cis-syn-cis-1,2,4,5-Tetracyclohexylcyclohexane. a Moderately Crowded Saturated Hydrocarbon Adopting a Twist-Boat Conformation

Full text of DOI:10.1021/jo990453q

J . Org. Chem. 1999, 64, 6505-6507
6505
cis-syn -cis-1,2,4,5-Tetr a cycloh exylcyclo-
Sch em e 1
h exa n e. A Mod er a tely Cr ow d ed Sa tu r a ted
Hyd r oca r bon Ad op tin g a Tw ist-Boa t
Con for m a tion
Oren Golan, Shmuel Cohen, and Silvio E. Biali*
Department of Organic Chemistry, The Hebrew University of
J erusalem J erusalem 91904, Israel
Received March 12, 1999
A cyclohexane ring usually prefers the chair (1) over
the twist-boat (TB, 2) conformation when present in
unconstrained saturated hydrocarbons.1 Bulky substit-
uents (e.g., tert-butyl groups) can modify the chair/TB
energy gap, and in some substitution patterns they may
formed with the MM3(92) program7 together with the
HUNTER conformational search procedure (Table 1). As
8
,2
indicated by the calculations, the cis,syn,cis form is
predicted to adopt a TB conformation. The unusually
large stability of the TB form relative to the chair form
even render the TB the preferred conformation by
-
1
preferentially destabilizing the chair form.1-4 A compu-
(7.1 kcal mol ) is most likely the result of unavoidable
,3-diaxial interactions in the chair form. These interac-
1
tational study predicted that four isopropyls or just two
isopropyls and two methyls attached to a cyclohexyl ring
in a cis,trans,trans-1,2,3,4 or cis,syn,cis-1,2,4,5 pattern
tions cannot be alleviated by ring inversion, because the
process relocates the pair of equatorial substituents into
axial positions (Scheme 2). The TB/chair energy gaps are
similar to those previously calculated for the correspond-
are sufficient for rendering the TB the preferred confor-
mation.4 This change in the normal conformational
4
ing 1,2,4,5-tetraisopropylcyclohexanes. This is reason-
preferences is due to the selective destabilization of the
chair conformation. A system with the first substitution
pattern (cis,trans,trans-1,2,3,4-tetracyclohexylcyclohex-
ane) was shown by X-ray crystallography to adopt a TB
able because isopropyl and cyclohexyl groups are nearly
isosteric near their attachment point.9 In all of the
configurational isomers of 3 calculated, in the lowest
energy conformation the peripheral cyclohexyl rings were
found to adopt a chair conformation and to be connected
to the central rings through their equatorial positions.
5
conformation. In this note we demonstrate experimen-
tally that a system with the cis,syn,cis-1,2,4,5 pattern
prefers the TB conformation.
Catalytic hydrogenation of 1,2,4,5-tetraphenylben-
zene10 (4) at 250 °C (Pd/C, 660 psi H
) afforded the trans,-
syn,trans and trans,anti,trans isomers of 3 (mp 221 and
40 °C), which were separated by fractional crystalliza-
2
2
tion. According to the calculations (Table 1), these
products correspond to the lowest energy isomers. X-ray
crystallography indicated that in both compounds all
1
1
rings adopt the chair conformation (Figures 1 and 2).
In the trans,syn,trans form the peripheral rings are all
located at equatorial positions of the central ring, whereas
in the trans,anti,trans form a pair of vicinal cyclohexyl
substituents are located at axial and a pair at equatorial
positions.
1
,2,4,5-Tetracyclohexylcyclohexane (3) exists in seven
trans,anti,trans-3 displays eight NMR signals in the
stereoisomeric forms (three meso forms and two enan-
tiomeric pairs, Scheme 1). Calculations of the TB/chair
gaps of 1,2,4,5-tetracyclohexylcyclohexanes were per-
1
3
6
C NMR spectrum (CDCl
temperature of a CD Cl solution, the signals broadened
and decoalesced. The barrier measured (∆G
3
, rt). Upon lowering of the
2
2
q
c
) 9.7 kcal
-
1
mol at 194 K) is ascribed to a ring inversion process of
the central ring that exchanges the axial with the
equatorial substituents (Scheme 3). This barrier is com-
(1) (a) Conformational Behavior of Six-Membered Rings; J uaristi,
E., Ed.; VCH Publishers: New York, 1995. (b) Eliel, E. L.; Wilen, S.
H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley: New
York, 1994.
q
(
2) For a review on nonchair conformations of cyclohexane see:
Kellie, G. M.; Riddell, F. G. Top. Stereochem. 1974, 8, 225.
3) A cyclohexane 1,4-cis-disubstituted by a quinone and a porphyrin
parable to the barrier of cyclohexane (∆G ) 10.2-10.5
(
moiety has been shown to adopt a twist-boat conformation, see: Dieks,
H.; Senge, M. O.; Kirste, B.; Kurreck, H. J . Org. Chem. 1997, 62, 8660.
(7) Allinger, N. L. MM3(92): Technical Utilization Corporation.
(8) Weiser, J .; Holthausen, M. C.; Fitjer, L. J . Comput. Chem. 1997,
18, 1264.
(4) Weiser, J .; Golan, O.; Fitjer, L.; Biali, S. E. J . Org. Chem. 1996,
6
1
1, 8277.
(9) For a comparison of the rotational barriers of tetraisopropyl-
ethene and tetacyclohexylethene see: Columbus, I.; Biali, S. E. J . Org.
Chem. 1994, 59, 3402.
(10) Harada, K.; Hart, H.; Du, C.-J . F. J . Org. Chem. 1985, 50, 5524.
(11) The authors have deposited atomic coordinates for the struc-
tures with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
U.K.
(5) Columbus, I.; Hoffman, R. E.; Biali, S. E. J . Am. Chem. Soc. 1996,
18, 6890.
(6) For simplicity, the configurational isomers of 3 will be described
by the method commonly used for fused-ring cyclohexanes. The mutual
disposition of two vicinal groups will be denoted as “cis” or “trans”. If
the two substituents at the 1 and 5 positions of the central ring are in
a mutual cis or trans relationship, this will be denoted by the “syn”
and “anti” descriptors, respectively.
1
0.1021/jo990453q CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/30/1999

6
506 J . Org. Chem., Vol. 64, No. 17, 1999
Notes
Ta ble 1. Ca lcu la ted Rela tive Ster ic En er gies a n d Hea ts
-
1
of F or m a tion (MM3, in k ca l m ol ) of 3
configuration chair(eq)a chair(ax)b
TBc
HFOd
trans,syn,trans
trans,anti,trans
cis,trans
cis,syn,cis
cis,anti,cis
0.0
0.0
nfe
9.8 (Ic,Ψa,Ic,Ψe)
4.8 (Ψe,Ψe,Ψe,Ψe) -110.95
3.3 (Ψe,Ic,Ψe,Ic)
0.0 (Ψe,Ic,Ψe,Ic)
2.2 (Ψe,Ψa,Ψa,Ψe) -101.15
-113.04
0.0
nf
-107.25
-101.84
7.1
0.0
a
Lowest energy conformation with all (or most) of the alkyl
b
groups in equatorial positions. Lowest energy conformation with
all (or most) of the alkyl groups in axial positions. c Lowest
calculated twist-boat conformation. Ic, Ψa, and Ψe denote that
the substituents are located at isoclinal, pseudoaxial, or pseu-
d
doequatorial positions of the central ring, respectively. Heat of
formation of the lowest energy conformation. No chair(ax) con-
e
formation was found.
F igu r e 2. Molecular structure of trans,anti,trans-3.
F igu r e 3. Numbering scheme of the crystal structure of cis,-
syn,cis-3. The central ring adopts a twist-boat conformation.
F igu r e 1. Crystal structure of trans,syn,trans-3.
Sch em e 2
kcal mol-1),1,12 indicating that the four cyclohexyl sub-
stituents in trans,anti,trans-3 do not markedly affect the
rigidity of the central ring.
According to heat of formation calculations, the cis,-
syn,cis isomer corresponds to a high energy form. To
avoid epimerization of the product, the hydrogenation of
Sch em e 3
4
was carried out at a relatively low temperature of 85
°
C (640 psi H ). Fractional crystallization of the product
2
afforded cis,syn,cis-3 together with 1,2,4,5-tetracyclo-
hexylbenzene (5). X-ray analysis of a single crystal of cis,-
syn,cis-311 corroborates the predictions of the calculations
and indicates that the central ring adopts a twist boat
3
conformation of approximately C
2
symmetry (Figure 3)
(for the TB form). The J values were calculated by the
Karplus equation (using Altona’s parameters)1 assuming
that the chair form undergoes fast chair inversion while
the TB form undergoes fast enantiomerization on the
NMR time scale (Scheme 4). The calculated J values
were 9.6 and 1.4 Hz for the chair form and 12.4 and 4.7
3
with the peripheral “chair” cyclohexyls located at isoclinal
and pseudoequatorial positions of the central ring. The
3
J coupling constants between the methylene and me-
3
thine protons of the central ring of the chair and TB
forms of cis,syn,cis-3 were estimated using the MM3
geometry (for the chair form) and the crystal coordinates
Hz for the TB. Analysis of the NMR spectrum of cis,syn,-
cis-3 (CDCl , rt, 600.132 MHz) indicated that these
3
(
12) For a recent determination of the inversion barrier of cyclo-
hexane see: O’Leary, B. M.; Grotzfeld, R. M.; Rebek, J ., J r. J . Am.
Chem. Soc. 1997, 119, 11701.
(13) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C.
Tetrahedron 1980, 36, 2783.

Notes
J . Org. Chem., Vol. 64, No. 17, 1999 6507
Sch em e 4
87.29; H, 12.71. Found: C, 87.00; H, 12.54. trans,anti,trans-3:
mp 221 °C; 13C NMR (CDCl
) δ 38.93 (C1), 37.01 (C1′), 31.97
3
(
C6′), 28.42 (C2′), 27.01 (C3′, C4′, or C5′), 26.94 (C3′, C4′, or C5′),
2
6.86 (C3′, C4′, or C5′), 22.92 (C2) ppm; MS m/z 412.4. Anal.
52: C, 87.29; H, 12.71. Found: C, 87.13; H, 12.44.
Calcd for C30
H
cis,syn ,cis-3. Compound 4 (0.15 g) dissolved in cyclohexane
(40 mL) was hydrogenated in a Parr pressure reactor (0.042 mg
2
Pd/C, 640 psi H , 85 °C). The full hydrogenation of 4 required
three hydrogenation cycles (22, 64, and 18 hs). After filtration
of the catalyst and evaporation of the solvent, the residue was
fractionally crystallized from CHCl
3
/EtOH affording cis,syn,cis-3
(
27%) and 1,2,4,5-tetracyclohexylbenzene (23%). cis,syn,cis-3:
1
3
mp 194 °C; H NMR (600.13 MHz, CDCl , rt) δ 1.80 (m, 4H,
H6′), 1.74 (m, 8H, H3′ + H4′ or H5), 1.67 (m, 4H, H4′ or H5′),
1
4
.58 (m, 4H, H2′), 1.54 (m, 2H, H2), 1.48 (m, 4H, H1), 1.41 (m,
H, H1′), 1.25 (m, 8H, H3′ + H4′ or H5′), 1.15 (m, 4H, H4′ or
1
3
H5′), 1.07 (m, 2H, H2), 1.02 (m, 8H, H6′ + H2′); C NMR (100.6
coupling constants are 13.0 ( 0.4 and 4.3 ( 0.4 Hz, in
agreement with the presence of a TB conformation in
solution.
MHz, CDCl
27.05 (C3′), 26.83 (C4′), 26.77 (C5′), 22.29 (C2) ppm; MS m/z
412.3. Anal. Calcd for C30 52: C, 87.29; H, 12.71. Found: C,
7.12; H, 12.71.
X-r a y Cr ysta llogr a p h y. Data were measured on an ENRAF-
3
, rt) δ 39.87 (C1), 38.13 (C1′), 33.02 (C2′), 29.77 (C6′),
H
8
In conclusion, we have shown experimentally that four
cyclohexyl groups in a cis,syn,cis-1,2,4,5 pattern render
the TB the lowest energy conformation of the central ring.
Nonius CAD-4 or PW1100/20 Philips four-circle computer-
controlled diffractometer. Cu KR (λ ) 1.541 78 Å) or Mo KR (λ
)
0.710 69 Å) radiation with a graphite crystal monochromator
in the incident beam was used. trans,syn,trans-3: space group
Exp er im en ta l Section
P 1h , a ) 10.098(1), b ) 15.157(1), c ) 9.672(3) Å, R ) 91.38(2)°,
Pd/C (5% Pd) was purchased from Aldrich. Different batches
of the catalyst showed different reactivity. Coupling constants
were determined from the active couplings in the cross-peaks
3
â ) 115.34(2)°, γ ) 81.76(1)°,V ) 1323.0(6) Å , z ) 2, Fcalc
)
-3
-1
1
4
0
1
4
.04 g cm , µ(Cu KR) ) 3.87 cm , no. of unique reflections )
862, no. of reflections with I g 3σ
I
) 4206, R ) 0.041, R )
w
1
4
of the COSY DQF spectrum.
.071. trans,anti,trans-3: space group P2/c, a ) 16.647(3), b )
tr a n s,syn ,tr a n s- a n d tr a n s,a n ti,tr a n s-3. Compound 410 (0.2
g) dissolved in cyclohexane (40 mL) and acetic acid (0.5 mL) was
hydrogenated using a Parr pressure reactor (0.21 g Pd/C, 650
3
0.172(2), c ) 16.868(3) Å, â ) 112.18(1)°, V ) 3644.6(8) Å , z )
-3
-1
, Fcalc ) 1.04 g cm , µ(Cu KR) ) 3.87 cm , no. of unique
reflections ) 5307, no. of reflections with I g 3σ
I
) 3248, R )
psi H
tion was performed (0.20 g Pd/C, 640 psi H
affording a mixture of trans,syn,trans-3 and trans,anti,trans-3
which were separated by fractional crystallization (CHCl
2
, 250 °C, 145 h). After work up, an additional hydrogena-
0
1
2
.045, R
w
) 0.065. cis,syn,cis-3: C30
H
52, space group P2 /n, a )
1
2
, 230 °C, 40 h),
6.336(3), b ) 16.057(2), c ) 10.388(1) Å, â ) 102.69(2)°,V )
3
-3
-1
658.3(7) Å , z ) 4, Fcalc ) 1.03 g cm , µ(Mo KR) ) 0.53 cm
,
3
/
no. of unique reflections ) 4882, no. of reflections with I g 3σ
I
EtOH). The first fraction was trans,syn,trans-3 (35%), and the
second fraction afforded the trans-anti-trans isomer in 25% yield.
)
2895, R ) 0.042, R ) 0.053.
w
1
3
trans,syn,trans-3: mp 240 °C; C NMR (CDCl
7.72 (C1′), 32.03 (C6′), 27.50 (C5′), 27.12 (C3′), 27.06 (C4′), 26.87
C2), 26.25 (C2′) ppm; MS m/z 412.4. Anal. Calcd for C30H52: C,
3
) δ 44.05 (C1),
Ack n ow led gm en t. This work was supported by the
United States-Israel Binational Science Foundation
BSF). We thank Dr. Roy E. Hoffman for assistance with
3
(
(
the NMR experiments.
(14) Derome, A. E. Modern NMR Techniques for Chemistry Research;
Pergamon Press: Oxford, 1987; p 221.
J O990453Q