Improper hydrogen-bonded cyclohexane C-Hax?Yax contacts: experimental evidence from 1H NMR spectroscopy of suitable axial cyclohexane models

Article abstract of DOI:10.1016/j.tetlet.2010.02.170

B3LYP/6-31+G(d,p) calculations predicted the presence of improper hydrogen-bonded C-H_ax?Y_ax contacts of different strength in cyclohexane derivatives;¹ it was predicted that the addition of an appropriate bridging fragment X_ax between an axial substituent Y₁ and a cyclohexane carbon would strengthen the improper hydrogen-bonded contact C-H_ax?Y₁ when the X_ax-Y₁ bond vector bisects the cyclohexane ring. To support the theoretical predictions with experimental evidence for this effect, several 2-substituted adamantane analogues with suitable improper H-bonded C-H_ax?O contacts of different strength were synthesized, as models of the corresponding cyclohexane derivatives, and their ¹H NMR spectra were recorded at 298 K. The ¹H NMR signal separation within the cyclohexane ring γ-CH₂s is increased when the B3LYP/6-31+G(d,p)-calculated strength of the H-bonded C-H_ax?O=C_ax contact interaction is increased.

Full text of DOI:10.1016/j.tetlet.2010.02.170

Tetrahedron Letters 51 (2010) 2453–2456
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Tetrahedron Letters
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Improper hydrogen-bonded cyclohexane C–H ꢀ ꢀ ꢀY contacts: experimental
ax
ax
1
evidence from H NMR spectroscopy of suitable axial cyclohexane models
Nikolaos Zervos, Antonios Kolocouris *
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, 15771 Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
B3LYP/6-31+G(d,p) calculations predicted the presence of improper hydrogen-bonded C–H ꢀ ꢀ ꢀY con-
ax
ax
Received 26 September 2009
Revised 5 February 2010
Accepted 26 February 2010
Available online 3 March 2010
1
tacts of different strength in cyclohexane derivatives; it was predicted that the addition of an appropri-
ate bridging fragment Xax between an axial substituent Y
1
and a cyclohexane carbon would strengthen
bond vector bisects the cyclohexane
the improper hydrogen-bonded contact C–Haxꢀ ꢀ ꢀY
1
when the Xax–Y
1
ring. To support the theoretical predictions with experimental evidence for this effect, several 2-substi-
tuted adamantane analogues with suitable improper H-bonded C–Haxꢀ ꢀ ꢀO contacts of different strength
Keywords:
Improper hydrogen bonding
1
were synthesized, as models of the corresponding cyclohexane derivatives, and their H NMR spectra
were recorded at 298 K. The 1H NMR signal separation within the cyclohexane ring
c-CH s is increased
2
2
-Substituted adamantanes
when the B3LYP/6-31+G(d,p)-calculated strength of the H-bonded C–Haxꢀ ꢀ ꢀO=Cax contact interaction is
Axial cyclohexane conformer
1
increased.
H NMR chemical shifts
Chemical shift difference
Ab initio B3LYP calculations
Hyperconjugative interactions
Overlap interactions
Ó 2010 Elsevier Ltd. All rights reserved.
Improper H-bonded X–Hꢀ ꢀ ꢀY contacts, which often include C–
H-donating groups, cause a shortening of the X–H bond in contrast
to the elongation observed for strong polar hydrogen bonding (X,
or any cyclohexane derivative in the chair conformation is replaced
by substituent Y.
1
In recent work the contacts between axial substituent Y and
2
Y = N, O, F). Whatever the sign of X–H bond deformation, it results
axial C–H bonds in cyclohexane derivatives, which are generally
termed as steric (Pauli repulsive forces), were revisited. It was
striking that the calculations located the overlap interactions
from a balance between elongation forces and interactions toward
contraction. A review of the literature revealed that the major
effects causing lengthening of the X–H bond are attractive
interactions between the positive H of the X–H dipole and the elec-
n(Yax)?r*(C–Hax), that is, it was reported for the first time that
the C–Haxꢀ ꢀ ꢀYax–C contacts include an improper hydrogen-bonding
tron-rich acceptor group Y (lone pair or
conjugative electron donation n(Y)?
p
electrons), and hyper-
*(X–H) which are
component even in the most common axial cyclohexane deriva-
1
,6
r
tives (methyl cyclohexane, cyclohexanol, etc.).
1
significant for electron-rich, highly polar, short X–H bonds. In con-
trast, the major X–H bond-shortening contributors are the Pauli
repulsive forces (exchange effect) and the increased electrostatic
attraction between the positive H and negative X (caused by a
net gain of electron density at the X–H bond region in the presence
of Y), which are significant for less polar, electron-deficient, short
X–H bonds, such as C–H bonds having a negative dipole moment
derivative for the isolated H-bond donor molecule.3 Experimental
A significant part of that paper encompassed structures with
contacts in which the improper hydrogen-bonding character was
enhanced because of a linker group. It was predicted that the
strength of the hydrogen-bonding component or the orbital inter-
6
action n(Yax)?
r
*(C–Hax) would be increased by the addition of an
appropriate bridging fragment X between the axial substituent
1,ax and the cyclohexane carbon C-1, and by constraining the con-
formation in such a way that the Xax–Y bond vector bisects the
cyclohexane ring; in this arrangement the lone pair orbital(s) (or
electron cloud in general) of substituent Y can transfer electron
charge to the *(C–Hax) anti-bonding orbitals (Scheme 1).
The structure depicted in Scheme 1 corresponds to real systems.
Axial-substituted cyclohexane derivatives having the cy-Xax–Y
Y
,4
1
and theoretical studies identified the improper hydrogen-bonded
3
contacts C(sp )–Hꢀ ꢀ ꢀY (Y = O, N, S,
p
-donors), whilst simple sys-
ꢀ ꢀ ꢀNH CH ꢀ ꢀ ꢀFH, CH ꢀ ꢀ ꢀSH
6 6
H have also been investigated. C(sp )–
1
1
tems such as CH
4
ꢀ ꢀ ꢀOH
2
,
CH
4
3
,
4
4
2
,
r
ꢁ
5
3
CH
4
ꢀ ꢀ ꢀCl , and CH
4
ꢀ ꢀ ꢀC
Hꢀ ꢀ ꢀY contacts are formed when the axial proton of a cyclohexane
1
structure were retrieved from the Cambridge Crystallographic
Database and the calculations revealed important improper hydro-
*
Corresponding author. Tel.: +30 1 210 7274834; fax: +30 1 210 7274747.
1
E-mail address: ankol@pharm.uoa.gr (A. Kolocouris).
gen-bonded contacts. It was therefore intriguing for us to find the
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.170

2
454
N. Zervos, A. Kolocouris / Tetrahedron Letters 51 (2010) 2453–2456
Y1
contact will mostly shift the axial proton resonance in a downfield
direction making d( -CH ) smaller and more positive. In each
cyclohexane ring sub-unit of the parent adamantane the protons
of a CH group are chemically equivalent, that is, the d( -CH ) va-
lue is zero in the parent ‘unperturbed’ adamantane molecule
Scheme 2, Y = A = H). A C–Haxꢀ ꢀ ꢀYax–C contact will result in a posi-
tive value of d( -CH ) which will certainly be higher in magni-
X
D
c
2
H
C
H
2
D
c
2
A
C
(
D
c
2
cy-Xax-Y1
tude than that of the relevant cyclohexane molecules. The
situation is similarly convenient for the evaluation of the changes
in hybridization and bond lengths.
Scheme 1. Structure of cyclohexane C–Haxꢀ ꢀ ꢀYax contacts that favor enhanced
improper H-bonded interactions.
The geometries of the conformational ground states of mole-
cules 1–6 were optimized using the B3LYP functional and the
experimental evidence to support the theoretical predictions. The
aim was to check, using appropriate model systems, if changes re-
lated to the proton C–Hax chemical shift follow changes in the
strength of the improper H-bonded contact C–Haxꢀ ꢀ ꢀYax
interaction.
1
2
6
-31+G** basis set; frequency calculations were also performed
6a
to confirm the minima. The natural bond orbital (NBO) analysis,
which analyzes the molecular wave function to a set of localized
bond and lone pair orbitals, at the same level of theory revealed
that in all the molecules the C–Haxꢀ ꢀ ꢀO contacts cause an increase
in % s-character and a contraction of the C–Hax bonds relative to
the equatorial bonds of the cyclohexane-subunit of the adaman-
tane ring (Table 1). In compounds 1–6, the C–Haxꢀ ꢀ ꢀO contact dis-
When an axial substituent is attached to the cyclohexane ring, a
1
major effect of the C–Haxꢀ ꢀ ꢀYax contact in the H NMR spectrum is
to increase the difference between the chemical shifts of the axial
and equatorial protons within the
ent work, we examine whether the proton signal separation within
the cyclohexane ring -CH group is changed according to the dif-
c-methylene group. In the pres-
13
tances were smaller than the sum of the van der Waals radii of
the relevant atoms which is always encountered in H-bonded
contacts. The existence of hyperconjugative interactions
c
2
ferent strengths of the improper H-bonded C–Haxꢀ ꢀ ꢀYax–C contacts.
1
n(O)?r*(C–Hax) in molecules 1–6 was examined by the NBO
To observe this effect the H NMR spectrum of the axial conformer
6
a
method at the B3LYP/6-31+G** level of theory. The calculations
located overlap interactions in all compounds 1–6, suggesting the
presence of improper hydrogen bonding in C–Haxꢀ ꢀ ꢀY contacts (Ta-
bles 1 and S1 in the Supplementary data). Although the first effects,
that is, rHꢀ ꢀ ꢀY < rvdw,H + rvdw,Y, the increase in % s-character and
contraction of the C–H bond, are common in improper H-bonded
of the desired cyclohexane derivative, being accessible only at low
7
temperatures when ring inversion is a slow process, requires anal-
ysis if the existing population of the axial conformer and spectral
resolution permits. However, 2-adamantane derivatives represent
8
models of axially substituted cyclohexanes; in these molecules
0
0
0
0
0
0
substituent Y is axial in the 1 -2 -3 -4 -5 -9 adamantane cyclohex-
ane ring (Scheme 2).
1
4
contacts,
C–Hꢀ ꢀ ꢀY contact, that is, the calculation of a hyperconjugative
interaction n(Y)? *(C–H) is diagnostic for the presence of impro-
the identification of a covalent component in a
1
This observation motivated us to synthesize and analyze the H
r
NMR spectra of several 2-adamantane analogues of the relevant
parent cyclohexane derivatives, which represent a subset of the
6
per hydrogen bonding. However, the degree of hyperconjugative
electron transfer is only one of the effects contributing to improper
hydrogen bonding, the strength of which is reflected by the in-
crease in the % s-character and contraction of the C–Hax bond
length.
structures included in Scheme 1. Thus, in this preliminary Letter
the 2-adamantane analogues 1–69 were prepared as models of
10
the relevant parent cyclohexane C–Haxꢀ ꢀ ꢀO=C contacts of differ-
1
1
ent improper H-bonding strength. The H NMR spectra of the ada-
In the acetyl derivative 1 and the cyclohexanones 4 and 6 the
mantane derivatives 1–6 enabled a study on how the proton
0
0
C@O bond eclipses the cyclohexyl C2 –C3 bond favoring impro-
per H-bonding interactions with only one C–Hax bond compared
to compounds 3 and 5 in which the C@O bond bisects the cyclo-
chemical shifts of the
C–Haxꢀ ꢀ ꢀO contacts; the proton signal separation within the cyclo-
hexane ring -CH group, d( -CH ), was obtained by measuring
c-methylene were affected by the various
c
2
D
c
2
0
0
11
1
hexane ring allowing oxygen lone pair(s) electrons and the
p-
the proton resonance separation within the 4 ,9 -CH
2
in the H
bond of the carbonyl group to transfer electron charge to both
C–Hax anti-bonding orbitals (Scheme 3, Tables 1 and S1). The
stronger H-bonded contacts in 3 and 5 are reflected by the short-
er C–Hꢀ ꢀ ꢀH–C distances, the higher increase in the % s-character,
and the contraction of the C–Hax bonds relative to the equatorial
bonds (Table 1). In cyclobutanone 2 the C@O bond vector also bi-
sects the cyclohexane ring, but the contact distances are 0.2–
NMR spectra of compounds 1–6 recorded at 298 K.
It should be noted that the study of intramolecular hydrogen-
bonding contacts using NMR spectroscopy has inherent difficulties
related to the definition of the reference system. Besides the sim-
plicity in obtaining the spectra at 298 K and in the data interpreta-
tion, the models used in this work provide an additional benefit. In
the unsubstituted chair cyclohexane the axial proton is located up-
field with respect to the geminal equatorial proton, so the sign of
the chemical shift difference between axial and equatorial protons
0
.3 Å longer resulting in weaker improper H-bonded C–Haxꢀ ꢀ ꢀO
contacts with respect to the cyclopentanone 3 (Table 1). It is also
interesting to analyze comparatively the magnitude of some sec-
ond order perturbative interactions. For example, the stronger
(D
d(c
-CH
2
) = d(
c
-CHax) ꢁ d( -CHeq)) is negative. A C–Haxꢀ ꢀ ꢀYax–C
c
orbital interaction n(O)?
r
*(C–Hax
)
in spirocyclopentanone
3
in
ꢁ1
ꢁ1
(E = 1.17 kcal mol ) compared to 0.39 and 0.58 kcal mol
9
H
CH 4'ax
C
'ax
spirocyclobutanone 2 and spirocyclohexanone 4, respectively, re-
sulted from the more effective orbital overlapping; while the en-
ergy difference between the interacting orbitals is similar in all
Y
1
: Y = COMe, A = H
9
'
2: Y,A = C O(CH2)2
3: Y, A = C O(CH2)3
2'
H
A
1'
cases (
e
ꢁ
e
n(O) = 0.74 ꢁ 0.76 a.u.), the matrix elements
r
*(C–Hax)
5
'
4: Y, A = C O(CH2)4
5
6
3
'
H
4'
<n|F| *> are larger on going from 2 or 4 to 3 (0.016 a.u. in 2
r
: Y, A = C O-CH -C H
2 6 4
and 0.019 a.u. in 4 vs 0.027 a.u. in 3 (see Table S1 in the Supple-
mentary data)).
: Y,A = C O-(CH ) -C H
6 4
2
2
Thus, in cyclopentanones 3 and 5 the % s-character and the
contraction of the C–Hax bonds relative to the equatorial bonds
(Table 1) or the improper H-bonding interaction C–Haxꢀ ꢀ ꢀO are
Scheme 2. Synthetic adamantane derivatives 1–6 (see also Scheme 3) that provide
1
models to study cyclohexane improper H-bonded C–Haxꢀ ꢀ ꢀY contacts using H NMR
spectroscopy.

N. Zervos, A. Kolocouris / Tetrahedron Letters 51 (2010) 2453–2456
2455
Table 1
a,b
Selected structural parameters and hyperconjugative energies for the cyclohexane ring C–Haxꢀ ꢀ ꢀO contacts included in the adamantane derivatives 1–6 calculated at the B3LYP/
1
c
and signal separation of the c-CH
2
pairsb of the adamantane cyclohexane ring sub-units
6
-31G+** level in addition to H NMR chemical shifts (CDCl
3
)
0
0
0
0
d
d
System
C4-Hax, C9-Hax
C4-Heq, C9–Heq
r(C4 Haxꢀ ꢀ ꢀY) h(C4 Haxꢀ ꢀ ꢀY)
D
D
r
r
4
9
0
D
%
Hyperconjugative interaction
d
4
0
,9
0
-Hax
d
4
0
,9
0
-Heq
D
D
d
d(
4
0
,9
0
or
-CH
a
b
ꢁ1
)e
2
r(C9 Haxꢀ ꢀ ꢀY) h(C9 Haxꢀ ꢀ ꢀY)
0
s-Char.
(kcal mol
)
c
(
Å)
(°)
(mÅ)
0
1
2
(Y
2
@COMe, A@H)c 1.0924, 1.0963
2.40
2.77
119.0
115.0
ꢁ6.4
ꢁ2.2
ꢁ3.3
ꢁ3.3
1.50
0.64
E[n
a
(O)?
r
*(C4 –Hax)] =0.49
1.75
2.18
1.57
1.62
0.18
0.56
0
.7
1.0988, 1.0985
a
= sp
0
0
0
0
[Y
2
, A @CO(CH
2 2
) ]
1.0952, 1.0963
.0985, 1.0985
2.63
2.63
121.2
121.1
0.88
0.87
E[n
a
E[n
a
E[n
b
E[n
b
(O)?
(O)?
(O)?
(O)?
r
r
r
r
*(C4 –Hax)]=0.10
1
*(C9 –Hax)]=0.11
*(C4 –Hax)]=0.38
*(C9 –Hax)]=0.39
0
.8
a
= sp , b = p
0
0
E[p
(C=O?
(C=O?
r
r
*(C4 –Hax)]=0.13
*(C9 –Hax)]=0.13
E[
p
0
0
0
0
3
[Y
2
, A@CO(CH
2
)
3
]
]
1.0939, 1.0918
.0985, 1.0988
2.33
2.46
120.7
119.2
ꢁ7.0
ꢁ4.6
1.59
1.10
E[n
E[n
E[n
E[n
a
a
b
b
(O)?
(O)?
(O)?
(O)?
r
r
r
r
*(C4 –Hax)]=0.20
2.42
1.38
1.04
1
*(C9 –Hax)]=0.60
*(C4 –Hax)]=0.26
*(C9 –Hax)]=1.17
0
.8
a
= sp , b = p
0
E[p
(C=O?
r
*(C9 –Hax)]=0.43
0
0
4
5
[Y
2
2
, A@CO(CH
)
2 4
1.0920, 1.0983
.0985, 1.0983
2.35
3.17
117.6
109.9
ꢁ6.5
1.46
0.18
E[n
E[n
a
(O)?r
*(C4 –Hax)]=0.42
2.01
2.80
1.57
1.55
0.44
1.25
1
0.0
b
(O)?
r
*(C4 –Hax)]=0.58
0
.8
a
= sp , b = p
0
E[p
(C=O?
r
*(C9 –Hax)]=0.37
0
0
0
0
[Y
, A@CO–CH
2
-
1.0919, 1.0928
1.0987, 1.0985
2.32
2.38
120.7
120.2
ꢁ6.8
ꢁ5.7
1.62
1.36
E[n
a
E[n
a
E[n
b
E[n
b
(O)?
(O)?
(O)?
(O)?
r
r
r
r
*(C4 –Hax)]=0.37
C
6
H
4
]
*(C9 –Hax)]=0.47
*(C4 –Hax)]=0.59
*(C9 –Hax)]=0.98
0
.7
a
= sp , b = p
0
0
E[p
(C=O?
(C=O?
r
r
*(C4 –Hax)]=0.21
*(C9 –Hax)]=0.45
E[
p
0
0
6
[Y
C
2
, A@CO–(CH
2
2
) -
1.0905, 1.0971
1.0988, 1.0983
2.27
2.96
119.3
112.2
ꢁ8.3
ꢁ1.2
1.81
0.41
E[n
E[n
a
(O)?
r
r
*(C4 –Hax)]=0.75
2.21
1.62
0.59
6
H
4
]
b
(O)?
*(C9 –Hax)]=1.06
0
.8
a
= sp , b = p
0
0
E[p
(C=O?
(C=O?
r
r
*(C4 –Hax)] = 0.12
*(C9 –Hax)] = 0.19
E[
p
a
b
c
0
0
D
D
r
4
0
= r(C4 –Hax) ꢁ r(C4 –Heq)].
0
0
% s-char. = (% s-char. C4 –Hax ꢁ % s-char C4 –Heq)].
3
Spectra were recorded at 298 K and the signal of residual CHCl was calibrated at 7.26 ppm.
d
e
0
0
Signals for 4 ,9 -H of the compounds are in general broad doublets with Jgem ꢂ12 Hz.
1
H NMR chemical shift separation within
c
-CY
2
s, [D
d(c
2
-CH )=
D
d
4
0
,9
0
= d(H
4
0
,9
0
ax) ꢁ d(H
0 0
eq).
4 ,9
r1=r2=2.63
θ1=θ2=121
r1=2.40
θ1=119
O
2
r1=2.33
θ1=121
O
O
2
H
Me
H
H
r2=2.77
θ2=115 2'
r2=2.46
θ2=119
H
H
2' 1
3'
4'
C
4' C
H
4'
1
C
H
9'C
2'
9'C
5
'
1'
9
'
1
0'
10'
1
0'
8
'
6'
8'
8
'
7
'
1
2
3
r1=2.32
θ1=119
r1=2.35
θ1=118
O
r1=2.27
3
2
H θ1=119
H
C
O
2
H
O
1
r2=2.38
θ2=120
r2=3.17
θ2=109
r2=2.96
θ2=112
H
4'C H
9'C
H
4
'
4'C
1
2
9
'
2'
2'
2'
9C'
C
1
1
0'
10'
8'
8'
4
5
6
Scheme 3. Improper hydrogen-bonded C–Haxꢀ ꢀ ꢀO@Cax contacts (colored in blue) in the axial cyclohexane models 1–6.
considerably stronger than those of compounds 1, 2, 4, and 6. The
stronger H-bonded contacts cause a more pronounced redistribu-
the cyclohexane ring
and 6 the signal separation
0.59 ppm whereas in compounds 3 and 5 it was 1.04 and
c
-CH
2
group. Indeed, in compounds 1, 2, 4,
D
d( -CH ) was 0.18, 0.56, 0.44, and
c
2
tion of electronic shielding within the cyclohexane ring
2
c-CH s
1
5
effecting higher values of proton chemical shift separation within
1.25 ppm, respectively (Table 1).

2
456
N. Zervos, A. Kolocouris / Tetrahedron Letters 51 (2010) 2453–2456
To summarize, in a preceding paper, the B3LYP/6-31+G(d,p) cal-
culations predicted that the improper H-bonding character of
cyclohexane C–Haxꢀ ꢀ ꢀY contacts (Scheme 1) could be increased if
the Xax–Y bond vector bisects the cyclohexane ring and a sample
Michels, H. H. J. Mol. Struct. 2007, 841, 22; (h) Tsuzuki, S.; Honda, K.;
Uchimaru, T.; Mikami, M.; Fujii, A. J. Phys. Chem. A 2006, 110, 10163. and
also Refs. 2c,4a cited therein.
The presence of a hyperconjugative interaction n(Yax)?r*(C–Hax) is
diagnostic for the presence of improper hydrogen bonding: (a) Reed, A. E.;
Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88, 899; (b) M r´ azkova, E.; Hobza,
P. J. Phys. Chem. A 2003, 107, 1032; (c) Chocholouîsova, J.; Špirko, V.; Hobza,
P. Phys. Chem. Chem. Phys. 2004, 6, 37; (d) Vijayakumar, S.; Kolandaivel, P.
THEOCHEM 2005, 734, 157; (e) Nilsson, A.; Ogasawara, H.; Cavalleri, M.;
Nordlund, D.; Nyberg, M.; Pettersson, L. G. M. J. Chem. Phys. 2005, 122,
1
6
.
1
1
of relevant structures was retrieved from the CCDC. Experimental
evidence for this structural consequence was needed and suitable
C–Haxꢀ ꢀ ꢀO contacts of different improper hydrogen-bonding inter-
action efficacy were prepared through the 2-substituted adaman-
tane derivatives 1–6, which represent the necessary cyclohexane
154505; (f) Wysokiînski, W.; Bieînko, D. C.; Michalska, D.; Zeegers-Huyskens,
T. Chem. Phys. 2005, 315, 17; (g) Kryachko, E. S.; Zeegers-Huyskens, T. J. Phys.
Chem. A 2002, 106, 6832.
See, for example: Eliel, E. L.; Manoharan, M. J. Org. Chem. 1981, 46, 1959.
(a) Engler, E. M.; Andose, J. D.; Schleyer, P. v. R. J. Am. Chem. Soc. 1973, 95, 8005;
1
models. The H signal separation within the cyclohexane ring
7
8
.
.
2
c-CH s increases when the strength of the hydrogen-bonding
interactions in the C–Haxꢀ ꢀ ꢀYax contacts is increased. This work
presents the first example of an experimental study of improper
H-bonded cyclohexane C–Haxꢀ ꢀ ꢀO contacts.
(
b) Belanger-Giarepy, F.; Brisse, F.; Harvey, P. D.; Butler, I. S.; Gilson, D. F. R. Acta
Crystallogr. 1987, C43, 756.
9.
Compounds 2–4 were synthesized according to the procedures reported in the
near past; Zoidis, G.; Kolocouris, N.; Fytas, G.; Foscolos, G. B.; Kolocouris, A.;
Fytas, G.; Karayannis, P.; Padalko, E.; Neyts, J.; De Clercq, E. Antivir. Chem.
Chemother. 2003, 14, 155. The preparation of compounds 5 and 6 has been
reported; Braga, D.; Chen, S.; Filson, H.; Maini, L.; Netherton, M. R.; Patrick, B.
O.; Scheffer, J. R.; Scott, C.; Xia, W. J. J. Am. Chem. Soc. 2004, 126, 3511. For the
synthesis of ketone 1, the 2-cyanoadamantane was used as the starting
material; 2-cyanoadamantane can be prepared through reaction of 2-
adamantanone with tosyl methyl isocyanate in the presence of a suitable
base. We used sodium ethoxide instead of potassium tert-butoxide as reported
by Oldenziel, O. H.; van Leusen, D.; van Leusen, A. M. J. Org. Chem. 1977, 42,
3114. The reaction of 2-cyanoadamantane with methyllithium afforded the 2-
acetyl adamantane 1:
Supplementary data
Supplementary data (computational methods used; Table S1 in-
cludes the complete second order perturbation NBO analysis for
the hyperconjugative interactions; cartesian coordinates for the
optimized conformational minima of compounds 1–6; representa-
1
tive H NMR spectra of the synthesized compounds) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.02.170.
O
C
N
O
EtONa, TosMIC
EtOH-THF, r.t.
H
1. MeLi, ether, 10 °C
2. HCl, 6N
H
References and notes
1
1
0. The C–Hꢀ ꢀ ꢀO contacts are the most common improper hydrogen-bonded
contacts encountered, especially the C–Hꢀ ꢀ ꢀO@C contacts in proteins (see Ref.
1
2
.
.
Kolocouris, A. J. Org. Chem. 2009, 74, 1842.
(a) Desiraju, G. R.; Steiner, T.. The Weak Hydrogen Bond in Structural Chemistry
and Biology. In IUCr Monographs on Crystallography; Oxford University Press,
1
).
1. For the assignment and analysis of the 1H NMR spectra of the 2-substituted
adamantane derivatives see: Kolocouris, A. Tetrahedron Lett. 2007, 48, 2117.
and Refs. 8a,9 of that paper.
1
999; Vol. 9; (b) Steiner, T. Angew. Chem., Int. Ed. Engl. 1995, 43, 2311; (c)
Panigrahi, S. K.; Desiraju, G. R. PROTEINS: Struct. Funct. Bioinform. 2007, 67, 128.
Joseph, J.; Jemmis, E. D. J. Am. Chem. Soc. 2007, 129, 4620. and references cited
therein.
Between the different theories included in the citations in Ref. 3, a useful
interpretation includes the combination of a hyperconjugative interaction
1
1
2. Details of the computational methods can be found in the Supplementary data.
3. Still the most popular source of van der Waals radii is an article by Bondii, A. J.
Phys. Chem. 1964, 68, 441 who gives the following values H: 1.20 Å, C: 1.70 Å,
O: 1.52 Å, N: 1.55 Å, F: 1.47 Å, Cl: 1.75 Å, S: 1.80 Å, P: 1.80 Å.; Si: 2.10 Å; using
these values the sum of the van der Waals radii is, for example, 2.72 Å for
Hꢀ ꢀ ꢀO.
3
.
.
4
n(Y)?
r
*(X–H) that weakens the X–H bond and
a
repolarization/
rehybridization in which the X–H bond s-character increases, as H becomes
more electropositive (Bent’s rule), causing strengthening of the X–H bond. The
second effect prevails, that is, improper H bonding is observed, when the
hyperconjugation is relatively weak. See: (a) Alabugin, I. V.; Manorahan, M.;
Peabody, S.; Weinhold, F. J. Am. Chem. Soc. 2003, 125, 5973; (b) Alabugin, I. V.;
Manorahan, M. J. Comp. Chem. 2007, 28, 373.
1
1
4. Taylor, R.; Kennard, O. J. Am. Chem. Soc. 1982, 104, 5063.
5. It is noted that changes of 0.1–1 ppm in the C–H proton chemical shift have
been observed in a limited number of cases and are taken as evidence for the
existence of C–HꢀꢀꢀO hydrogen bonds in solution. Intermolecular: (a) Xiang, S.;
Yu, G.; Liang, Y.; Wu, L. J. Mol. Struct. 2006, 789, 43; (b) Wang, B.; Hinton, J. F.;
Pulay, P. J. Phys. Chem. A 2003, 107, 4683; (c) Karger, N.; Amorim da Costa, A.
M.; Ribeiro-Claro, P. J. A. J. Phys. Chem. A 1999, 103, 8672; (d) Mizuno, K.; Ochi,
T.; Shindo, Y. J. Chem. Phys. 1998, 109, 9502; (e) Godfrey, P. D.; Grigsby, W. J.;
Nichols, P. J.; Raston, C. L. J. Am. Chem. Soc. 1997, 119, 9283; Intramolecular: (f)
Donati, A.; Ristori, S.; Bonechi, C.; Panza, L.; Nartini, G.; Rossi, C. J. Am. Chem.
Soc. 2002, 124, 8778; (g) Barone, V.; Bolognese, A.; Correale, G.; Diurno, M. V.;
Monterrey-Gomez, I.; Mazzoni, O. J. Mol. Graph. Model. 2001, 19, 318; (h)
Nagawa, Y.; Yamagaki, T.; Nakanishi, H.; Nakagawa, M.; Tezuka, T. Tetrahedron
Lett. 1998, 39, 1393.
5
.
See for example: (a) CH
Chem. Phys. Lett. 1996, 251, 33; (b) Vasunov, A.; Dannenberg, J. J.; Contreras,
R. H. J. Phys. Chem. 2001, 105, 4737; CH (c) Gu, Y.; Kar, T.;
ꢀ ꢀ ꢀNH
Scheiner, S. J. Mol. Struct. 2000, 552, 17; CH
4
ꢀ ꢀ ꢀOH
2
: (a) Novoa, J. J.; Planas, M.; Rovira, M. C.
A
4
3
:
4
ꢀ ꢀ ꢀFH: (d) Vizioli, C.; Ruiz de
Azua, M. C.; Giribet, C. G.; Contreras, R. H.; Turi, L.; Dannenberg, J. J.; Rae, I.
D.; Weigold, J. A.; Malagoli, M.; Zanasi, R.; Lazzeretti, P. J. Phys. Chem. 1994,
9
1
8, 8558; CH
4
ꢀ ꢀ ꢀSH
2
: (e) Rovira, M. C.; Novoa, J. J. Chem. Phys. Lett. 1997, 279,
ꢁ
40; CH
4
ꢀ ꢀ ꢀCl : (f) Hiraoka, K.; Mizuno, R.; Iino, T.; Eguchi, D.; Yamade, S. J.
3
J. Phys. Chem. A 2001, 105, 4887; C(sp )-Hꢀ ꢀ ꢀ
p
: (g) Utzat, K.; Bohn, R. K.;