•
•
–
•
the fact was that only 1 afforded the competitive 6-endocy-
–
•
assumed 6-endocyclizatin of 7 was not generated actually.
clization as well as 5-exocyclization. Moderate temperature
•
Table 2 lists the relative values of the heat of formation to that
dependence in the competitive cyclization of 1 – should be as-
–
–
of 7 to be 0.00. The value of ∆∆H‡
for 7 was
cribed to the difference of entropies of activation. In cases of
•
•
(5-exo – 6-endo)
Table 3. Characteristic Parameters of the Transition States of 5-Exo- and 6-Endocyclization of 1•− Obtained by PM3/UHF
Calculation
Atom
CK
O
Cα
Spin Density (Formal Charge)
0.262 (+0.153)
Atom
CK
O
Cα
Spin Density (Formal Charge)
0.525 (−0.042)
1)
1)
0.223 (−0.525)
0.270 (−0.595)
−0.182 (−0.219)
0.718 (−0.333)
0.478 (−0.258)
Cβ
Cβ
−0.339 (−0.093)
Bond Order (Interatomic Distance/pm)
1.390 (127.2)
Bond
CK–O
Cα –Cβ
CK–Cα
CK–Cβ
O–Cα
O–Cβ
Bond Order (Interatomic Distance/pm)
1.533 (125.3)
Bond
CK–O
Cα –Cβ
CK–Cα
CK–Cβ
O–Cα
O–Cβ
1.415 (137.8)
0.218 (235.6)
0.019 (306.5)
0.050 (303.4)
1.658 (135.6)
0.016 (274.2)
0.116 (249.1)
0.000 (372.6)
0.001 (321.5)
0.020 (304.5)
1) The carbon, CK, was originally derived from ketyl radical center.

H. Itoh et al.
Bull. Chem. Soc. Jpn., 74, No. 2 (2001) 345
of both the reaction efficiency and the product ratio (5/6).
References
–
•
•
7
and 8 , both the cyclizations were derived substantially
–
•
from the 2-centered interaction. In case of 1 , though 6-en-
docyclization was derived from the same 2-centered interac-
tion as in the case of 7 and 8 , 5-exocyclization was initially
–
•
•
1
T. Shono and Y. Matsumura, “Electron transfer processes in
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rigidity. Preference in the entropy term of 6-endocyclization of
•
1
– was evidenced by the experimental result (∆∆S‡
;
(5-exo – 6-endo)
–11 cal mol–1 K–1).
Effect of the Additives on the Regioselectivity. Finally,
2
3
J. E. Baldwin, J. Chem. Soc., Chem. Comm., 1976, 734.
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ethanol, and 2-propanol on the regioselectivity of the electroly-
sis. On increasing the concentration of water from 0 to 1000
mM (1 M = 1 mol dm–3), the ratio of 5 to 6 increased from 0.86
to 5.2 (Table 1, entries 2b, 3a–3d). Particularly, increasing the
solvent polarity of alcohol (entries 4, 5, and 6) enhanced not
only the conversion of 1 but also the regioselectivity of 5. The
fact that the addition of proton source caused the enhancement
of both the reaction efficiency and the product ratio (5/6) must
Perkin Trans. 2, 1981, 90.
4
J.-I. Ishiyama, Y. Senda, and S. Imaizumi, Chem. Lett.,
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5
(1977).
6
C. A. Grob and H. Katayama, Helv. Chim. Acta, 60, 1890
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7
(1978).
8
T. Momose and O. Muraoka, Chem. Pharm. Bull., 26, 288
be attributed to stabilizing the electrostatic repulsion in 5 – for-
•
mation further than that in 6 – formation.
J. P. Schaefer, J. C. Lark, C. A. Flegal, and L. M. Honig, J.
•
Org. Chem., 32, 1372 (1967).
M. Eakin, J. Martin, and W. Parker, J. Chem. Soc., Chem.
9
Conclusion
Comm., 1965, 206.
Contrary to the non-mediated electroreduction of the acyclic
6-hepten-2-one which gave only the δ,ε-unsaturated alcohol,
the corresponding reaction of the bicyclic 1 showed competi-
tive transannular reaction. The intramolecular through-space
interaction in the LUMO of 1 is responsible for the occurrence
of the reactivity even in the non-mediated reduction. The ap-
pearance of 6-endocyclization is ascribed to the unavoidable
electrostatic repulsion between the eclipsed methylene
terminal carbon and the oxygen atom in the 5-exocyclization.
The differences in parameters of activation between the 5-exo-
10 C. J. Pouchert and J. R. Campbell, “The Aldrich Library of
NMR Spectra,” Aldrich Chemical Co., Inc. (1974), 1, p.120 C.
11 C. J. Pouchert, “The Aldrich Library of Infrared Spectra,”
Aldrich Chemical Co., Inc. (1970), p. 86 F.
12 Molecular orbital calculations were carried out by using a
program of “CAChe MOPAC ver. 94” for power Machintosh with
the permission by SONY Tektronix.
13 J. J. P. Stewart, J. Comput. Chem., 10, 209 (1989).
14 For the UHF calculation, see especially Chap. 9 of “Bunshi-
kidoho MOPAC guide book (2nd ed),” ed by T. Hirano and K.
Tanabe, Kaibundo Shuppan, Tokyo (1994).
15 J. E. Swartz, E. Kariv-Miller, and S. J. Harrold, J. Am.
Chem. Soc., 111, 1211 (1989); F. Lombardo, R. A. Newmark, and
E. Kariv-Miller, J. Org. Chem., 56, 2422 (1991).
–
and 6-endocyclizations of 1 , ∆∆H‡
and
•
(5-exo – 6-endo)
∆∆S‡(5-exo – 6-endo), were experimentally evaluated to be –3.1
kcal mol–1 and –11 cal mol–1 K–1, respectively. Semiempirical
PM3 calculation also supported the proposed reaction mecha-
nism. The addition of a proton source caused the enhancement
16 A. M. Mueller and P. Chen, J. Org. Chem., 63, 4581 (1998).