Stereoelectronic effects: Perlin effects in cyclohexane-derived compounds

Article abstract of DOI:10.1002/poc.4165

Stereoelectronic effects in cyclohexanones, methylenecyclohexanes, spiro, and epoxy compounds of cyclohexanes and further derivatives were investigated by measuring ¹J_C,H coupling constants and by identification of Perlin effects, th

Full text of DOI:10.1002/poc.4165

Received: 22 September 2020
DOI: 10.1002/poc.4165
Revised: 2 November 2020
Accepted: 5 November 2020
R E S E A R C H A R T I C L E
Stereoelectronic effects: Perlin effects in cyclohexane-
derived compounds
Sebastian T. Jung1
Burkhard Luy1,2
| Roman Nickisch1
| Joachim Podlech1
| Tony Reinsperger1,2
|
1Institute for Organic Chemistry,
Abstract
Karlsruher Institute of Technology (KIT),
Karlsruhe, Germany
Stereoelectronic effects in cyclohexanones, methylenecyclohexanes, spiro, and
2Institute for Biological Interfaces 4—
Magnetic Resonance, Karlsruher Institute
of Technology (KIT), Eggenstein-
Leopoldshafen, Germany
epoxy compounds of cyclohexanes and further derivatives were investigated by
1
measuring JC,H coupling constants and by identification of Perlin effects, that
is, of differences in the coupling constants for equatorial and axial C H bonds
in the methylene groups of six-membered rings. The Perlin effects were corre-
lated with results from natural bond orbital analyses. NMR experiments and
calculations were performed with conformationally restricted 4-tert-butyl-
substituted derivatives. It turned out that the coupling constants are strongly
influenced not only by stereoelectronic interactions with C C, C O, and
C N π bonds, or with the π-type C C or C O bonds of the three-membered
rings, but also by the s character of the respective C H bonds' carbon orbital.
Reliable correlations of measured and calculated coupling constants were
achieved with B3LYP/6-311++G(d,p) and BP86/aug-cc-pVTZ-J functionals.
Correspondence
Joachim Podlech, Institute for Organic
Chemistry, Karlsruher Institute of
Technology (KIT), Fritz-Haber-Weg
6, 76131 Karlsruhe, Germany.
Email: joachim.podlech@kit.edu
Present address
Tony Reinsperger, Bruker BioSpin GmbH,
Silberstreifen 4, 76287 Rheinstetten,
Germany.
Funding information
K E Y W O R D S
HGF program BIFTM; Deutsche
Forschungsgemeinschaft, Grant/Award
Number: LU 835/13-1
coupling constants, cyclohexane derivatives, DFT calculations, NBO analysis, spiro compounds,
stereoelectronic effects
1 | INTRODUCTION
we realized that most of the desired data had not been
investigated or published, we decided to collect these in a
Stereoelectronic effects have a significant influence on
the stability, structure, and reactivity of chemical com-
pounds and on their physical and spectroscopic proper-
ties.[1] A profound knowledge of these effects allows for a
better understanding and prediction of these features. In
the course of our research in the field of stereoelectronic
effects, especially of those in sulfur compounds,[2] we
recently investigated thianes and oxidized substrates
thereof.[3] Here, we considered it useful to compare the
then obtained data with those of cyclohexanones and of
further cyclohexane derivatives. Nevertheless, because
discrete project.
It has already been mentioned by Perlin and Casu
that those equatorial hydrogens in tetrahydropyranes
(actually in carbohydrates), which are next to the ring
1
oxygen, show a larger JC,H coupling than the respective
axial hydrogens.[4] This effect, which was later called the
normal Perlin effect, can be traced back to an
nO ! σ*C,Hax interaction weakening the axial C H
bond.[5] A so-called reversed Perlin effect has later been
observed in 1,3-dithianes. At position C-2 (between the
1
two sulfur atoms), the JC,Hax coupling is larger than the
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
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© 2020 The Authors. Journal of Physical Organic Chemistry published by John Wiley & Sons Ltd
J Phys Org Chem. 2020;e4165.
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https://doi.org/10.1002/poc.4165

2 of 15
JUNG ET AL.
1JC,Heq coupling. This was explained by the rather poor
donor ability of the lone pairs at the sulfur atoms; the
stereoelectronic effects of these are overcompensated by
strong σC,S ! σ*C,Heq and σC,Heq ! σ*S,C inter-
actions.[2c,6] Stereoelectronic interactions in cyclohexa-
nones[7] and the resultant Perlin effects[8] have intensely
been studied, because these seem to have a significant
influence on the stereoselectivity of cyclohexanone reac-
tions, especially in nucleophilic attacks to the carbonyl
group.[9] Experimental investigations of these effects are
preferentially performed with conformationally con-
strained substrates to unambiguously differentiate the
two faces of the carbonyl group. 4-tert-Butyl-substituted
cyclohexanones are mostly used in this context, because
this bulky substituent prefers an equatorial position and
thus leads to an unambiguous fixation of the conforma-
tion.[10] On the other hand, it is located far enough from
the reaction center and has no significant influence on
the stereochemistry of the investigated reactions nor on
the bond properties of bonds around the carbonyl group.
It has been argued for nucleophilic attacks in cyclo-
hexanones that the axial hydrogen atoms at positions C-2
CHART 1 Investigated derivatives of cyclohexane
decreased bond order should result in smaller coupling
constants.[13]
Herein we report on the synthesis of cyclohexane
derivatives 1–9 (Chart 1), on the determination of JC,H
coupling constants in these compounds, and on their cor-
relation with stereoelectronic effects, calculated by quan-
tum chemical methods. We used conformationally
constrained 4-tert-butyl-substituted substrates in all spec-
troscopic investigations to allow for the unambiguous dif-
ferentiation of the axial and the equatorial hydrogen
atoms. These substituted molecules were similarly used
for the quantum chemical calculations.
1
and C-6 interact with the C O bond in a σC,Hax ! πC
O
interaction, which leads to a weakening of the axial C H
bonds and of the π bond (double bond/no bond
resonance,[1a,11] Figure 1a), to a rehybridization of the
carbonyl's carbon atom (to facilitate and increase this
interaction), and thus to a pyramidalization (Figure 1b).
The augmented lobe of the carbon's p orbital leads to a
preferred attack of a nucleophile from the top face of the
molecule, at least for small nucleophiles, which are not
hindered by the axial hydrogen atoms at carbons C-3 and
C-5.[9] Nevertheless, alternative explanations have been
given for the observed selectivities.[12]
2 | SYNTHESIS OF
CYCLOHEXANE-DERIVED
COMPOUNDS
Oxime 4[14] and an analogous hydrazone were synthe-
sized with standard protocols starting with commercially
available 4-tert-butylcyclohexanone (1). Reaction of 1 with
hydrazine hydrate did not furnish the expected simple
The σC,Hax ! πC
interaction or double bond/no
cyclohexylidenehydrazone
but
a
O
bond resonance reduces the bond order of the respective
axial C H bonds and can thus not only be quantified
by quantum chemical methods but can further be esti-
1,2-dicyclohexylidenehydrazine 5,[15] which we consid-
ered similarly suitable for the intended investigations
(Scheme 1).
1
mated by measuring the JC,H coupling constants. A
Wittig olefination[16] of cyclohexanone 1 yielded
methylenecyclohexane
2
with 46% yield, and
dichloromethylenation[17] as the first step of a Corey–
Fuchs reaction gave access to a dichloroalkene 3 (96%).
FIGURE 1 (a) Double bond/no bond resonance in
cyclohexanones and (b) σC,Hax ! πC O interaction leads to
rehybridization and pyramidalization of the carbonyl carbon.
Nucleophilic attack from the top is preferred for small nucleophiles
SCHEME 1 Synthesis of oxime 4 and hydrazone 5.
Conditions: (a) H2NOHꢀHCl, NaOH, grinding, rt, 50 min (27%
[89%–96%[14]]) and (b) H2NNH2ꢀH2O, MeOH, 0ꢁC ! 60ꢁC,
1 h (38%)

JUNG ET AL.
3 of 15
1
These alkenes could be reacted with in situ-generated
dichlorocarbene[18] to yield the respective spiro com-
pounds 7 and 10. A comparison of measured and calcu-
lated spectra suggested that the major isomer of dichloro
compound 10 should bear the chlorinated carbon in
pseudo-axial orientation. However, reduction of 10 with
lithium in liquid ammonia[19] led to the parent substrate
6, whose isolation turned out to be quite tedious. Its vola-
tility prevented an immediate isolation. It was thus puri-
fied by preparative thin-layer chromatography (TLC)
with pentane as mobile phase. Deuterated chloroform
(CDCl3) was used as eluent and residual pentane was
removed as azeotrope with CDCl3 to yield the product as
a solution suitable for NMR spectroscopic investigations
(Scheme 2).
A practical synthesis of epoxides 8 and 9 has already
been described by Franssen and coworkers.[20] Although
the preparation of these compounds is either achieved
starting with cyclohexanone 1 using a Corey–Chaykovsky
reaction or by epoxidation of alkene 2 with meta-
chloroperbenzoic acid (mcpba), their separation had
turned out to be not possible with conventional
methods. It has therefore been proposed to react the
3 | DETERMINATION OF JC,H
COUPLING CONSTANTS
1JC,H coupling constants of the cyclohexane-derived com-
pounds 1–9 were determined; the experimental data are
here ordered in two sets for the compounds 1–5 con-
taining double bonds (Figure 2, left section) and for the
1
spiro compounds 6–9 (right section). JC,H coupling con-
stants are given as green data points with error bars for
every distinguishable C H bond of the six-membered
rings. Perlin effects for methylene groups are given as
vertical blue bars, where the upward bars indicate nor-
mal Perlin effects (1JC,Heq–1JC,Hax > 0). Reversed Perlin
effect (1JC,Heq–1JC,Hax < 0) were not observed for these
compounds. Numeric values for all measured coupling
constants and Perlin effects are given in the supporting
information. Oxime 4 and hydrazone 5 show different
values for carbon atoms C-2 and C-6 and for C-3 and C-5,
respectively, because the lifetime of the C N bonds' con-
figurations is longer than the NMR time scale. Hydrazone
5 is present as a ꢂ1:1 mixture of two rotamers, which
showed slightly differing 13C shift and coupling con-
stants. The small shift differences and the close to 1:1
mixture prevented an assignment of the signals to the
respective rotamer. Consequently, we give average values
for the coupling constants in the figure, where the respec-
tive measured values are specified in the supporting
information.
mixture of epoxides with
a
bromide source
(bromodimethylsulfonium bromide[21]) to obtain the
respective bromohydrins 11 and 12 again as a mixture of
isomers. These isomers could now be separated and
reacted with sodium hydroxide as base to obtain epoxides
8 and 9 in isomerically pure form. Starting with cyclohex-
anone 1, we obtained epoxides 8 and 9 over three steps in
total yields of 6% and 9%, respectively (Scheme 3).
Significant (normal) Perlin effects are observed for
the α positions of the cyclohexanone derivatives 1–5, that
is, the 1J coupling constants of equatorial C H bonds are
SCHEME 2 Synthesis of alkenes 2 and
3 and of spiro compounds 6 and 7. Condition:
(a) CCl4, PPh3, MeCN, 0ꢁC ! rt, 75 min (96%);
(b) CHCl3, NaOH, cat. Me(CH2)15NMe3Br, H2O,
rt, 21 h (7: 35%; 10: 57%); (c) Ph3PMeBr, BuLi,
Et2O, rt, 35 min (46%); and (d) Li, NH3 (l) (6 is
obtained as solution in CDCl3)
SCHEME 3 Synthesis of epoxides 8 and 9.
Conditions: (a) Me3SI, KOtBu, DMSO, rt, 21 h;
(b) BrSMe2Br; MeCN, rt, 20 min; separation of
isomers (11: 8%, two steps [9%[20]]; 12: 10%
[13%[20]]); and (c) NaOH, H2O/iPrOH, rt, 1 h (8:
6%, three steps [7%[20]]; 9: 9%, three
steps [10%[20]])

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JUNG ET AL.
FIGURE 2 Experimental 1JC,H coupling constants of cyclohexane derivatives 1–9 (green data points with error bars; left scale) and
Perlin effects (1JC,Heq–1JC,Hax; blue bars; right scale)
larger than those of the axial bonds. For none of the car-
bons, a reversed Perlin effect was observed as has, for
example, been noted for thianes,[3] 1,3-dithianes,[6d,e] and
related compounds.[6e] The most pronounced Perlin
effects were measured for cyclohexanone 1 and for the
condensation products 4 and 5, whereas they are signifi-
cantly smaller in alkenes 2 and 3. Different coupling con-
stants are observed for both α (and β) positions in the
non-symmetric compounds 4 and 5. The lone pairs at the
nitrogen atoms as well as the N O and N N bonds obvi-
ously have a significant influence, which is discussed in
the next section. Perlin effects are somewhat smaller at
the α positions of spiro compounds 6–9, especially in spir-
ooctane 6. Perlin effects at the β positions are smaller
than those at the α positions and are quite similar for all
investigated compounds 1–9. Homoanomeric effects, as
have been proposed by Alabugin et al., seem to play a
negligible role in these substrates.[22] This is quite obvi-
ous especially for compounds 6–9 considering that the
endocyclic lone pairs in the three-membered rings are
depleted of p character and are hence relatively weak
donors.[23]
4 | NBO ANALYSES OF
CYCLOHEXANONE AND
METHYLENECYCLOHEXANE
DERIVATIVES 1–5
A commonly used tool for the quantification of stereo-
electronic interactions is the natural bond orbital (NBO)
method developed by Weinhold and coworkers,[24] where
the canonical delocalized Hartree–Fock molecular
orbitals (MOs) are transformed into localized hybrid
orbitals (NBOs). The interactions between filled and anti-
bonding or Rydberg orbitals quantify the energetic contri-
bution of a distinct stereoelectronic effect. The orbital
overlap (Fij) as given in the standard NBO output and the
energy difference (ΔE) are the basis for the E(2) resonance
energies, in which neither competing resonance interac-
tions nor changes of the dipole moment are considered.
More meaningful values are obtained by deletion of the
corresponding off-diagonal elements of the Fock matrix
in the NBO basis. It has already been noted by
Alabugin,[6e] by Juaristi,[6f] and by us[3] that there is no
simple and evident correlation between resonance

JUNG ET AL.
5 of 15
energies obtained from NBO analyses and coupling con-
stants. Contreras et al. investigated the influence of
stereoelectronic effects on coupling constants[25] to get
deeper insight into the theoretical interrelation. They
were able to explain both the missing of correlations and
some of the observed trends. They split Fermi contact
interactions (which is the dominant coupling mecha-
nism) into orbital contributions of occupied and unoccu-
pied localized MOs (LMOs). They thus obtained
contributions to the coupling constant of a C H bond,
which are due to the respective σ orbital (Jb, with b:
bond), due to the respective σ* orbital (Jab; ab: antibond),
or due to further bonds at the coupling atoms (Job; ob:
other bond). Contreras and coworkers could take advan-
tage of well-chosen model compounds, in which the
“other bonds” are symmetry equivalent. The influence of
“other bonds” is plausible: when the s character in an
“other bond's” hybrid orbital is altered by resonance, this
must have an immediate effect on the hybridization of
the respective atom's other bonds—there is a total of only
one 2s orbital for every carbon. As the s character is sig-
nificant for the Fermi contact, this must have an influ-
ence on the coupling constants. The subtle interplay of
hybridization and hyperconjugation has similarly been
reported in other systems and is of relevance, for exam-
ple, in the blue-shifting hydrogen bonding.[26]
that in alkene 2, (C1 C2 in 1: 152 pm, 2: 151 pm) due to
an nO ! σ*C1,C2 interaction. However, the σC2,Hax ! π*
interaction is still stronger in ketone 1, because the
expanded orbital lobe at carbon C1 of the polarized π*
orbital allows for a better overlap (Figure 3a). Conse-
quently, the E(2) energy for the σC2,Hax ! π* interaction
is calculated to be higher for ketone 1 than for alkene 2.
An inverted trend for the Edel energies can be explained
with the higher dipole moment of the ketone. This dipole
would be further increased by transfer of electron density
into π* (Figure 3b). Without competing influence of
1
“other bond's” resonances, the JC2,Hax coupling constant
in alkene 2 could be expected to be smaller than that of
ketone 1. Nevertheless, the nO ! σ*C1,C2 interaction in
1 leads to an increased s character of the C C bond and
thus to a reduced s character of the adjacent C H bonds,
ultimately reducing the coupling. The smaller Perlin
effect in the α positions of alkene 2 cannot be explained
with a resonance interaction of the axial C H bond but
has its origin mainly in that of the equatorial C H bonds.
The σC2,Heq ! σ*C1,C6 interaction in ketone 1 competes
with an nO ! σ*C1,C6 interaction (Figure 3c) and is thus
smaller than that in alkene 2. Consequently, the equato-
rial C2 H bond in ketone 1 is stronger and a larger cou-
pling constant (133.6 Hz as compared with 129.4 Hz in 2)
and thus a stronger Perlin effect is observed.
We performed quantum chemical investigations with
tert-butyl-substituted substrates 1–9, but Martínez-
Mayorga et al. have already performed similar
calculations (calculation of coupling constants and NBO
analyses) with the parent cyclohexanone and
methylenecyclohexane.[6f] In full agreement with the
experimental data obtained by us, they observed a larger
Perlin effect for cyclohexanone. They argued that π* of
the carbonyl group is a better acceptor as compared with
that of the C C bond in methylenecyclohexane. Never-
theless, this was in dissent with the resonance energies
(Edel) they obtained from NBO analyses; here, the
σC2,Hax ! π* interaction in methylenecyclohexane turned
out to be more pronounced. They assumed the C1 C2
bond of the alkene to be shorter than that of cyclohexa-
none, which would lead to an increased overlap. Actu-
ally, the C1 C2 bond of ketone 1 is slightly longer than
The coupling constants in the α positions of
dichloroalkene 3 are larger than those of alkene 2. Both
the σ* and the π* orbital turned out to be poor acceptors
in the interaction with the σC2,Hax orbitals because both
bonds are significantly involved in interactions with lone
pairs at the chlorine atoms. Surprisingly, the
σC2,Heq ! σ*C1,C6 is similarly poor (4.7 kcal/mol) in the
chlorinated compound 3 and in the parent compound
2 (5.6 kcal/mol). Significant differences are observed for
the C1 C6 bonds of alkenes 2 and 3 (Table 1). In
dichloroalkene 3, this bond is antiperiplanar to a C Cl
bond, which acts as acceptor in a stereoelectronic interac-
tion and furthermore is inductively electron-withdrawing.
This polarizes the C1 C6 bond, where the occupied σ
orbital has a larger coefficient at C1 and the σ* orbital has
as larger coefficient at C6. The latter is distal of the C2,Heq
bond; a significant overlap is thus not possible. The
FIGURE 3 (a) Polarization in the C O bond leads to orbital lobes of different sizes; (b) the σC2,Hax ! π* interaction would lead to an
increased dipole moment; and (c) the donor ability of the equatorial σCH orbital competes with that of the nO orbital

6 of 15
JUNG ET AL.
TABLE 1 Structural differences in
the C1 C2 bonds of alkene 2 and
dichloroalkene 3
C1
C2
Occupation
Coefficients σ/σ*
%s
Coefficients σ/σ*
%s
σ
σ*
49.6/50.4
30.5
50.4/49.6
29.1
1.973
0.029
51.4/48.7
31.0
48.7/51.4
27.1
1.960
0.026
polarization furthermore reduces the s character at C2, pro-
viding a larger share of the s orbital for the C H bonds.
Oxime 4 and hydrazone 5 show significant differences
of the coupling constants in both branches of the six-
membered rings (i.e., C2 vs. C6 and C3 vs. C5). This and
the deviating data for the two rotamers of hydrazone
5 suggest a strong dependence of the coupling constants
on the respective configuration and on subtle conforma-
tional changes. This is further supported by somewhat
more pronounced differences between measured and cal-
culated coupling constants in comparison with those of
the other investigated compounds. Nevertheless, the
trends in the data are consistent. As for cyclohexanone 1,
the Perlin effects at the α positions are distinct, albeit
with significant differences for the syn and anti positions
with regard to the double bond's configurations. This
again emphasizes the importance of the molecules'
dipoles and of additional resonances with participation of
seemingly innocent, adjacent bonds. CH2 groups in posi-
tions C6 (anti to the heteroatom) show stronger Perlin
effects than those at positions C2, especially for oxime 4.
Whereas a π ! σ*C,Hax interaction is dominant for posi-
tions C6, it is the inverted σC,Hax ! π* interaction that is
more pronounced for positions C2 (Figure 4a). Both
interactions lead to a reduced total dipole moment. Nev-
ertheless, the local dipole in the vicinity of the double-
bonded nitrogen atoms is higher in hydrazone 5 than in
oxime 4, because the oxygen's lone pair in the oxime
gives rise to an antagonistic local dipole moment
(Figure 4b). This has an influence on the donor and on
the acceptor abilities of the C C bonds. As a conse-
quence of the dipole moments, the C1 C6 bond in
hydrazone 5 is a better donor in the interaction with the
antiperiplanar C2 Heq bond and a worse acceptor than
the opposed C1 C2 bond. A reversed effect is operative
in oxime 4, because the donor ability of the C1 C6 bond
is reduced by a σC1,C6 ! σ*N,O interaction (Figure 4c).
FIGURE 4 (a) In hydrazone 5, the dipole moment controls
whether a C H bond is predominantly a donor or an acceptor;
(b) bond dipole moments compensate each other in oxime 4; and
(c) the acceptor ability of the N O bond in oxime 4 competes with
that of the C2 Heq bond
The stereoelectronic interactions between the π bonds
in cyclohexane derivatives 1–5 and the axial C H bonds
at the adjacent carbon atoms (C2 and C6) are summa-
rized in Table 2. Both the π ! σ*C,Hax and the converse
σC,Hax ! π* interactions would reduce the bond order of
the respective C Hax bond. Interaction with the π bond
as donor (left column) is somewhat less pronounced in
ketone 1 and in alkenes 2 and 3 than the respective inter-
actions with the π bond as acceptor (right column). An
inverted (or at least slightly less pronounced) effect is
observed for oxime 4 and for hydrazone 5. The somewhat
higher donor ability of the C N π bond in the latter com-
pounds is possibly due to an effect caused by the neigh-
boring O and N atoms, respectively. This effect, which
could be related to the α effect,[27] is stronger in oxime
4 than in hydrazone 5, possibly due to the fact that the

JUNG ET AL.
7 of 15
TABLE 2 Stereoelectronic
interactions of the π bonds in
cyclohexane derivatives 1–5, 13, and 14
Compound
X
π ! σ*C,Hax (kcal/mol)
σC,Hax ! π* (kcal/mol)
1
O
5.1
6.1
2
CH2
5.8
7.5
3
CCl2
NOH
NN CR2
NCH3
NNH2
5.3
6.8
4
5.9a, 7.6b
5.1a, 6.4b
5.4a, 6.4b
6.1a, 7.4b
6.0a, 4.6b
6.0a, 5.0b
6.6a, 5.8b
5.9a, 5.0b
5
13c
14c
aC2 Hax (syn to the substituent at the N atom).
bC6 Hax (anti to the substituent at the N atom).
cStereoelectronic interactions in imine 13 and hydrazone 14 were calculated for comparison.
neighboring nitrogen in 5 is part of a further π bond. We
checked this by calculating these stereoelectronic interac-
tions in two reference compounds 13 and 14, in which
either no α-like effect is possible (in imine 13) or the
nitrogen causing this effect is no longer part of a double
bond (in hydrazone 14). It turned out that oxime 4 and
the simple hydrazone 14 similarly show strong
π ! σ*C,Hax interactions; a clear α-like effect can here be
assumed. This interaction is significantly smaller in
hydrazone 5 and in imine 13, most likely due to a smaller
or even non-existing α-like effect.
in which the bonds are constructed from sp2 and p
orbitals,[28] and the model from Coulson and Moffitt,
who suggested bent bonds built from hybrid orbitals.[29]
The similarities of cyclopropanes and ethene and of
oxiranes and carbonyl compounds have been emphasized
repeatedly.[28–30] The features of both models are given in
Table 3 for cyclopropane and for ethene.
In this analogy, it is not astonishing that both the sol-
volysis of allylic compounds and of cyclopropylmethyl
substrates proceed with remarkably high reaction
rates.[31] The intermediate carbocations are stabilized by
delocalization of the positive charge into the neighboring
π
system.[32] In that way, the delocalization of
5 | NBO ANALYSES OF SPIRO
COMPOUNDS 6–9
carbanionic[33] or radical centers[34] into C C double
bonds leads to a stabilization of the respective allyl
anions and radicals. However, cyclopropylmethyl radicals
are not similarly stabilized. The bond dissociation energy
of the respective C H bond in methylcyclopropane
Two models for the description of the bonding in three-
membered rings are well established: the Walsh model,
TABLE 3 Orbital models in
cyclopropane and ethene
Model (orbitals)
Cyclopropane
Ethene
Bond types
Walsh (sp2 + p)
σ + π
Coulson–Moffitt (2 × sp5)
τ

8 of 15
JUNG ET AL.
FIGURE 5 Stabilization of
reactive intermediates relative
to the respective methyl species
[B3LYP/6-311++G(d,p)]
(412 kJ/mol) is only slightly lower than that of the Et H
bond (420 kJ/mol).[35] Likewise, the stabilization of
carbanionic centers by a cyclopropyl group is much
smaller than that in an allyl anion.[36] To quantify these
findings, we calculated the energies of cations, anions,
and radicals of propene, methylcyclopropane, and iso-
butene. We chose the methyl cation, its anion, and its
radical as references for all calculations (Figure 5).
Conformations of the cyclopropylmethyl species were
chosen for these calculations, in which the empty or sin-
gly occupied p orbital, or the lone pair, are in bisectic
orientations.
Whereas the cyclopropylmethyl cation is even better
stabilized than the allyl cation, the stabilization of the
respective cyclopropylmethyl radical is significantly less
pronounced than that in the allyl radical. Hardly any sta-
bilization is observed for the cyclopropylmethyl anion.
Obviously, the cyclopropyl group is a good donor in a
positive hyperconjugation, whereas it is a poor acceptor
in a negative hyperconjugation. Inspection of the MOs
makes this behavior understandable. Because the π
system of methylcyclopropane contains two electrons
more than propene, the HOMO of the former needs to
have one nodal plane more than the latter. Actually, the
methylcyclopropyl cation's HOMO is isolobal to the allyl
anion's HOMO (and to the allyl cation's LUMO). Simi-
larly, the HOMO of the neutral methylcyclopropane is
isolobal to the LUMO+1 of propene (Table 4). Conse-
quently, in neutral hyperconjugation, the cyclopropyl
unit in 6 should be a worse acceptor than the double
bond in alkene 2. The NBO software considers a double
bond to be built from sp2 and p orbitals, whereas a cyclo-
propane is here constructed from sp5 hybrid orbitals. To
compare the acceptor quality of both systems, it is thus
essential to additionally consider the acceptor ability of
the double bond's σ* orbital. A comparison of the respec-
tive deletion energies (Edel) confirms this assumption: As
compared with a C C double bond, the cyclopropyl unit
is a poor acceptor and a better donor. The chlorinated
spiro compound 7 shows a stronger Perlin effect at C2
than the parent spirooctane 6. This can similarly be
traced back to the influence of bond polarizations, which
TABLE 4 π-Type orbitals in allyl and cyclopropylmethyl species
na
1
LUMO
HOMO
HOMO
HOMO
2
HOMO
HOMO
LUMO+1
aNumber of nodal planes in the π system.

JUNG ET AL.
9 of 15
has already been discussed for alkenes 2 and 3 (vide
supra).
6 | COMPARISON OF
EXPERIMENTAL AND
CALCULATED COUPLING
CONSTANTS
A comparison of the epoxides 8 and 9 with cyclohex-
anone 1 shows that the C O double bond of the latter is
a better acceptor and a better donor. The bond order of
the axial C H bonds in the epoxides is not notably
reduced, and the Perlin effect in these compounds is
smaller. The small differences in the coupling constants
and in the Perlin effects of 8 and 9 are most probably
due to dipole effects and to an nO ! σ*C2,Hax interaction
in epoxide 9.
We previously reported the investigation of Perlin effects
in conformationally constrained thiane-derived com-
pounds.[3] These were determined with the very same
methods as reported herein. Together with the data col-
lected in the now presented study of cyclohexanone
derivatives, we can provide a sufficiently large dataset to
TABLE 5 Correlation of calculated
and measured coupling constants
GIAO
Method
Correlation
Perlin effects (PE)
B3LYP/6-311+
+G(d,p)//
B3LYP/6-311+
+G(d,p)
GIAO
BP86/aug-cc-
pVTZ-J//
B3LYP/6-311+
+G(d,p)
GIAO
CPCM-
B3LYP/6-311+
+G(d,p)//
CPCM-
B3LYP/6-311+
+G(d,p)
GIAO
CPCM-BP86/
aug-cc-pVTZ-
J//
CPCM-
B3LYP/6-311+
+G(d,p)

10 of 15
JUNG ET AL.
compare experimental and calculated values. For the sta-
tistic evaluation, compounds with a certain degree of
flexibility such as hydrazone 5 and oxime 4 as well as
thiane derivatives with N-tosylsulfilimine (S NTs) func-
tionalities were omitted. A chart depicting all compounds
used for this survey is given in the supporting informa-
interactions and allowed to rationalize the observed
coupling constants. Calculation of NBO deletion ener-
gies turned out to be significantly more meaningful
than a simple consideration of E(2) energies, when
competing interactions are operative in the investigated
compounds. The interplay of delocalization and dipole
effects is especially obvious in oxime 4 and hydrazone
5. The investigation of spiro compounds revealed the
influence of additional π-type electrons: donor abilities
are preserved, whereas acceptor abilities are signifi-
cantly reduced. A comparison of experimental and cal-
culated coupling constants proved that the B3LYP
functional in combination with Pople basis sets gives
an adequate correlation.
1
tion. J coupling constants of these compounds were cal-
culated on the B3LYP/6-311++G(d,p) level of theory. We
additionally optimized all structures using the CPCM sol-
vatization model in chloroform and again calculated the
coupling constants. In previous work, it seemed to be
common to calculate NMR parameters using dedicated
basis sets. Maximoff et al. identified the aug-cc-pVTZ-J
basis set with the BP86 functional to be superior to
B3LYP.[37] Consequently, we compared results obtained
with this basis set with those calculated with B3LYP-
optimized structures (with and without solvatization).
We used aug-cc-pVTZ-J for all first row elements,
whereas aug-cc-pVTZ was used for sulfur and chlorine.
We studied the correlation of calculated and experimen-
tal values as well as the deviation of calculated and
observed Perlin effects (Table 5).
Seemingly, the overall quality of the correlations is
very satisfactory. R2 values (0.97–0.98) and the mean
average errors (MAEs; 0.9–1.0) suggest a strong linear
correlation. It should be mentioned that we applied an
error weighting (using 1/S). It turned out that no signifi-
cant improvement is obvious with the BP86/aug-cc-
pVTZ-J functional. Astonishingly, a solvent correction
results in slightly increased errors and smaller coeffi-
cients of determination. A linear correction of calculated
coupling constants, as commonly used for chemical shift
calculations, seems reasonable, especially when future
experiments complement the database for correlation
studies.
8 | EXPERIMENTAL
8.1 | NMR spectroscopic investigations
1JC,H coupling constants of the cyclohexane-derived com-
pounds 1–9 were measured on a Bruker Avance III HD
500-MHz spectrometer using CLIP-HSQC experiments[38]
and analyzed using the TopSpin software package.[39]
CLIP-HSQC spectra result in clean in-phase doublets in
the directly detected dimension, so that accurate coupling
constants can be determined without further phase cor-
rection. Spectra were acquired using broadband BEBOP
excitation,[40] BIBOP inversion,[41] and BURBOP
refocusing pulses.[42] When a signal overlap obscured the
coupling constants, we used ω1-iINEPT experiments with
BIP inversion pulses during the BIRD-element[43] for
clarification.[44] Number of scans as well as acquisition
times and spectral widths were optimized for each com-
pound individually. In all cases, digital resolution in the
dimension with coupling evolution was below 0.1 Hz for
CLIP-HSQC experiments and below 1.0 Hz for the
ω1-iINEPT experiments. Due to highly symmetric multi-
plets and sufficient chemical shift difference of coupling
partners, second-order contributions could be neglected
in most cases. The individually estimated experimental
errors of the coupling constants were generally on the
order of the digital resolution, sometimes even below (see
Figure 2).
A deviating picture can be seen when Perlin effects
are studied. Slightly improved results are observed with
the more expensive method and the scattering is signifi-
cantly reduced when solvent correction is applied. If one
aims for a prediction of Perlin effects as precise as possi-
ble, the use of solvent correction seems to be mandatory.
However, the investigation of stereoelectronic effects
based on calculated coupling constants turned out to be
possible without the solvent correction.
7 | CONCLUSION
8.2 | Quantum chemical calculations
We investigated the influences of stereoelectronic inter-
actions on Perlin effects in conformationally con-
strained cyclohexanones and structurally related spiro
compounds. Careful analysis of NMR spectroscopic
data shed light on the crucial donor/acceptor
All structures were optimized at the B3LYP[45]/6-311+
+G(d,p)[46] level by using the Gaussian 09 software pack-
age.[47] Coupling constants were calculated with the
gauge-including atomic orbital (GIAO) method[48] either
at the same level or with the BP86[49]/aug-cc-pVTZ-J[50]

JUNG ET AL.
11 of 15
functional. Solvent was modeled with the CPCM-SCRF
method with chloroform as solvent.[51] The NBO 3.1 soft-
ware for NBO analyses[24] was used as implemented in
Gaussian 09.
cyclohexanone 1 (2.00 g, 13.0 mmol) in anhydrous Et2O
(ꢂ5 ml) was added slowly at rt and a colorless precipitate
formed. The mixture was stirred for 20 h and H2O
(ꢂ65 mL) was added. The organic layer was separated,
dried (Na2SO4), concentrated at reduced pressure, and
purified by column chromatography (silica gel, cyclohex-
ane/EtOAc, 100:1) to yield alkene 2 (912 mg, 5.99 mmol,
46%) as a yellowish oil. 1H NMR (500 MHz, CDCl3):
8.3 | Synthetic procedures: General
3
3
Compound 1 was purchased (Sigma-Aldrich). Et2O and
pentane were distilled from sodium benzophenone ketyl
radical prior to use, and CH2Cl2 was distilled from CaH2.
All moisture-sensitive reactions were carried out under
oxygen-free argon using oven-dried glassware and a vac-
uum line (Schlenk technique). Flash column chromatog-
raphy was carried out using Merck silica gel 60 (230–400
mesh), and TLC was carried out by using commercially
available Merck F254 pre-coated sheets. Pre-coated TLC
plates SIL G-200 (Macherey-Nagel) were used for prepar-
ative TLC. Spots were detected by fluorescence
quenching and staining in an iodine chamber. NMR
spectra were recorded on Bruker Avance AV 300 or
Bruker Avance III HD 500 spectrometers. 13C NMR spec-
tra were recorded with broad band decoupling, and sig-
nals were assigned by HSQC experiments. The spectra
were calibrated using the residual solvent signals. IR
spectra were recorded on a Bruker FT-IR spectrometer
“Alpha” using ATR on diamond. EI mass spectra were
recorded with a Finnigan MAT-95 and APCI spectra were
recorded with a Q Exactive Orbitrap (Thermo Fisher).
Melting points were measured with an Optimelt MPA100
apparatus and are not corrected.
δ = 0.85 (s, 9 H, tBu), 1.04 (dddd, 2J = J = J = 12.5 Hz,
3
3J = 3.4 Hz, 2 H, 2-Hax, 6-Hax), 1.14 (tt, J = 11.8 Hz,
2
3J = 2.6 Hz, 1 H, 1-H), 1.86 (br d, J = 11.8 Hz, 2 H,
2
3
2-Heq, 6-Heq), 1.98 (br dd, J = J = 12.9 Hz, 2 H, 3-Hax,
5-Hax), 2.33 (br d, 3J = 12.9 Hz, 2 H, 3-Heq, 5-Heq), 4.57 (t,
4J = 1.5 Hz, 2 H, CH2); 13C NMR (125 MHz, CDCl3):
δ = 27.8 [C (CH3)3], 29.1 (C-2, C-6), 32.6 [C (CH3)3], 35.5
(C-3, C-5), 48.0 (C-1), 106.2 ( CH2), 150.5 (C-4). The
spectroscopic data are in full agreement with those from
the literature.[52]
8.3.3 | 1-(tert-Butyl)-
4-(dichloromethylene)cyclohexane (3)
This compound was prepared in analogy to a published
protocol.[17] A flame-dried flask was equipped succes-
sively under argon with cyclohexanone 1 (770 mg,
5.00 mmol), PPh3 (5.24 g, 20.0 mmol), and MeCN
(10 ml). CCl4 (1.0 ml, 1.54 g, 10.0 mmol) was added at
0ꢁC and the mixture was stirred for 75 min at rt, by
which it turned yellow and then reddish-brown. Et2O
(25 ml) was added and the mixture was washed with
H2O (2 × 25 ml) and brine (2 × 40 ml). The organic layer
was dried (Na2SO4), concentrated at reduced pressure,
and purified by column chromatography (silica gel, cyclo-
hexane/EtOAc, 100:1) to yield dichloroalkene 3 (662 mg,
2.99 mmol, 96%) as a pale yellow solid. 1H NMR
(500 MHz, CDCl3): δ = 0.86 (s, 9 H, tBu), 1.08 (dddd,
8.3.1 | 4-(tert-Butyl)cyclohexanone (1)
1H NMR (500 MHz, CDCl3): δ = 0.91 (s, 9 H, tBu),
1.39–1.53 (m, 3 H, 3-Hax, 5-Hax, 4-H), 2.04–2.11 (m, 2 H,
2
3
3
3
3-Heq, 5-Heq), 2.39 (d, J = 14.1 Hz, 2 H, 2-H, 6-H), 2.31
2J = J = 12.4 Hz, J = 12.2 Hz, J = 3.9 Hz, 2 H, 2-Hax,
(ddd, 2J = 14.1, 3J = 13.5, 3J = 5.4 Hz, 2 H, 2-H, 6-H); 13
C
6-Hax), 1.16 (tt, J = 12.2 Hz, J = 2.4 Hz, 1 H, 1-Hax),
1.82–1.91 (m, 4 H, 2-Heq, 6-Heq, 3-Hax, 5-Hax), 2.94 (br d,
2J = 12.8 Hz, 2 H, 3-Heq, 5-Heq); 13C NMR (125 MHz,
CDCl3): δ 27.6 (C-2, C-6), 27.7 [C (CH3)3], 31.8 (C-3, C-5),
32.5 [C (CH3)3], 47.7 (C-1), 138.1 (CCl2), 153.7 (C-4); the
peak for CCl2 is given in the literature at δ = 110.8.[53]
3
3
NMR (125 MHz, CDCl3): δ = 27.8 [(CH3)3C, C-3, C-5],
32.6 [(CH3)3C], 41.5 (C-2, C-6), 46.9 (C-4).
8.3.2 | 1-(tert-Butyl)-
4-methylenecyclohexane (2)
This compound was prepared in analogy to a published
protocol.[16] BuLi (2.5 M in hexane, 5.8 ml, 14.4 mmol)
was added dropwise via a syringe to a solution of
Ph3PMeBr (5.14 g, 14.4 mmol) in anhydrous Et2O
(100 ml) placed in a dried flask equipped with a septum.
The mixture turned intensely yellow (ylide formation)
and was stirred for 35 min at rt. A solution of
8.3.4 | 4-(tert-Butyl)cyclohexanone
oxime (4)
This known compound was prepared according to a pub-
lished protocol.[14]
A
mixture of cyclohexanone
1 (500 mg, 3.24 mmol), H2NOHꢀHCl (270 mg, 3.89 mmol),
and NaOH (156 mg, 3.89 mmol) was finely grounded in a

12 of 15
JUNG ET AL.
mortar (10 min). Grinding was repeated every 4 min for
1 min over a period of 40 min. The mixture was washed
with H2O (ꢂ12 ml) and the remnant was dried for 3 h
over CaCl2 and recrystallized from Et2O/pentane (1:2,
ꢂ15 ml, −18ꢁC) to yield 4 (149 mg, 0.880 mmol, 27%
[89%–96%[14]]) as colorless needles. Further product
could have been isolated from the mother liquor. 1H
NMR (500 MHz, CDCl3): δ = 1.86 (s, 9 H, tBu), 1.11–1.29
8.3.6 | 6-(tert-Butyl)-1,1-dichlorospiro
[2.5]octane (10)
This compound was prepared in analogy to a published
protocol.[18] A solution of NaOH (458 mg, 11.4 mmol) in
H2O (1 ml) was added to a stirred solution of alkene
2 (150 mg, 0.985 mmol) and Me (CH2)15NMe3+Br−
(CTAB; 12.1 mg, 33.2 μmol) in CHCl3 (1.53 ml, 2.26 g,
18.9 mmol). The mixture was stirred for 21 h and CH2Cl2
(5 ml), H2O (5 ml), and saturated aqueous NH4Cl solu-
tion (ꢂ2 ml) were added. The organic layer was sepa-
rated, dried (Na2SO4), and concentrated at reduced
pressure to yield dichlorospiroalkane 10 as a mixture of
isomers (ꢂ85:15; 133 mg, 0.563 mmol, 57%) as colorless
solid. Major isomer: 1H NMR (500 MHz, CDCl3): δ = 0.87
(s, 9 H, tBu), 0.98–1.12 (m, 5-Hax, 6-Hax, 7-Hax), 1.16 (s,
(m,
3
H, 3-Hax, 5-Hax, 4-Hax), 1.69 (ddd,
3
3
2J = J = 13.8 Hz, J = 5.2 Hz, 1 H, 2-Hax), 1.88–1.96 (m,
2 H, 3-Heq, 5-Heq), 2.05 (ddd, 2J = 3J = 13.2 Hz,
3J = 4.4 Hz, 1 H, 6-Hax), 2.44 (br d, J = 14.0 Hz, 1 H,
2
6-Heq), 3.36 (br d, J = 14.4 Hz, 1 H, 2-Heq); 13C NMR
2
(125 MHz, CDCl3): δ = 24.4 (C-2), 26.4 (C-3), 27.7
[(CH3)3C, C-5], 32.1 (C-6), 32.6 [(CH3)3C], 47.6 (C-4),
161.8 (C-1). The spectroscopic data are in full agreement
with those from the literature.[54]
2
2 H, 1-H), 1.52 (d, J = 13.3 Hz, 2 H, 4-Heq, 8-Heq), 1.77
2
3
(br dd, J = J = 12.4 Hz, 2 H, 4-Hax, 8-Hax), 1.86 (d,
2J = 9.3 Hz, 2 H, 5-Heq, 7-Heq); 13C NMR (125 MHz,
CDCl3): δ = 26.0 (C-5, C-7), 27.7 [C (CH3)3], 29.8 (C-3),
31.6 (C-1), 32.5 [C (CH3)3], 33.3 (C-4, C-8), 47.5 (C-6); IR
(ATR): ~υ (cm−1) = 2973, 2917, 2850, 1441, 1427, 1394,
1365, 1275, 1242, 1168, 1046, 961, 883, 821, 755, 665, 535,
463; MS (EI, 20ꢁC): m/z (%) = 236.2 (1), 234.2 (2), 219.2
(13), 82.1 (19), 81.1 (12), 80.1 (18), 57.1 (100); HRMS (EI):
calcd. for C12H2035Cl2 [M+]: 234.0942; found: 234.0940.
8.3.5 | 1,2-Bis-[4-(tert-butyl)
cyclohexylidene]hydrazine (5)
This compound was prepared in analogy to a published
protocol.[15] A solution of cyclohexanone 1 (500 mg,
3.24 mmol) in MeOH (2 ml) was added with stirring
at ꢁC to H2NNH2ꢀH2O (ꢂ85%, 1.7 ml, 1.67 g, 44.3 mmol)
in a Pyrex tube. A colorless precipitate developed and
the mixture was stirred for 1 h at 60ꢁC and cooled to
rt. CH2Cl2 (ꢂ10 ml) was added and the layers were sepa-
rated. The aqueous layer was extracted with CH2Cl2
(3 × 5 ml) and the combined organic layers were con-
centrated at reduced pressure and recrystallized from
CH2Cl2/pentane (1:2, ꢂ12 ml, −18ꢁC) to yield hydrazone
5 (208 mg, 1.24 mmol, 38%) colorless needles. Further
product could have been isolated from the mother
liquor. m.p. 174–175ꢁC; 1H NMR (500 MHz, CDCl3):
δ = 0.87 (s, 18 H, 2 × tBu), 1.09–1.24 (m, 2 H, 5-Hax,
50-Hax), 1.24–1.34 (m, 4 H, 3-Hax, 30-Hax, 4-Hax, 40-Hax),
1.64–1.76 (m, 2 H, 2-Hax, 20-Hax), 1.87–1.94 (m, 2 H,
5-Heq, 50-Heq), 1.96–2.04 (m, 2 H, 3-Heq, 30-Heq),
2.14–2.23 (m, 2 H, 6-Hax, 60-Hax), 2.49–2.55 (m, 2 H,
6-Heq, 60-Heq), 3.11–3.19 (m, 2 H, 2-Heq, 20-Heq); 13C
NMR (125 MHz, CDCl3): δ = 27.1, 27.2 (C-5, C-50),
27.6, 27.6 (C-2, C-20), 27.7 [2 × (CH3)3C], 28.2, 28.3
(C-3, C-30), 32.5, 32.6 [2 × (CH3)3C], 35.5 (C-6, C-60),
47.7, 47.7 (C-4, C-40), 166.2, 166.2 (C-1, C-10); IR
(ATR): ~υ (cm−1) = 2952, 2860, 1638, 1466, 1439, 1393,
1363, 1343, 1240, 1219, 1176, 984, 951, 916, 774,
570, 427; MS (APSC): m/z (%) = 306.3 (22), 305.3
(100), 121.1 (21); HRMS (EI): calcd. for C20H37N2
[M + H]+: 305.2951; found: 305.2944; elemental analy-
sis calcd. for C20H37N2: C 78.88, H 11.92, N 9.20,
found: C 78.53, H 12.09, N 9.18.
8.3.7 | 6-(tert-Butyl)spiro[2.5]octane (6)
This compound was prepared in analogy to a published
protocol.[19]
A solution of dichlorospiroalkane 10
(200 mg, 1.30 mmol) in anhydrous Et2O (ꢂ3 ml) was
added to lithium (18.7 mg, 2.68 mmol) dissolved at
−78ꢁC in liquid NH3 (4 ml). The cooling bath was
removed after 75 min and the mixture was slowly
brought to rt. MeOH (1 ml) was added and the mixture
was extracted with pentane (3 × 3 ml). The organic layers
were dried (Na2SO4), concentrated at reduced pressure,
purified by preparative TLC (silica gel, pentane, extrac-
tion of the product with CDCl3), and distilled using a
short path distillation apparatus to remove residual pen-
tane as azeotrope with CDCl3 (80ꢁC). A sufficient amount
of spiro compound 6 was obtained as a solution in CDCl3.
1H NMR (500 MHz, CDCl3): δ = 0.15 (br dd, 2J = 8.3 Hz,
2
3J = 5.7 Hz, 2 H, 2-H or 1-H), 0.24 (dd, J = 8.6 Hz,
3J = 5.5 Hz 2 H, 1-H or 2-H), 0.80–0.90 (m, 2 H, 4-Heq,
3
8-Heq), 0.86 (s, 9 H, tBu), 0.99 (br t, J = 11.9 Hz, 1 H,
2
3
3
3
6-Hax), 1.12 (dddd, J = J = J = 12.7 Hz, J = 3.2 Hz,
2 H, 5-Hax, 7-Hax), 1.67–1.74 (m, 4 H, 4-Hax, 8-Hax, 5-Heq,
7-Heq); 13C NMR (125 MHz, CDCl3): δ = 11.6 (C-1 or C-2),
12.4 (C-2 or C-1), 19.1 (C-3), 26.5 (C-5, C-7), 27.7
[C (CH3)3], 32.5 [C (CH3)3], 36.2 (C-4, C-8), 48.0 (C-6).

JUNG ET AL.
13 of 15
8.3.8 | 6-(tert-Butyl)-
1,1,2,2-tetrachlorospiro[2.5]octane (7)
(65 ml) and the mixture was stirred for 20 min at rt. H2O
(130 ml) was added and the mixture was extracted with
EtOAc (3 × 65 ml). The combined organic layers were
dried (Na2SO4), concentrated at reduced pressure, and
purified by column chromatography (silica gel, cyclohex-
ane/EtOAc, 10:1) to yield bromohydrins 11 (274 mg,
1.10 mmol, 8% [Lit: 9%[20]]) and 12 (311 mg, 1.25 mmol,
This compound was prepared in analogy to a publi-
shed protocol.[18]
A solution of NaOH (210 mg,
5.25 mmol) in H2O (0.5 ml) was added to a stirred
solution of dichloroalkene 3 (100 mg, 0.452 mmol) and
Me (CH2)15NMe3+Br− (CTAB; 6.00 mg, 15.0 μmol) in
CHCl3 (0.703 ml, 1.04 g, 8.68 mmol). The mixture was
stirred for 21 h and CH2Cl2 (5 ml), H2O (5 ml), and
saturated aqueous NH4Cl solution (ꢂ2 ml) were added.
The organic layer was separated, dried (Na2SO4), con-
centrated at reduced pressure, and purified by bulb-to-
bulb distillation (30 mbar, 100ꢁC) to yield
tetrachlorospiroalkane 7 (47.3 mg, 0.156 mmol, 35%) as
colorless crystals. m.p. 115ꢁC; 1H NMR (500 MHz,
1
10% [Lit: 13%[20]]) as yellow oils. 11: H NMR (300 MHz,
CDCl3): δ = 0.86 (s, 9 H, tBu), 0.93–1.07 (m, 2 H),
1.17–1.30 (m, 1 H), 1.49–1.62 (m, 2 H), 1.69–1.78 (m,
2 H), 2.00 (mc, 2 H), 2.14 (br s, 1 H), 3.63 (br s, 2 H). 12:
1H NMR (300 MHz, CDCl3): δ = 0.87 (s, 9 H, tBu),
0.89–0.99 (m, 2 H), 1.29–1.38 (m, 4 H), 1.59–1.70 (m,
2 H), 1.80–1.89 (m, 2 H), 3.42 (br s, 1H). The spectro-
scopic data are in full agreement with those from the
literature.[20]
3
CDCl3): δ = 0.89 (s, 9 H, tBu), 1.08 (tt, J = 12.6 Hz,
3J = 2.5 Hz, 1 H, 6-H); 1.16 (dddd, J = J = 12.9 Hz,
3J = 12.6 Hz, 3J = 2.9 Hz, 2 H, 5-Hax, 7-Hax), 1.67
(ddd, 2J = 3J = 13.1 Hz, 3J = 2.3 Hz, 2 H, 4-Hax,
8-Hax), 1.88 (br d, 2J = 12.9 Hz, 2 H, 5-Heq, 7-Heq),
2
3
8.3.10 | (3r,6r)-6-(tert-Butyl)-1-oxaspiro
[2.5]octane (8)
2
1.99 (br d, J = 13.5 Hz, 2 H, 4-Heq, 8-Heq); 13C NMR
This compound was prepared in analogy to a publi-
shed protocol.[20] NaOH solution (10%, 0.5 ml,
44.0 mg, 1.10 mmol) was added dropwise with stirring
to a solution of bromohydrin 11 (311 mg, 1.25 mmol)
in H2O/iPrOH (2:3, 10 ml). The mixture was stirred
for 55 min and extracted with pentane (3 × 7 ml). The
combined organic layers were washed with H2O
(3 × 7 ml), dried (Na2SO4), concentrated at reduced
pressure, and purified by column chromatography (sil-
ica gel, cyclohexane/EtOAc, 50:1) to yield epoxide
8 (140 mg, 0.832 mmol, 6% [7%[20]]) as a colorless oil.
1H NMR (500 MHz, CDCl3): δ = 0.88 (s, 9 H, tBu),
1.08 (tt, 3J = 11.9 Hz, 3J = 2.6 Hz, 1 H, 6-H), 1.19
(dddd, 2J = 3J = 3J = 12.6 Hz, 3J = 3.1 Hz, 2 H,
5-Hax, 7-Hax), 1.32 (br d, 2J = 12.5 Hz, 2 H, 4-Heq,
8-Heq), 1.84 (dd, 2J = 12.9 Hz, 3J = 3.5 Hz, 2 H,
4-Hax, 8-Hax), 1.91 (br d, 2J = 13.2 Hz, 2 H, 5-Heq,
7-Heq), 2.59 (s, 2 H, 2-H); 13C NMR (125 MHz,
CDCl3): δ = 26.8 (C-5, C-7), 27.8 [C (CH3)3], 32.5
[C (CH3)3], 34.1 (C-4, C-8), 47.3 (C-6), 55.3 (C-2), 60.0
(C-3). The spectroscopic data are in full agreement
with those from the literature.[20]
(125 MHz, CDCl3):
δ
=
25.5 (C-5, C-7), 27.7
[C (CH3)3], 31.6 (C-4, C-8), 32.5 [C (CH3)3], 41.2 (C-3),
47.1 (C-6), 72.0 (C-1 or C-2), 72.7 (C-2 or C-1); IR
(ATR): ~υ (cm−1) = 2962, 2859, 1437, 1395, 1361, 1254,
1172, 1027, 977, 950, 934, 897, 838, 771, 724, 665,
610, 539, 482, 410 cm−1; MS (EI, 20ꢁC): m/z (%) = 306
(1), 304 (2), 302 (1) [M+], 291 (3), 289 (6), 267 (3),
251 (4), 233 (8), 231 (12), 211 (7), 181 (8), 175 (9),
161 (5), 131 (7), 125 (3), 91 (3), 83 (4), 69 (17),
57 (100); HRMS (EI): calcd. for C12H1837Cl2 [M+]:
302.0163; found: 302.0164.
8.3.9 | (1s,4s)-1-Bromo-4-(tert-butyl)
cyclohexyl methanol (11) and (1s,4s)-
1-(bromomethyl)-4-(tert-butyl)cyclohexan-
1-ol (12)
Epoxides 8 and 9[20] and bromohydrins 11 and 12[55] were
prepared in analogy to published protocols. Cyclohexa-
none 1 (2.00 g, 13.0 mmol) was added at rt to a stirred
solution of Me3SI (4.45 g, 21.8 mmol) in anhydrous
DMSO (22 ml). A solution of KOtBu (2.56 g, 22.8 mmol)
in anhydrous DMSO (14 ml) was added dropwise and the
mixture was stirred for 21 h at rt. H2O (60 ml) was added
and the mixture was extracted with Et2O (3 × 30 ml). The
combined organic layers were washed with H2O (30 ml),
dried (Na2SO4), and concentrated at reduced pressure to
yield a mixture of epoxides 8 and 9.
8.3.11 | (3s,6s)-6-(tert-Butyl)-1-oxaspiro
[2.5]octane (9)
This compound was prepared in analogy to a published
protocol.[20] NaOH solution (10%, 0.6 ml, 50.0 mg,
1.25 mmol) was added dropwise with stirring to a solu-
tion of bromohydrin 12 (311 mg, 1.25 mmol) in H2O/
iPrOH (2:3, 10 ml). The mixture was stirred for 55 min
Me2SBr+Br− (BDMS,[21] 2.88 g, 13.0 mmol) was added
to a solution of these epoxides in anhydrous MeCN

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and extracted with pentane (3 × 7 ml). The combined
organic layers were washed with H2O (3 × 7 ml), dried
(Na2SO4), concentrated at reduced pressure, and purified
by column chromatography (silica gel, cyclohexane/
EtOAc, 50:1) to yield epoxide 9 (192 mg, 1.14 mmol, 9%
1
[10%[20]]) as a colorless oil. H NMR (500 MHz, CDCl3):
3
3
δ = 0.88 (s, 9 H, tBu), 1.06 (tt, J = 11.9 Hz, J = 2.8 Hz,
2
3
1 H, 6-H), 1.29 (br dd, J = 14.0 Hz, J = 13.0 Hz, 2 H,
3
2
3
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4-Heq, 8-Heq), 1.36 (dddd, J = 13 Hz, J = J = 12.8 Hz,
3J = 3.0 Hz, 2 H, 5-Hax, 7-Hax), 1.79 (br d, J = 12.6 Hz,
2
2 H, 5-Heq, 7-Heq), 1.86 (ddd, 2J = 3J = 13.4 Hz,
3J = 3.9 Hz, 2 H, 4-Hax, 8-Hax), 2.63 (s, 2 H, 2-H); 13C
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[C (CH3)3], 32.7 [C (CH3)3], 33.6 (C-4, C-8), 47.3 (C-6),
54.0 (C-2), 58.5 (C-3). The spectroscopic data are in full
agreement with those from the literature.[20]
ACKNOWLEDGEMENTS
We are deeply indebted to Florian Weigend, Kevin
Reiter, and Willem Klopper for continuous support and
helpful discussions. T.R. and B.L. thank the Deutsche
Forschungsgemeinschaft (LU 835/13-1) and the HGF
program BIFTM for financial support. Open access
funding enabled and organized by Projekt DEAL.
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ORCID
Sebastian T. Jung https://orcid.org/0000-0002-8692-
5113
Roman Nickisch https://orcid.org/0000-0002-3350-5609
Burkhard Luy https://orcid.org/0000-0001-9580-6397
Joachim Podlech https://orcid.org/0000-0001-7881-6905
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Jung ST, Nickisch R,
Reinsperger T, Luy B, Podlech J. Stereoelectronic
effects: Perlin effects in cyclohexane-derived
compounds. J Phys Org Chem. 2020;e4165. https://
doi.org/10.1002/poc.4165
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