2-Substituted and 2,2-disubstituted adamantane derivatives as models for studying substituent chemical shifts and C-Hax?Yax cyclohexane contacts - results from experimental and theoretical NMR spectroscopic chemical shifts and DFT structures

Article abstract of DOI:10.1016/j.tet.2015.01.044

Abstract The complete ¹H and ¹³C NMR chemical shifts assignment for various 2-substituted and 2,2-disubstituted adamantane derivatives 1-38 in CDCl₃ solution was realized on the basis of NMR experiments combined with chemical structure information and DFT-GIAO (B3LYP/6-31+G(d,p)-GIAO) calculations of chemical shifts in solution. Substituent-induced ¹³C NMR chemical shifts (SCS) are discussed. C-H_ax?Y_ax contacts are a textbook prototype of steric hindrance in organic chemistry. The nature of these contacts will be further investigated in this work on basis of new adamantane derivatives, which are substituted at C-2 to provide models for 1,4-C-H_ax?Y_ax and 1,5-C-H_ax?Y_ax contacts. The B3LYP/6-31+G(d,p) calculations predicted the presence of NBO hyperconjugative attractive interactions between C-H_ax and Y_ax groups along C-H_ax?Y_ax contacts. The ¹H NMR signal separation, Δδ(γ-CH₂), reflects the strength of the H-bonded C-H_axa?Y_ax contact.

Full text of DOI:10.1016/j.tet.2015.01.044

Accepted Manuscript
2-Substituted and 2,2-Disubstituted Adamantane Derivatives as models for Studying
Substituent Chemical Shifts and C-H ∙∙∙Y Cyclohexane Contacts - Results from
ax
ax
experimental and theoretical NMR spectroscopic chemical shifts and DFT structures
Antonios Kolocouris, Andreas Koch, Erich Kleinpeter, Ioannis Stylianakis
PII:
S0040-4020(15)00087-3
10.1016/j.tet.2015.01.044
TET 26367
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 October 2014
Revised Date: 7 January 2015
Accepted Date: 19 January 2015
Please cite this article as: Kolocouris A, Koch A, Kleinpeter E, Stylianakis I, 2-Substituted and 2,2-
Disubstituted Adamantane Derivatives as models for Studying Substituent Chemical Shifts and C-
H
∙∙∙Y Cyclohexane Contacts - Results from experimental and theoretical NMR spectroscopic
ax
ax
chemical shifts and DFT structures, Tetrahedron (2015), doi: 10.1016/j.tet.2015.01.044.
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ACCEPTED MANUSCRIPT
2-Substituted and 2,2-Disubstituted Adamantane Derivatives as models for
Studying Substituent Chemical Shifts and C-Hax···Yax Cyclohexane Contacts -
Results from experimental and theoretical NMR spectroscopic chemical shifts
and DFT structures
Antonios Kolocouris,*† Andreas Koch,§ Erich Kleinpeter,§ Ioannis Stylianakis†
†Faculty of Pharmacy, Department of Pharmaceutical Chemistry,University of Athens,
Panepistimioupolis-Zografou, 15771 Athens, Greece; §Universität Potsdam, Institut für Chemie,
Karl-Liebknecht-Str. 24-25, D-14476 Potsdam(Golm), Germany
Corresponding author: Antonios Kolocouris, ankol@pharm.uoa.gr

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1
13
Abtract: The complete H and C NMR chemical shifts assignment for various 2-substituted and
2,2-disubstituted adamantane derivatives 1−38 in CDCl3 solution was realized on the basis of NMR
experiments combined with chemical structure information and DFT-GIAO (B3LYP/6-31+G(d,p)-
GIAO) calculations of chemical shifts in solution. Substituent-induced 13C NMR chemical shifts
(SCS) are discussed. C-HaxꢀꢀꢀYax contacts are a textbook prototype of steric hindrance in organic
chemistry. The nature of these contacts will be further investigated in this work on basis of new
adamantane derivatives which are substituted at C-2 to provide models for 1,4-C-HaxꢀꢀꢀYax and 1,5-
C-HaxꢀꢀꢀYax contacts. The B3LYP/6-31+G(d,p) calculations predicted the presence of NBO
hyperconjugative attractive interactions between C-Hax and Yax groups along C-HaxꢀꢀꢀYax contacts.
1
The H NMR signal separation, ꢁδ(γ-CH2), reflects the strength of the H-bonded C-HaxꢀꢀꢀYax
contact.
1
Keywords: 2-substituted adamantane derivatives; 2,2-disubstituted adamantane derivatives; H
NMR; 13C NMR; B3LYP/6-31G**+ calculations; GIAO calculations; substituent chemical shifts
1. Introduction
Cyclohexane derivatives are popular model compounds in organic chemistry and are
particularly useful, both experimentally and theoretically for studying the shielding tensors
contributing to proton and carbon chemical shifts; these shielding tensors are strongly linked with
1
the position of the atoms and their interactions in a molecule. Concerning H NMR spectroscopy,
rather than discern and analyze the axial or equatorial proton resonances, the difference in chemical
1
shift [ꢁδ(γ-CH2)] and one-bond JC-H coupling constants between the axial and equatorial protons
within one methylene group in the cyclohexane chair are used as experimental probes.1 Regarding
the carbon nuclei, the substituent effects upon carbon atoms especially in the γ position (γ SCS, γ

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Substituent Chemical Shifts) are of considerable interest because their magnitude and sign depend
strongly on the stereochemistry of the attached substituent. Steric and electronic substituent
phenomena are responsible for stabilizing a particular cyclohexane conformer and for the
differentiation of the values of certain NMR parameters like 1J coupling constants.2 In addition, the
interpretation of the chemical ꢁδ(γ-CH2) in terms of the magnetic contributions and the underlying
intramolecular bonding interactions are currently being studied.1a,3,4 Similarly the origin of the
substituent effects on the carbon resonances shifts is not fully understood, even for the familiar γ-
gauche effect.5
Adamantane derivatives are rigid and include fixed cyclohexane rings providing useful
models employing NMR parameters to study of intramolecular interactions.6 In the general formula
of a 2,2-disubstituted adamantane shown in Scheme 1, each of the substituents Y and A is axial in
the different adamantane cyclohexane ring 1′-2′-3′-4′-5′-9′ and 1′-2′-3′-10′-7′-8′, respectively
(Scheme 1).
Scheme 1. In 2,2-disubstituted adamantanes each of the two geminal substituents adopts an axial
orientation in a different cyclohexane ring sub-unit of adamantane. Scheme 1 also depicts the 2-
substituted and 2,2-disubstituted adamantane derivatives 1−38 that were studied for this report.

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Y
A
2'
H
H
1'
9'axH 4'ax
H
8'ax
H
H10'ax
3'
H
H
H
H
H
5'
6'
7'
H
H
H
1 (Y = H, A = H)c
2 (Y = CH3, A = H)c
3 (Y = C(CH3)3, A = H)c
4 (Y = C≡N, A = H)c
5 (Y = OH, A = H)c
6 (Y = OMe, A = H)c
7 (Y = NH2, A = H)c
8 (Y = NMe2, A = H)c
9 (Y = NH-CO-Me, A = H)
10(Y = NO2, A = H)
11 (Y = F, A = H)c
13 (Y = SH, A = H)c
14 (Y = OH, A = CH3)
15 (Y = OH, A = C(CH3)3
16 (Y = OH, A = Ph)
25 (Y, A = NH(CH2)4)
26 (Y, A = NMe(CH2)4)d
27 (Y = NHCOMe, A = CH3)
28 (Y = NHCOtBu, A = CH3)
29 (Y = N-N≡N, A = CH3)
30 (Y = F, A = CH3)
17 (Y = OH, A = C≡CH)
18 (Y = OH, A = C≡N)
19 (Y = OSiMe3, A = C≡N)
20 (Y = O-COMe, A = CH3)
21 (Y = O-COtBu, A = CH3)
22 (Y = NH2, A = CH3)
23 (Y = NMe2, A = CH3)
31 (Y = Cl, A = CH3)
32 (Y = CMe2OH, A = H)
33 (Y = CMe2F, A = H)
34 (Y = COMe, A = H)
35 (Y = CO2H, A = H)
36 (Y, A= CO(CH2)2
+
12 (Y = Cl, A = H)c
24 (Y = NHMe2 , A = CH3)
37 (Y, A= CO(CH2)3
38 (Y, A= CO(CH2)4
When an axial substituent is attached to the cyclohexane ring, the major effect of the C-
HaxꢀꢀꢀYax contact in the 1H NMR spectrum increases ꢁδ(γ-CH2 values and causes an upfield shift on
the resonance of γ-carbons. From a single NMR spectrum of a disubstituted adamantane at ambient
temperature, the corresponding spectroscopic characteristics on the relative effect of two axial
substituents Yax and Aax can be investigated.6 To observe such effects in the flexible cyclohexane
derivatives, the NMR spectra of axial conformers are accessible only at low temperatures when ring
inversion is slow on the NMR time scale.7
The studied compounds 1−38 are 2-substituted or 2,2-disubstituted adamantane derivatives
bearing alkyl groups of various sizes (A = H, Me, HC≡C, Ph, t-Bu) and some common second row
+
polar groups (Y = OH, OCOR, NR2, NHCOR, NO2, NHMe2 , N3, CN, F, Cl, SH, CMe2OH,
CMe2F, CO(CH2)n, n=2-4) (Scheme 1).
In a preceding paper, DFT calculations at the B3LYP/6-31+G(d,p) level predicted an
improper H-bonding character of C-HaxꢀꢀꢀYax contacts in common cyclohexane derivatives, due to
the presence of n(Y) → σ*(C-H or σ(C-H) → σ*(C-H) hyperconjugative interactions, and the
variation of its strength according to the nature of contact atom in group Yax.8 By increasing the

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strength of the contact the electronic redistribution inside the γ-methylene is affected consistently,
raising the relevant chemical shift separation between axial and equatorial protons inside a γ-CH2,
ꢁδ(γ-CH2).9 The present research work is a continuation of our previous studies.9 A large set of 2-
1
substituted and 2,2-disubstituted adamantane derivatives 1−38 have been synthesized and both H
and 13C NMR spectra assigned to analyze conformational effects due to present C-HaxꢀꢀꢀYax
interactions.
2. Results and Discussion
2.1 1H and 13C NMR spectra assignment
2.1.1 1H NMR spectroscopy
The most characteristic feature in the 1H NMR spectrum of a 2-substituted adamantane, is the
appearance of a downfield and an upfield doublet (Jgem= 11-12 Hz), assigned to 4′ax,9′ax-H and
4′eq,9′eq-H, respectively.10 In these molecules the equivalent axial protons of γ-syn carbons 4′ or 9′
interact with substituent Y, which is axial with respect to the 1′-2′-3′-4′-5′-9′ cyclohexane ring sub-
unit (Scheme 1), and their resonances are shifted downfield from the geminal 4′eq, 9′eq protons. In
contrast, the separation of the signals due to the protons attached to the γ-anti carbons 8′ and 10′,
that is, the chemical shift difference between 8′ax,10′ax-H and 8′eq,10′eq-H, is small because of the
equatorial position of substituent Y in the 1′-2′-3′-10′-7′-8′ cyclohexane ring (Scheme 1). When a
second substituent A is attached at the 2-adamantane position, the resonances of 8′ax,10′ax-H and
8′eq,10′eq-H should be affected mainly by their interaction with A which is axial in the 1′-2′-3′-10′-
7′-8′ cyclohexane ring. In a 2,2-disubstituted adamantane derivative, 4′,9′-H resonances are affected
by the Yax, Aeq substitution, with Y having an axial orientation in the 1′-2′-3′-4′-5′-9′ cyclohexane

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ring, and the 8′,10′-H doublets are affected by Aax, Yeq substitution, with substituent A being axial
in the 1′-2′-3′-10′-7′-8′ cyclohexane ring (Scheme 1).
In order to: a) differentiate the doublets between 4′ax,9′ax-H and 8′ax,10′ax-H protons and
between 4′eq,9′eq-H and 8′eq,10′eq-H protons and also to compare the proton chemical shift separation
effect within the cyclohexane ring γ-CH2 for the two orientations Yax, Aeq and Yeq, Aax
(correspoinding to fixed 1Y,1A-cyclohexane conformational isomers included inside the
adamantane framework), b) to study the effect of the different orientations Yax, Aeq and Yeq, Aax on
the resonances of γ-carbons 4′,9′-C and δ-carbons 5′,7′-C, and c) to study the substituent effects on
the carbons chemical shifts, the full assignment of the 1H and 13C NMR spectra of compounds 1−38
is a precondition. Although the 13C spectra of some substituted adamantanes at C-2 have been
investigated,11 there is no detailed report on their 1H NMR spectra.12,7a
The geometry of each compound was optimized at B3LYP/6-31+G(d,p) level.13a This level of
theory is adequate with reproducing accurately geometries; nevertheless we are more interested in
relative geometrical changes and not absolute values.13b The gauge-invariant atomic orbital
(GIAO)14 for calculation of the magnetic shielding tensors of nuclei was applied for compounds
1−38 after optimizing their geometry using the IEF-PCM solvent model15 (solvent CHCl3) for
consistency with the experimental conditions. For GIAO calculations we used the global minimum
which is more than 2.7 kcal/mol lower in potential energy for all molecules, that is, every other
conformer is less than 1% populated. It has been recently published that B3LYP/6-31G(d,p) gave a
deviation within 0.2 ppm for 1H chemical shifts and B3LYP/6-31G(d) gave a deviation of 5 ppm for
16b
13C chemical shifts;16a also that a DZ basis set is a fair choise.
For the calculation of proton
chemical shifts it was recommended that the modeling of solvent through SCRF-type calculation
may improve predictions significantly in certain cases; TMS was found to be an acceptable
reference since the deviation from experimental values was found to be inside acceptable limits.16
We applied here GIAO calculations in order to check their ability to reproduce experimentally
determined assignments for example the relative location of 8′,10′-H and 4′,9′-H proton doublets in

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the studied adamantane derivatives. The calculated chemical shifts follow the same order compared
to the experimental chemical shifts; we checked if the GIAO calculated chemicals shifts predict the
same relative chemical shift positions with experimental results and we did not attempt to predict
absolute calculated values. It is known that this can be accomplished for example for 13C only with
demanded computational methods, possibly with CCSD(T).16c We used GIAO results for
assignment purposes when differentiation was difficult like for 5′, 7′ protons and carbons. In most
of the cases the deviation of the calculated chemical shift is similar for the same carbon or proton
inside series 1−38. In all cases we used the results from the GIAO calculations to compare relative
chemical shifts positions, for example the position of 8′,10′ carbons compared to 4′,9′ carbons or
the position of 5′ proton or carbon compared to 7′ proton or carbon, and not absolute values. Since
the chemical shifts difference for 5′ and 7′ carbons and protons is small (see discussion followed)
even the more accurate MP2 level can not give accurate chemical shifts for these carbons and
protons having an error of ~ 2 ppm and 0.1 ppm for carbons and proton chemical shifts
respectively;16b this last level is also computationally expensive for this large set of compounds.
The 1H chemical shifts of compounds 1−38 (experimental and calculated values) are depicted
in Table 1.

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Table 1. 1H chemical shifts (400 MHz, CDCl3)a and signal separation of the γ-CH2 pairsb of adamantane cyclohexane ring sub-units for 2,2-disubstituted adamantanes 1−38.
Compound
1′, 3′
2′
5′
7′
6′
4′ax, 9′ax
8′ax, 10′ax
4′eq, 9′eq
8′eq, 10′eq
ꢁδ4′,9′-H
ꢁδ8′,10′-H
1 (Y = H, A = H)c
Exp.
Calc.
1.87
1.78, 1.80
(ꢁδ=-0.08)
1.57
1.58, 1.58
(ꢁδ=0.01)
2.05
1.92, 1.91
(ꢁδ=-0.14)
2.16
1.98, 1.98
(ꢁδ=-0.18)
1.88
1.49, 1.96
(ꢁδ=-0.16)
2.02
1.88, 2.05
(ꢁδ=-0.06)
1.75
1.50, 1.50
(ꢁδ=-0.25)
1.96
1.75
1.84
(ꢁδ=0.09)
1.75
1.86
(ꢁδ=0.11)
1.86
1.21
(ꢁδ=-0.65)
2.89
2.71
(ꢁδ=-0.18)
3.86
3.91
(ꢁδ=0.05)
3.34
3.27
(ꢁδ=-0.07)
2.99
3.33
(ꢁδ=0.34)
2.10
1.84
(ꢁδ=-0.26)
4.03
4.13
(ꢁδ=0.10)
4.38
4.11
(ꢁδ=-0.27)
4.65
4.84
(ꢁδ=0.19)
4.38
4.44
(ꢁδ=0.06)
3.34
1.87
1.78
(ꢁδ=-0.09)
1.84
1.73
(ꢁδ=-0.13)
1.86
1.54
(ꢁδ=-0.32)
1.90
1.79
(ꢁδ=-0.11)
1.79
1.67
(ꢁδ=-0.12)
1.77
1.36
(ꢁδ=-0.41)
1.78
1.67
(ꢁδ=-0.11)
1.78
1.66
(ꢁδ=-0.12)
1.82
1.70
(ꢁδ=-0.12)
1.97
1.71
(ꢁδ=-0.26 )
1.81
1.65
(ꢁδ=-0.16)
1.84
1.62
(ꢁδ=-0.22)
1.79
1.87
1.78
1.75
1.84
1.75
1.82, 1.84
1.75
1.75
1.75
0.0
0
(ꢁδ=0)
0.45
0.53
0.0
0
(ꢁδ=0)
-0.09
0.13
(ꢁꢁδ=0.22)
0.10
0.13
(ꢁꢁδ=0.03)
0.16
1.82, 1.84
(ꢁδ=0.08)
1.81
1.92, 1.92
(ꢁδ=0.11)
1.81
1.82, 1.84
(ꢁδ=0.08)
1.46
1.55, 1.56
(ꢁδ=0.09)
1.53
1.82, 1.84
(ꢁδ=0.08)
1.72
1.79, 1.79
(ꢁδ=-0.02) (ꢁꢁδ=0.08)
(ꢁδ=-0.09) (ꢁδ=0.09) (ꢁδ=0.08)
2 (Y = CH3, A = H)c
3 (Y = C(CH3)3, A = H)c
4 (Y = C≡N, A = H)c
5 (Y = OH, A = H)c
6 (Y = OMe, A = H)c
7 (Y = NH2, A = H)c
8 (Y = NMe2, A = H)c
Exp.
Calc.
1.75
1.71
1.69
1.77, 1.76
1.91
2.09, 2.08
(ꢁδ=-0.02) (ꢁδ=0.08) (ꢁδ=0.18)
Exp.
Calc.
1.79
1.56
1.70
1.45, 1.43
2.03
1.88, 1.98
1.71
1.43, 1.48
0.50
0.62
1.57, 1.61
1.33, 1.28
(ꢁδ=-0.43) (ꢁδ=-0.26) (ꢁδ=-0.10) (ꢁδ=-0.22) (ꢁδ=-0.23) (ꢁδ=-0.25) (ꢁꢁδ=0.12)
Exp.
Calc.
1.83
1.70
1.68
1.81, 1.81
2.14
2.33, 2.33
1.88
1.70, 1.70
1.73
1.66, 1.66
1.72
0.41
0.67
1.90, 1.90
(ꢁδ=0.18)
1.68
1.68, 1.70
(ꢁδ=0.01)
1.84
-0.20
(ꢁδ=-0.13) (ꢁδ=0.13) (ꢁδ=0.19) (ꢁδ=-0.18) (ꢁδ=-0.07)
(ꢁꢁδ=0.26) (ꢁꢁδ=-0.36)
Exp.
Calc.
1.81
1.67
1.71
1.77, 1.76
2.06
2.43, 2.48
1.84
1.90, 1.89
(ꢁδ=0.06) (ꢁδ=-0.06)
1.52
1.47, 1.45
0.54
1.00
0.16
-0.02
(ꢁδ=-0.14) (ꢁδ=0.06) (ꢁδ=0.40)
(ꢁꢁδ=0.46) (ꢁꢁδ=-0.18)
Exp.
Calc.
1.83
1.68
1.70
1.77, 1.72
2.01
2.26, 2.38
1.65
1.47
1.43, 1.46
0.54
0.87
0.19
-0.07
1.90, 1.89
(ꢁδ=0.25)
1.84
1.90, 1.90
(ꢁδ=0.06)
1.80
1.91, 1.91
(ꢁδ=0.11)
1.82
1.91, 1.83
1.62, 1.74
(ꢁδ=-0.15) (ꢁδ=0.05) (ꢁδ=0.31)
(ꢁδ=-0.03) (ꢁδ=-0.16) (ꢁꢁδ=0.33) (ꢁꢁδ=-0.26)
Exp.
Calc.
1.81
1.70
1.70
1.78, 1.78
1.97
2.73, 2.73
1.52
1.72
1.72, 1.72
(ꢁδ=0)
1.63
1.72, 1.72
(ꢁδ=0.09)
1.67
1.89, 1.90
(ꢁδ=0.23)
1.83
0.45
1.33
ꢁꢁδ=0.88)
0.87
0.98
ꢁꢁδ=0.11)
0.27
0.16
ꢁꢁδ=-0.11)
0.53
0.12
0.18
ꢁꢁδ=0.06)
0.17
-0.19
ꢁꢁδ=-0.36)
0.15
-0.05
ꢁꢁδ=-0.20)
0.12
1.40, 1.40
(ꢁδ=-0.12)
1.41
1.44, 1.44
(ꢁδ=0.03)
(ꢁδ=-0.11) (ꢁδ=0.08) (ꢁδ=0.76)
(
(
(
Exp.
Calc.
1.82
1.72
1.71
1.72, 1.72
2.28
2.42, 2.42
1.94, 1.94
(ꢁδ=-0.02)
(ꢁδ=-0.10) (ꢁδ=0.01) (ꢁδ=0.14)
(
(
9 (Y = NH-CO-Me, A = H)
10(Y = NO2, A = H)
11 (Y = F, A = H)c
Exp.
Calc.
1.93
2.06, 2.47
(ꢁδ=0.33)
2.75
2.98, 2.95
(ꢁδ= 0.22 )
2.09
2.05, 2.05
(ꢁδ=-0.04)
2.06
1.94, 1.94
(ꢁδ=-0.12)
1.82
1.83
1.68
(ꢁδ=-0.15)
1.97
1.78
1.90
1.62, 1.90
(ꢁδ=-0.14) (ꢁδ=0.04)
2.05
1.81, 1.84
1.63
1.79, 1.77
(ꢁδ=0.0)
1.70
1.73, 1.61
(ꢁδ=0.04)
1.52
(
Exp.
Calc.
1.95
2.00, 2.00
(ꢁδ=0.05) (ꢁδ=0.12 )
1.86
1.90, 1.89
(ꢁδ=0.04)
1.93
1.94, 1.94
(ꢁδ=0.01)
1.86
1.71
1.78, 1.78
1.64, 1.63
1.72, 171
0.19
0.28
(ꢁδ=-0.26) (ꢁδ=0.08 ) (ꢁδ=-0.22)
(ꢁδ=-0.11) (ꢁꢁδ=-0.34) (ꢁꢁδ= 0.14)
Exp.
Calc.
1.81
1.73
1.73
1.75, 1.76
2.08
2.34, 2.34
1.55
1.67
1.67, 1.67
(ꢁδ=0)
1.78
0.53
0.81
ꢁꢁδ=0.28)
0.70
0.93
ꢁꢁδ=0.23)
0.68
-0.19
-0.05
ꢁꢁδ=0.14)
-0.15
-0.19
ꢁꢁδ=-0.04)
-0.10
1.53, 1.53
(ꢁδ=0.02)
1.55
1.51, 1.51
(ꢁδ=-0.04) (ꢁδ=-0.03)
1.50
1.58, 1.49
(ꢁδ=0.04)
(ꢁδ=-0.08) (ꢁδ=0.03) (ꢁδ=0.26)
(
(
(
(
12 (Y = Cl, A = H)c
13 (Y = SH, A = H)c
Exp.
Calc.
1.84
1.72
1.73
1.75, 1.75
2.25
2.44, 2.44
1.75, 1.75
(ꢁδ=-0.12) (ꢁδ=0.02) (ꢁδ=0.19)
(
(
Exp.
Calc.
1.80
1.78
1.69
1.79, 1.80
2.15
2.31, 2.87
1.76
1.77, 1.82
(ꢁδ=0.04)
1.53, 1.99
(ꢁδ=-0.06)
3.68
(ꢁδ=0.34)
1.72
(ꢁδ=-0.07)
1.98, 1.94
(ꢁδ=0.10)
1.05
ꢁꢁδ=0.37)
-0.17
ꢁꢁδ=-0.07)
(ꢁδ=-0.02) (ꢁδ=0.11) (ꢁδ=0.44)

ACCEPTED MANUSCRIPT
14 (Y = OH, A = CH3)
15 (Y = OH, A = C(CH3)3
16 (Y = OH, A = Ph)
Exp.
Calc.
1.65
1.33, 1.71
(ꢁδ=-0.13)
2.02
1.85, 2.07
(ꢁδ=-0.06)
2.60
1.96, 1.96
(ꢁδ=0.64)
1.93
1.81, 2.10
(ꢁδ=0.03)
1.73
1.31, 1.70
(ꢁδ=-0.22)
2.05
1.77, 1.79
(ꢁδ=-0.27)
2.20
3.03, 1.67
(ꢁδ=0.15)
2.24
2.97, 1.51
(ꢁδ=0.0)
1.55
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1.76
1.66
(ꢁδ=-0.10)
1.73
1.71
(ꢁδ=-0.02)
1.94
1.55
(ꢁδ=-0.39)
1.79
1.55
(ꢁδ=-0.24)
1.80
1.73
(ꢁδ=-0.07)
1.76
1.51
(ꢁδ=-0.25)
1.73
1.65
(ꢁδ=-0.07)
1.73
1.48
(ꢁδ=-0.25)
1.81
2.02
(ꢁδ=0.21)
1.75
1.69
(ꢁδ=-0.06)
1.93
1.97
(ꢁδ=0.04)
1.74
1.68
(ꢁδ=-0.06)
1.80
1.44
(ꢁδ=-0.36)
1.81
1.67
(ꢁδ=-0.14)
1.76
1.66
1.64
1.71, 1.70
2.15
2.64, 2.69
1.83
1.52
1.45, 1.45
(ꢁδ=-0.07)
1.47
1.45, 1.38
(ꢁδ=-0.06)
1.77
1.70
0.63
1.22
ꢁꢁδ=0.59)
0.79
1.44
ꢁꢁδ=0.65)
0.68
1.16
ꢁꢁδ=0.48)
0.62
0.67
ꢁꢁδ=0.05)
0.51
0.89
ꢁꢁδ=0.38)
0.55
0.94
ꢁꢁδ=0.39)
0.46
0.64
ꢁꢁδ=0.24)
0.46
0.71
ꢁꢁδ=0.25)
0.48
0.13
0.16
ꢁꢁδ=0.03)
0.49
0.59
ꢁꢁδ=0.10)
0.02
0.24
ꢁꢁδ=0.22)
0.36
0.08
ꢁꢁδ=0.28)
0.19
0.38
ꢁꢁδ=0.19)
0.21
0.43
ꢁꢁδ=0.22)
0.15
0.24
ꢁꢁδ=0.09)
0.15
0.25
ꢁꢁδ=0.11)
0.31
1.92, 1.94
(ꢁδ=0.10)
2.17
2.32, 2.32
(ꢁδ=0.15)
1.76
1.78, 1.75
(ꢁδ=0.07)
1.68
1.69, 1.78
(ꢁδ=0.06)
1.74
(ꢁδ=-0.10) (ꢁδ=0.07) (ꢁδ=0.52)
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
Exp.
Calc.
1.59
1.64
(ꢁδ=0.05)
1.74
1.66
1.70, 1.68
(ꢁδ=0.03) (ꢁδ=0.44)
1.73
1.43, 1.44
2.26
2.53, 2.86
Exp.
Calc.
2.45
2.58, 2.48
1.42
1.25, 1.57
1.36, 1.38
1.39, 1.83
(ꢁδ=-0.32) (ꢁδ=-0.29) (ꢁδ=0.08) (ꢁδ=-0.35) (ꢁδ=-0.40) (ꢁδ=-0.13)
17 (Y = OH, A = C≡CH)
18 (Y = OH, A = C≡N)
19 (Y = OSiMe3, A = C≡N)
20 (Y = O-COMe, A = CH3)
21 (Y = O-COtBu, A = CH3)
22 (Y = NH2, A = CH3)
23 (Y = NMe2, A = CH3)
Exp.
Calc.
1.66
1.39
1.66
1.46, 1.47
2.14
1.61, 1.70
2.11
1.72, 1.75
1.52
0.98, 1.01
1.75
1.67, 1.65
(ꢁδ=-0.27) (ꢁδ=-0.20) (ꢁδ=-0.48) (ꢁδ=-0.37) (ꢁδ=-0.52) (ꢁδ=-0.09)
Exp.
Calc.
1.92
1.61
1.73
1.72, 1.71
2.13
2.37, 2.47
2.10
1.62
1.53, 1.53
(ꢁδ=-0.09) (ꢁδ=-0.06)
1.55
1.22, 1.25
1.91
1.85, 1.84
2.22, 2.22
(ꢁδ=0.12)
2.07
(ꢁδ=-0.31) (ꢁδ=-0.01) (ꢁδ=0.29)
Exp.
Calc.
1.84
1.39
1.71
1.53, 1.51
2.10
2.10, 2.26
1.86
1.52, 1.52
1.95, 1.96
(ꢁδ=-0.45) (ꢁδ=-0.19) (ꢁδ=0.08) (ꢁδ=-0.12) (ꢁδ=-0.31) (ꢁδ=-0.34)
Exp.
Calc.
1.73
1.67
1.63
1.73, 1.78
1.95
2.47, 1.94
1.80
1.49
1.65
2.01, 1.92
(ꢁδ=0.16)
1.80
1.56, 1.56
(ꢁδ=0.07)
1.49
1.74, 1.71
(ꢁδ=0.07)
1.65
(ꢁδ=-0.06) (ꢁδ=0.12) (ꢁδ=0.25)
Exp.
Calc.
1.73
1.49
1.64
1.49, 1.52
1.95
2.24, 1.69
1.79, 1.64
1.30, 1.19
1.48, 1.44
(ꢁδ=-0.24) (ꢁδ=-0.13) (ꢁδ=0.01) (ꢁδ=-0.08) (ꢁδ=-0.24) (ꢁδ=-0.19)
Exp.
Calc.
1.78
1.68
1.65
1.73, 1.73
2.07
2.87, 2.87
1.93
1.59
1.62
1.33, 1.33
(ꢁδ=-0.22)
1.75
1.81, 1.81
(ꢁδ=0.06)
2.03
2.02, 2.02
(ꢁδ=-0.01)
1.78
2.02, 2.02
(ꢁδ=0.09)
1.85
1.99, 1.99
(ꢁδ=0.14)
1.97
1.38, 1.38
(ꢁδ=-0.21)
1.34
1.33, 1.33
(ꢁδ=-0.01)
1.72
2.21, 2.21
(ꢁδ=0.49)
1.45
1.40, 1.34
(ꢁδ=-0.08)
1.43, 1.39
1.08, 1.10
1.73, 1.73
(ꢁδ=0.11)
1.64
1.70, 1.70
(ꢁδ=0.06)
1.87
2.17, 2.17
(ꢁδ=0.30)
1.53
1.71, 1.65
(ꢁδ=0.15)
1.47, 1.60
1.41, 1.32
1.44
ꢁꢁδ=0.96)
0.88
1.24
ꢁꢁδ=0.36)
0.46
0.76
ꢁꢁδ=0.30)
0.48
0.29
ꢁꢁδ=0.02)
0.21
0.29
ꢁꢁδ=0.08)
0.10
0.05
ꢁꢁδ=0.05)
0.34
(ꢁδ=-0.10) (ꢁδ=0.08) (ꢁδ=0.82)
Exp.
Calc.
1.75
1.66
1.63
1.70, 1.70
2.22
2.57, 2.57
(ꢁδ=-0.09) (ꢁδ=0.07) (ꢁδ=0.35)
+
24 (Y = NHMe2 , A = CH3)
Exp.
Calc.
2.00
2.04
(ꢁδ=0.04)
1.74
1.73
1.92, 1.92
2.18
1.45, 1.46
2.11, 2.13
(ꢁδ=0.19) (ꢁδ=-0.72) (ꢁδ=0.15)
1.60
1.70, 1.70
25 (Y, A = NH(CH2)4)
Exp.
Calc.
1.93
2.67, 2.74
1.87
1.00, 2.24
(ꢁδ=-0.16)
1.60, 2.43
1.36, 2.24
(ꢁδ=-0.24, -0.19)
2.15
1.65
1.91, 2.01
(ꢁδ=0.09)
1.60, 1.82
1.62, 1.63
1.33
0.28
(ꢁδ=-0.09) (ꢁδ=0.10) (ꢁδ=0.77)
ꢁꢁδ=0.85)
0.81, 0.71
1.43, 1,13
ꢁꢁδ=0.52)
0.36
0.51
ꢁꢁδ=0.15)
ꢁꢁδ=0.06)
0.13, 0.22
0.30, 0.22
ꢁꢁδ=0.08)
0.29
0.40
ꢁꢁδ=0.11)
26 (Y, A = NMe(CH2)4)d
Exp.
Calc.
1.80
1.42
1.65
1.34, 1.35
2.24, 2.10
2.53, 2.21
(ꢁδ=-0.38) (ꢁδ=-0.30) (ꢁδ=0.20) (ꢁδ=-0.10) (ꢁδ=-0.32) (ꢁδ=-0.17)
27 (Y = NHCOMe, A = CH3) Exp.
1.81
1.67
1.70
1.75, 1.74
1.97
2.03, 2.15
1.95
1.67, 1.66
1.61
1.62, 1.53
1.66
2.15, 2.01
(ꢁδ=0.42)
Calc.
3.16, 1.28
(ꢁδ=0.07)
(ꢁδ=-0.14) (ꢁδ=0.04) (ꢁδ=0.12) (ꢁδ=-0.29) (ꢁδ=-0.03)

ACCEPTED MANUSCRIPT
28 (Y = NHCOtBu, A = CH3) Exp.
2.13
3.18, 0.98
(ꢁδ=-0.05)
1.72
1.46, 1.94
(ꢁδ=-0.02)
1.90
1.83, 1.83
(ꢁδ=-0.07)
1.67
1.91, 1.91
(ꢁδ=0.24)
2.18
2.16, 2.16
(ꢁδ=-0.02)
2.15
2.20, 2.21
(ꢁδ=0.05)
2.36
1.95, 2.02
(ꢁδ=-0.37)
2.35
2.35, 2.52
(ꢁδ=0.08)
1.90
-
-
-
-
1.77
1.49
(ꢁδ=-0.28)
1.80
1.66
(ꢁδ=-0.14)
1.78
1.65
(ꢁδ=-0.10)
1.79
1.65
(ꢁδ=-0.14)
1.86
1.75
(ꢁδ=-0.11)
1.82
1.77
(ꢁδ=-0.05)
1.79
1.56
(ꢁδ=-0.23)
1.90
1.70
(ꢁδ=-0.20)
1.79
1.77
1.47
1.65
1.47, 1.46
1.94
2.18, 2.12
1.86
1.42, 1.42
1.62
1.25, 1.23
1.57
1.81, 1.75
(ꢁδ=0.31)
1.68
1.97, 1.94
(ꢁδ=0.27)
1.67
1.84, 1.84
(ꢁδ=0.17)
1.73
1.76, 1.76
(ꢁδ=0.03)
1.70
1.70, 1.70
(ꢁδ=0.00)
1.69
1.96, 1.96
(ꢁδ=0.27)
1.75
0.32
0.91
ꢁꢁδ=0.59)
0.55
0.82
ꢁꢁδ=0.27)
0.61
0.95
ꢁꢁδ=0.34)
0.63
1.07
ꢁꢁδ=0.44)
0.65
1.41
ꢁꢁδ=0.76)
0.64
1.04
ꢁꢁδ=0.40)
0.29
0.56
ꢁꢁδ=0.27)
0.27
0.00
ꢁꢁδ=0.27)
0.56
0.29
0.36
ꢁꢁδ=0.07)
0.19
0.18
ꢁꢁδ=0.01)
0.13
0.03
ꢁꢁδ=0.10)
0.13
0.30
ꢁꢁδ=0.17)
0.13
0.24
ꢁꢁδ=0.11)
0.13
0.27
ꢁꢁδ=0.14)
0.13
0.18
ꢁꢁδ=0.05)
0.12
0.15
ꢁꢁδ=0.03)
0.12
Calc.
(ꢁδ=-0.30) (ꢁδ=-0.18) (ꢁδ=0.11) (ꢁδ=-0.44) (ꢁδ=-0.38)
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
29 (Y = N-N≡N, A = CH3)
30 (Y = F, A = CH3)
Exp.
Calc.
1.81
1.73
1.67
1.74, 1.74
2.11
2.48, 2.29
1.87
1.71, 1.82
1.56
1.51, 1.62
(ꢁδ=0.00)
1.56
1.53, 1.53
(ꢁδ=-0.03)
1.55
1.59, 1.59
(ꢁδ=0.04)
1.53
1.51, 1.51
(ꢁδ=-0.02)
1.48
(ꢁδ=-0.07) (ꢁδ=0.07) (ꢁδ=0.27) (ꢁδ=-0.10)
Exp.
1.82
1.68
1.69
1.73, 1.73
2.17
2.48, 2.48
1.80
1.81, 1.81
Calc.
(ꢁδ=-0.17) (ꢁδ=0.04) (ꢁδ=0.31) (ꢁδ=0.01)
31 (Y = Cl, A = CH3)
32 (Y = CMe2OH, A = H)
33 (Y = CMe2F, A = H)
34 (Y = COMe, A = H)
35 (Y = CO2H, A = H)
36 (Y, A= CO(CH2)2
37 (Y, A= CO(CH2)3
38 (Y, A= CO(CH2)4
Exp.
Calc.
1.80
1.69
1.67
1.71, 1.71
2.18
2.66, 2.66
1.86
2.06, 2.06
(ꢁδ=0.20)
1.82
1.94, 1.94
(ꢁδ=0.12)
1.82
(ꢁδ=-0.11) (ꢁδ=0.04) (ꢁδ=0.48)
Exp.
Calc.
1.54
1.38
(ꢁδ=1.16)
2.87
1.85
1.71
1.73
1.75, 1.75
2.18
2.92, 2.93
(ꢁδ=-0.14) (ꢁδ=0.02) (ꢁδ=0.74)
Exp.
Calc.
1.60
1.77
(ꢁδ=0.17)
1.70
1.65
1.76, 1.77
2.12
2.59, 2.61
1.69, 1.70
1.57, 1.56
(ꢁδ=0.08)
1.59
(ꢁδ=0.24)
2.47
2.63
(ꢁδ=0.16)
2.66
2.53
(ꢁδ=-0.13)
-
(ꢁδ=0.11) (ꢁδ=0.48) (ꢁδ=-0.13)
1.71
1.47, 1.45
Exp.
Calc.
1.88
1.33, 2.32
1.77
1.65, 1.59
1.47
1.32, 1.21
1.55, 1.33
(ꢁδ=-0.23) (ꢁδ=-0.25) (ꢁδ=-0.06) (ꢁδ=-0.26) (ꢁδ=-0.32) (ꢁδ=-0.31)
Exp.
Calc.
1.85
1.76
1.74
1.78, 1.81
1.91
1.62, 1.69
1.87
1.94, 1.91
1.64
1.75
1.62, 1.69
(ꢁδ=0.01)
1.62
1.72, 1.82
(ꢁδ=0.02)
1.62
1.82, 1.82
(ꢁδ=0.20)
1.62
2.14, 1.81
(ꢁδ=0.35)
1.63
(ꢁδ=-0.09) (ꢁδ=0.05) (ꢁδ=-0.25) (ꢁδ=0.05)
Exp.
Calc.
1.77
1.67
1.70
1.75, 1.75
2.18
2.53, 2.53
1.74
1.63, 1.63
1.73, 1.73
(ꢁδ=-0.17)
1.84
1.45, 1.62
(ꢁδ=-0.31)
2.16
1.75
(ꢁδ=-0.04)
1.78
1.75
(ꢁδ=-0.03)
1.80
1.56, 1.56
0.97
ꢁꢁδ=0.41)
1.04
1.53
ꢁꢁδ=0.49)
0.44
0.19
ꢁꢁδ=0.07)
0.33
0.37
ꢁꢁδ=0.04)
0.25
(ꢁδ=-0.10) (ꢁδ=0.05) (ꢁδ=0.35) (ꢁδ=-0.11) (ꢁδ=-0.06)
Exp.
Calc.
-
-
1.78
1.68
1.69
1.77, 1.75
2.42
2.40, 3.47
1.95
1.62, 1.57
1.38
1.45, 1.36
(ꢁδ=0.02)
1.57
(ꢁδ=-0.10) (ꢁδ=0.07) (ꢁδ=0.51) (ꢁδ=-0.35)
Exp.
1.67
1.67
(ꢁδ=0)
1.65
1.70, 1.73
2.01
2.77, 1.57
1.88
1.51, 1.62
Calc.
1.64, 1.71
(ꢁδ=-0.49)
1.69
(ꢁδ=-0.11)
1.44, 1.66
1.95, 2.24
(ꢁδ=0.41)
0.62
ꢁꢁδ=0.18)
0.48
ꢁꢁδ=0.23)
(ꢁδ=0.06) (ꢁδ=0.16) (ꢁδ=-0.31) (ꢁδ=-0.02)
aspectra were recorded at 298 K (unless otherwise stated) and the signal of CHCl3 residue was calibrated at 7.26 ppm.
bSignals for 4′,9′-H and 8′,10′-H pairs of compounds 1−38 appear in general as broad doublets with Jgem ~ 12 Hz.
bSignal for the 5′,7′-H of compounds 1−38 appeared either as a broad singlet or as a narrow broad multiplet.
bSignal for the 1′,3′-H and 6′-H of compounds 1−38 is broad singlet.
cData taken from the literature.17
dSpectra recorded at 273 K.18

ACCEPTED MANUSCRIPT
As a representative example, the assignment of the 4′,9′-H and 8′,10′-H doublets is described
for the conformationally homogeneous N,N-dimethyl-2-methyl-2-adamantanamine 23 (see Figure 1
and Scheme 2).
N-CH3
1′, 3′, 5′, 7′
C-CH3
8′eq, 10′eq, 6′
4′eq, 9′eq′
4′ax, 9′ax
8′ax, 10′ax
2.20
2.10
2.00
1.90
1.80
1.70
1.60
(ppm)
1.50
1.40
1.30
1.20
1.10
1.00
0.90
1
Figure 1. H NMR spectrum of the N,N-dimethyl-2-methyl-2-adamantanamine 23 in CDCl3
solution (400 MHz) at 298 K (Nitrogen quadruple moment broadening effect combined with a
defined orientation of lone pair effects a broadening of the proton spectrum).
Molecular mechanics calculations using MM3 or MMFF94 force fields19 predicted that
conformer 23a, having an anti arrangement with respect to the CH3-C2′-N-lp dihedral angle, is the
only populated conformer for 23 since the next different conformer 23g is more than 10 kcal mol-1
higher in energy (Scheme 2). Conformer 23g results from 23a, either by rotation around the C2′-N
bond or nitrogen inversion; in 23g the N-Me group lies above the 1′-2′-3′-4′-5′-9′ cyclohexane ring
where 1,5-steric interactions with the 4′ax and 9′ax methine groups are severe (Scheme 2).

ACCEPTED MANUSCRIPT
Scheme 2. Scheme depicts nOe connectivities obtained for compound 23 being consistent with
conformer 23a; 1,5-interactions strongly destabilize conformer 23g and thus conformer 23a is the
only populated conformer.
nOe
CH3
CH3
CH3
9'ax
H
H
9'ax
H
CH3
CH3
N
N
4'ax
4'ax
H
H
H
2'
2'
1'
1'
H
H
H
H
CH3
3'
3'
H
H
5'
5'
6'
H
H
H
H
8'ax
8'ax
6'
nOe
H
H
H
H
H
7'
H
7'
H
H
H
H
10'ax
10'ax
H
H
23a
23g
The doublet resonance at 1.85 ppm was assigned to the protons 8′ax, 10′ax (J ~ 12 Hz)
because of its dipolar nOe correlation with C-Me at 0.88 ppm, and differentiated from the 4′ax,9′ax-
H doublet (J ~ 12 Hz) at 2.22 ppm which showed an nOe correlation with N-Me at 2.08 ppm
1
(Scheme 2, Figure 1). Using the scalar connectivities in the H-1H COSY spectrum, the
corresponding pairs of equatorial protons were identified at lower frequencies, the signal of
4′eq,9′eq-H appeared at 1.34 ppm and that of 8′eq,10′eq-H occurred at 1.64 ppm. In general, for the
assignment of the different doublets 4′ax,9′ax-H and 8′ax,10′ax-H, 4′eq,10′eq-H and 8′eq,10′eq-H in 2,2-
disubstituted adamantanes 14
−
31, 36 38 a similar procedure was used; in 2-substituted adamantanes
−
1
−
13, 32 35 the assignment of the relevant protons was straightforward as described into the first
−
paragraph of Results and Discussion section.
In all cases, the ꢁδ(γ-CH2) value is higher for the C-H4′axꢀꢀꢀYax or C-H9′axꢀꢀꢀYax contacts (Yax =
NR2, OR, F, CN, CMe2-OH or C = O) than for the C-H8′axꢀꢀꢀAax or C-H10′axꢀꢀꢀAax contacts (Aax = H,
CH3, t-Bu, C≡CH, C≡N); chemical shift difference ranges of ꢁδ4 -H = 0.30 - 1.05 ppm for the 4′,9′-
′,9′

ACCEPTED MANUSCRIPT
H pairs (higher separation is observed in compound 37) and ꢁδ8 -H = 0.1 - 0.5 ppm for the 8′,10′-
′
,10′
H pairs (Table 1) were obtained. Protons 4′ax, 9′ax-H are more deshielded than the 8′ax,10′ax-H
protons. For example, in the spectrum of compound 23 (Figure 1) the ꢁδ(γ-CH2) value is 0.88 ppm
for the 4′,9′-H pairs compared to 0.21 ppm for the 8′,10′-H pairs; this in turn implies that
redistribution of electronic shielding over the γ-cyclohexane CH2 group is affected more from C-
HaxꢀꢀꢀNMe2 contact rather than the C-HaxꢀꢀꢀH-C contact (Y = NMe2, A = CH3). The GIAO
calculations predicted correctly the relative chemical shifts positions.
The positions of the other resonances in the 1H NMR spectrum were identified as follows. The
broad signal of the equivalent protons 1′,3′-H was easily assigned using the corresponding carbon
resonances 1′,3′-C via 1JCH correlations in the HMQC 2D spectra. The resonances of the chemically
non equivalent protons 5′,7′-H were coincident for compounds 11, 12, 14, 20, 21, 23, 25 28 and 37;
−
in all the other cases the broad signals of the 5′-H and 7′-H protons, differing a little in the chemical
3
shift, can be differentiated through their J scalar correlations with 4′,9′-H or 8′,10′-H doublets,
respectively, in the 2D COSY spectra. A discussion about the relative position of 5′-H and 7′-H
resonances can be found in the Supporting Information. The GIAO calculations predicted correctly
the relative chemical shifts position of 5′- and 7′-H proton resonances in the above cases. The
deviation of GIAO calculated values from experimental values for most 1H NMR chemical shifts is
<0.7 ppm; this deviation is similar to the values previously observed.16,21
2.1.2 13C NMR Spectroscopy
The 13C chemical shifts of the adamantane derivatives 1
38 are given in Table 2. The
−
differentiation between γ-, and δ-carbons, that is, between 4′,9′-C and 8′,10′-C and between 5′-C
and 7′-C was the main task of the 13C NMR spectra assignment.
The first reported assignment of carbons 4′,9′ and 8′,10′ of a 2,2-disubstituted adamantane
was made for 2-methyl-2-adamantanol 14 on the basis of lanthanide-induced shift experiments.11e

ACCEPTED MANUSCRIPT
In another previous work, the signals of 4′,9′-C and 8′,10′ carbon pairs were assigned systematically
13
by measuring the C-13C coupling constants using the 2D INADEQUATE experiment.11c,20 This
experiment was first applied to 2-substituted adamantanes for the differentiation of 5′,7′-C signals;
however the assignment of these carbon signals in 2,2-disubstituted adamantanes was not
unambiguous. Rather than performing time consuming and sample demanded experiments, we
identified the location of 4′,9′-C and 8′,10′-C peaks (see Table 2) using the unequivocal assignment
1
of 4′,9′-H and 8′,10′-H proton signals and their JC-H correlations with the studied carbons (2D
HSQC or HMQC experiment). The resonances of 5′,7′-carbon resonances were differentiated using
1
the JC-H correlations and the assigned 5′,7′-proton resonances. When 5′,7′-H signals were almost
overlapped (see for example compounds 17, 26 etc), the 2JC-H correlations between 4′,9′-H and 5′-C
carbon or between 8′,10′-H and 7′ were employed as obtained from 2D HMBC spectra, but also the
GIAO calculations results were used to assign 5′,7′-C signals and to confirm other carbon resonance
assignments.21
Table 2. 13C Chemical shifts of adamantane carbons for the adamantanes derivatives 1
38.
−
Compounda
α-C
C(2′)
β-C
C(1′,3′)
γ-syn
C(4′,9′)
γ-anti
C(8′,10′)
δ-syn
C(5′)
δ-anti
C(7′)
ε-C
C(6′)
1 (Y = H, A = H)
Exp.
Calc.
37.90
41.78
28.60
35.02
37.90
41.66
37.90
41.79
28.60
34.90
28.60
34.90
38.90
41.63
(ꢁδ=3.88)
39.10
45.14
(ꢁδ=6.04)
54.10
57.63
(ꢁδ=3.53)
37.16
40.93
(ꢁδ=3.77)
74.66
79.37
(ꢁδ=6.42) (ꢁδ=3.76) (ꢁδ=3.89)
(ꢁδ=6.30)
28.50
35.10
(ꢁδ=6.60)
28.80
34.53
(ꢁδ=5.73)
27.05
33.60
(ꢁδ=6.55)
27.62
34.28
(ꢁδ=6.30)
28.20
34.56
(ꢁδ=6.36)
27.80
33.39
(ꢁδ=5.59)
26.89
33.57
(ꢁδ=6.68)
27.17
33.94
(ꢁδ=2.73)
38.60
42.66
(ꢁδ=4.06)
38.70
40.89
(ꢁδ=2.19)
36.86
40.90
(ꢁδ=4.04)
37.69
41.49
2 (Y = CH3, A = H)
3 (Y = C(CH3)3, A = H)
4 (Y = C≡N , A = H)
5 (Y = OH, A = H)
Exp.
Calc.
33.80
40.10
31.20
35.73
39.50
43.40
(ꢁδ=6.30) (ꢁδ=4.53) (ꢁδ=3.90)
Exp.
Calc.
29.50
35.64
33.10
35.05
41.90
43.94
(ꢁδ=6.14) (ꢁδ=1.95) (ꢁδ=2.04)
Exp.
Calc.
30.54
38.05
33.24
36.48
36.77
41.04
(ꢁδ=7.51) (ꢁδ=3.24) (ꢁδ=4.27)
Exp.
Calc.
34.64
41.45
31.12
35.09
36.62
40.59
(ꢁδ=4.64)
83.41
87.37
(ꢁδ=3.96)
55.62
60.59
(ꢁδ=4.97)
70.20
74.55
(ꢁδ=6.81) (ꢁδ=3.97) (ꢁδ=3.97)
(ꢁδ=6.66)
27.61
34.33
(ꢁδ=6.72)
27.84
35.00
(ꢁδ=7.16)
28.05
34.19
(ꢁδ=6.77)
27.57
34.12
(ꢁδ=6.62)
27.40
34.34
(ꢁδ=6.94)
27.67
33.75
(ꢁδ=3.80)
37.75
41.76
(ꢁδ=4.01)
38.06
42.14
(ꢁδ=4.08)
38.19
42.32
6 (Y = OMe, A = H)
7 (Y = NH2, A = H)
8 (Y = NMe2, A = H)
Exp.
Calc.
31.47
37.53
31.58
35.48
36.65
40.56
(ꢁδ=6.06) (ꢁδ=3.90) (ꢁδ=3.91)
Exp.
Calc.
35.08
40.82
30.86
34.63
37.82
41.19
(ꢁδ=5.74) (ꢁδ=3.77) (ꢁδ=3.37)
Exp.
Calc.
31.64
36.90
30.20
35.37
37.54
41.21

ACCEPTED MANUSCRIPT
(ꢁδ=4.35)
(ꢁδ=5.26) (ꢁδ=5.17) (ꢁδ=3.67)
(ꢁδ=6.14)
27.34
34.01
(ꢁδ=6.08)
27.23
33.99
(ꢁδ=4.13)
37.65
41.37
9 (Y = NHCOMe, A = H)
10 (Y = NO2, A = H)
11 (Y = F, A = H)
Exp.
Calc.
53.42
57.65
30.45
38.03
32.03
36.45
37.24
41.52
(ꢁδ=4.23)
89.13
92.75
(ꢁδ=3.62)
95.60
99.61
(ꢁδ=7.58) (ꢁδ=4.42) (ꢁδ=4.28)
(ꢁδ=6.65)
27.10
33.28
(ꢁδ=6.78)
27.10
33.01
(ꢁδ=3.72)
37.44
41.26
(ꢁδ=3.82)
37.30
41.45
Exp.
Calc.
31.54
36.53
32.50
36.71
37.44
40.98
(ꢁδ= 4.99) (ꢁδ=4.21) (ꢁδ=3.54) (ꢁδ=6.18 ) (ꢁδ=5.91)
Exp.
Calc.
32.90
39.22
31.50
35.90
35.80
39.72
27.70
33.90
27.30
33.39
(ꢁδ=4.01)
68.10
78.56
(ꢁδ=6.32) (ꢁδ=4.40) (ꢁδ=3.92)
(ꢁδ=6.20)
27.60
33.89
(ꢁδ=6.09)
27.00
33.34
(ꢁδ=4.15)
37.90
41.78
12 (Y = Cl, A = H)
Exp.
Calc.
36.00
42.25
35.00
34.95
38.30
42.31
(ꢁδ=10.46)
46.50
(ꢁδ=6.25) (ꢁδ=0.05) (ꢁδ=4.01)
(ꢁδ=6.29)
27.90
34.92
(ꢁδ=6.34)
27.10
34.11
(ꢁδ=3.88)
37.90
42.02
13 (Y = SH, A=H)
Exp.
Calc.
35.70
41.32
31.0
34.99
38.90
43.51
57.29
(ꢁδ=10.46)
73.97
77.25
(ꢁδ=3.28)
77.40
82.68
(ꢁδ=5.28)
75.71
(ꢁδ=5.62) (ꢁδ=3.99) (ꢁδ=4.61)
(ꢁδ=7.02)
27.61
34.37
(ꢁδ=6.76)
27.10
33.84
(ꢁδ=6.68)
27.02
33.27
(ꢁδ=7.01)
27.11
33.80
(ꢁδ=6.69)
27.00
33.78
(ꢁδ=6.84)
27.53
34.13
(ꢁδ=4.12)
38.39
41.92
(ꢁδ=3.53)
39.50
43.36
(ꢁδ=3.86)
37.77
40.07
14 (Y = OH, A = CH3)
15 (Y = OH, A = C(CH3)3
16 (Y = OH, A = Ph)
Exp.
Calc.
39.19
45.27
33.06
38.93
35.22
37.31
(ꢁδ=6.08) (ꢁδ=5.87) (ꢁδ=2.09)
Exp.
Calc.
34.60
41.35
35.60
38.50
35.00
39.50
(ꢁδ=6.75) (ꢁδ=3.50) (ꢁδ=4.90)
Exp.
Calc.
35.69
42.34
33.05
36.12
34.97
37.14
81.12
(ꢁδ=5.41)
72.76
74.50
(ꢁδ=1.74)
74.01
76.63
(ꢁδ=2.62)
74.89
81.31
(ꢁδ=6.42)
86.69
90.84
(ꢁδ=4.15)
86.08
86.49
(ꢁδ=0.41)
52.85
57.91
(ꢁδ=5.06)
58.77
64.06
(ꢁδ=6.65) (ꢁδ=3.07) (ꢁδ=2.17)
(ꢁδ=6.25)
26.84
33.73
(ꢁδ=6.89)
26.47
32.80
(ꢁδ=6.33)
26.54
32.18
(ꢁδ=6.60)
26.63
32.72
(ꢁδ=6.09)
26.36
33.04
(ꢁδ=6.68)
26.37
32.27
(ꢁδ=5.90)
26.71
33.54
(ꢁδ=6.83)
26.56
33.40
(ꢁδ=6.84)
27.57
34.82
(ꢁδ=7.25)
27.44
34.34
(ꢁδ=2.30)
37.60
41.35
(ꢁδ=3.75)
37.16
41.40
(ꢁδ=4.24)
38.28
39.55
(ꢁδ=1.27)
38.15
41.86
(ꢁδ=3.71)
38.27
40.79
(ꢁδ=2.52)
39.53
42.75
(ꢁδ=3.22)
37.43
42.58
17 (Y = OH, A = C≡CH)
18 (Y = OH, A = C≡N)
19 (Y = OSiMe3, A = C≡N)
20 (Y = O-COMe, A = CH3)
21 (Y = O-COtBu, A = CH3)
22 (Y = NH2, A = CH3)
23 (Y = NMe2, A = CH3)
Exp.
Calc.
38.64
48.30
31.51
39.76
35.33
33.67
(ꢁδ=9.66) (ꢁδ=8.25) (ꢁδ=1.66)
Exp.
Calc.
37.17
44.03
30.84
38.53
35.00
35.31
(ꢁδ=6.86) (ꢁδ=7.69) (ꢁδ=0.31)
Exp.
Calc.
37.39
44.87
31.13
36.71
34.91
36.57
(ꢁδ=7.48) (ꢁδ=5.58) (ꢁδ=1.66) (ꢁδ=6.26)
Exp.
Calc.
36.09
41.50
33.10
38.86
34.42
37.57
27.35
34.23
(ꢁδ=6.88)
26.82
26.52
(ꢁδ=0.30)
27.88
34.51
(ꢁδ=6.63)
27.44
(ꢁδ=5.41) (ꢁδ=5.76) (ꢁδ=3.15)
Exp.
Calc.
36.32
41.02
33.12
37.21
34.57
35.32
(ꢁδ=4.70) (ꢁδ=4.09) (ꢁδ=0.75)
Exp.
Calc.
38.89
44.58
33.10
37.12
34.66
38.19
(ꢁδ=5.69) (ꢁδ=4.02) (ꢁδ=3.53)
Exp.
Calc.
34.48
40.42
32.15
36.37
34.18
38.18
33.58
(ꢁδ=5.29)
~77.0
83.24
(ꢁδ=5.94) (ꢁδ=4.22) (ꢁδ=4.00)
(ꢁδ=6.14)
26.03
31.57
(ꢁδ=6.90)
25.55
31.45
(ꢁδ=5.15)
37.71
40.07
+
24 (Y = NHMe2 , A = CH3)
Exp.
Calc.
33.23
39.94
30.61
36.47
34.29
37.66
(ꢁδ=6.24)
54.40
58.98
(ꢁδ=4.58)
57.90
64.74
(ꢁδ=6.71) (ꢁδ=5.86) (ꢁδ=3.37)
(ꢁδ=5.54)
28.00
35.12
(ꢁδ=7.12)
27.20
33.92
(ꢁδ=5.90)
27.50
35.44
(ꢁδ=7.94)
27.00
33.83
(ꢁδ=2.36)
39.10
42.80
(ꢁδ=3.70)
38.60
40.52
25 (Y, A = NH(CH2)4)
26 (Y, A = NMe(CH2)4)b
Exp.
Calc.
34.06
42.17
32.19
36.68
33.47
37.26
(ꢁδ=8.11) (ꢁδ=4.49) (ꢁδ=3.79)
Exp.
Calc.
34.50
38.57
31.40
34.65
33.00
35.78
(ꢁδ=6.84)
58.52
63.98
(ꢁδ=5.46)
57.75
65.61
(ꢁδ=7.86)
67.31
72.59
(ꢁδ=4.07) (ꢁδ=3.25) (ꢁδ=2.78)
(ꢁδ=6.72)
27.55
33.83
(ꢁδ=6.28)
27.56
33.17
(ꢁδ=5.61)
26.97
34.42
(ꢁδ=6.83)
26.91
34.33
(ꢁδ=7.42)
26.96
34.16
(ꢁδ=7.20)
27.42
33.72
(ꢁδ=1.98)
38.54
42.15
(ꢁδ=3.61)
38.54
40.48
(ꢁδ=1.94)
38.35
42.25
27 (Y = NHCOMe, A = CH3)
28 (Y = NHCOtBu, A = CH3)
29 (Y = N-N≡N, A = CH3)
Exp.
Calc.
35.36
40.84
33.22
37.63
33.32
37.70
(ꢁδ=5.48) (ꢁδ=4.41) (ꢁδ=4.38)
Exp.
Calc.
35.49
41.32
33.34
35.93
33.37
36.48
(ꢁδ=5.83) (ꢁδ=2.59) (ꢁδ=3.11)
Exp.
Calc.
36.38
42.33
33.54
37.90
34.04
37.98

ACCEPTED MANUSCRIPT
(ꢁδ=5.28)
(ꢁδ=5.95) (ꢁδ=4.36) (ꢁδ=3.94)
(ꢁδ=7.45)
25.53
33.24
(ꢁδ=6.30)
26.80
34.06
(ꢁδ=3.90)
37.93
41.47
30 (
Y
= F , A = CH3
)
Exp.
98.88c
102.30
37.96d
43.88
33.14
37.51
35.55
39.21
Calc.
(ꢁδ=3.42)
73.78
93.92
(ꢁδ=20.14)
53.78
(ꢁδ=5.92) (ꢁδ=4.37) (ꢁδ=3.66)
(ꢁδ=7.71)
27.68
33.99
(ꢁδ=6.31)
27.73
34.26
(ꢁδ=6.53)
27.60
34.26
(ꢁδ=6.66)
27.67
33.72
(ꢁδ=6.05)
27.51
33.88
(ꢁδ=6.35)
27.14
33.05
(ꢁδ=5.91)
27.58
33.95
(ꢁδ=6.37)
28.26
34.93
(ꢁδ=7.26)
27.17
33.50
(ꢁδ=6.33)
27.14
35.19
(ꢁδ=8.05)
26.30
35.01
(ꢁδ=8.71)
27.67
33.50
(ꢁδ=5.83)
27.53
34.04
(ꢁδ=6.53)
26.88
34.00
(ꢁδ=7.12)
27.25
34.54
(ꢁδ=7.29)
27.61
34.34
(ꢁδ=3.54)
38.45
43.04
(ꢁδ=4.59)
41.23
42.59
31 (Y = Cl, A = CH3)
32 (Y = CMe2OH, A = H)
33 (Y = CMe2F, A = H)
34 (Y= COMe, A = H)
35 (Y= CO2H, A = H)
36 (Y, A= CO(CH2)2
37 (Y, A= CO(CH2)3
38 (Y, A= CO(CH2)4
Exp.
Calc.
39.26
46.92
33.10
39.52
35.27
38.16
(ꢁδ=7.66) (ꢁδ=6.42) (ꢁδ=2.89)
Exp.
Calc.
29.25
37.07
33.12
36.25
38.55
44.98
57.12
(ꢁδ=3.34)
(ꢁδ=7.82) (ꢁδ=3.13) (ꢁδ=6.43)
(ꢁδ=1.36)
e
e
Exp.
Calc.
-
29.0
36.82
32.60
36.20
38.50
44.62
-
56.16
42.44
(ꢁδ=7.82) (ꢁδ=3.60) (ꢁδ=6.12)
Exp.
Calc.
57.86
62.48
(ꢁδ=4.62)
49.60
53.59
(ꢁδ=3.99)
71.57
76.55
(ꢁδ=4.98)
53.09
59.01
(ꢁδ=5.92)
55.38
29.39
35.71
33.45
35.13
38.49
40.85
37.40
39.88
(ꢁδ=2.48)
38.20
41.38
(ꢁδ=3.18)
37.34
41.29
(ꢁδ=3.95)
38.17
42.78
(ꢁδ=4.61)
38.55
(ꢁδ=6.32) (ꢁδ=1.68) (ꢁδ=2.36)
Exp.
Calc.
29.50
35.67
37.45
37.40
33.68
42.33
(ꢁδ=6.17) (ꢁδ=0.05) (ꢁδ=8.65)
Exp.
Calc.
33.44
40.48
33.72
38.13
33.84
36.98
(ꢁδ=7.04) (ꢁδ=4.41) (ꢁδ=3.14)
Exp.
Calc.
32.17
39.90
32.03
35.12
33.97
38.80
(ꢁδ=7.73) (ꢁδ=3.09) (ꢁδ=4.83)
Exp.
Calc.
32.54
38.99
32.10
38.39
34.51
35.94
61.33
42.46
(ꢁδ=5.95)
(ꢁδ=6.45) (ꢁδ=6.29) (ꢁδ=1.43)
(ꢁδ=6.67)
(ꢁδ=6.73)
(ꢁδ=3.91)
aspectra recorded at 298 K or otherwise stated; brecorded at 273 K; cdoublet 1JC-F=171.8, ddoublet 2JC-F=19.2,3 enot clearly resolved.
The spectra of compounds 1
relative to the carbon resonances of the parent adamantane molecule. For the monosubstituted
adamantane derivatives 1 13 and 32 35, these are the resonances of the 4′,9′-C carbons which are
−
38 showed that 4′,9′-C or 8′,10′-C resonances are shifted upfield
−
−
shifted upfield with respect to 8′,10′-C signals because of the γ-gauche effect exerted from
substituent Yax on the resonances of 4′,9′-C carbons.3,11 In the 2,2-disubstituted adamantanes 14
−
17
and 20
−
31 and 36 38, 4′,9′-C resonances are generally shifted upfield with respect to 8′,10′-C
−
signals, that is, a stronger upfield γ-effect of (Yax, Aeq) compared to that of (Aax, Yeq) was observed.
In the above cases, carbons 4′,9′-C are in a syn-orientation with Yax group, which is, in general, a
second or third row heteroatom or C=O group, and 8′,10′-C are in a γ-syn-orientation with Aax
group, which can be considered in general as an alkyl group. Compound 15 (Y = OH, A = tBu)
represents the only exception, having a ꢁδ(γa,s) = - 0.60 ppm; in this last compound 8′,10′-C
resonances are shifted upfield with respect to 4′,9′-C signals (Table 2). The spectra of the

ACCEPTED MANUSCRIPT
adamantane derivatives showed that 5′-C resonance lies slightly downfield relative to 7′-C in most
cases and the relevant discussion is provided in the Supporting information. The deviation of GIAO
13
calculated values from experimental values for C NMR chemical shifts is < 7ppm; this deviation
is similar to the values previously observed.16,21 In some cases GIAO failed to predict correctly the
relative position of carbon signals (see Supporting Information).
2.2 13C Substituent Chemical Shifts
The upfield shift of 4′,9′-C with respect to 8′,10′-C carbons in the disubstituted adamantane
derivatives 15
−
31 and 36 38 results from the effect of (Yax, Aeq) and (Aax, Yeq) fragments on the
−
resonances of γ-carbons 4′,9′-C and 8′,10′-C, respectively. We will try next to comprehend the
relative position of carbon resonances through considering the γ-effect (γg and γa) contributions
from each of the two substituents Y, A on the resonances of these carbons. In the next paragraphs,
we shall discuss first the γg and the γa effect contributions on the resonances of 4′,9′-C and then on
the resonances of the 8′,10′-C carbons. Useful schemes first published by Duddeck's group are
depicted also in the present study and the results for common substituents are similar (see Schemes
3-10).11
4′,9′-C resonances: The existence of a γ-gauche shielding effect on the resonances of 4′,9′-C,
which can be attributed to the interaction between the polar substituent Yax (NR2, OH, F, Cl, SH,
N3, CN, OCOR, NHCOR etc) and these carbons, is legitimate. In the related 2-substituted
adamantanes 1-13, the γg SCS value on the 4′,9′-C resonances exerted by the group Y, where Y =
NR2, OH, F, CN, OCOR, NHCOR, NO2, COMe, CO2H, OCOR, NHCOR, alkyl, CMe2OH, CMe2F,
ranges from -2.9 to -7.3 ppm (Scheme 3).11h From Scheme 4 it becomes obvious that the presence
of an alkyl substituent (A = Me, C2H, Ph, t-Bu) at the same carbon doesn’t substantially influence
the γg SCS of these substituents Y. And also from Scheme 5 is obvious that the addition of an alkyl
group at the C-2 carbon of a monosubstituted adamantane derivative although it causes a downfield

ACCEPTED MANUSCRIPT
shift (an exception is present in the case of the 2-chloro group), will not change the upfield effect on
the 4′,9′-C carbon resonances. Overall, it seems that a net upfield shift of the 4′,9′-C resonances
relative to the corresponding carbon resonances of parent adamantane molecules is legitimate based
on the γg effect of the substituent Yax (NR2, OH, F, Cl, etc).
Scheme 3
4'
4'
9'
9'
10'
10'
.
.
8'
H
Y
.
.
8'
Hα
Hα
H
γ
Hγ
Y
Me
tBu
CN
NH2 NMe2
NH-COMe
-5.8
OH
O-Me O-COMe NO2
F
Cl
SH
COMe
-4.5
γgSCS
Y
-6.6
-4.9
-4.8
-7.3
-6.3
-6.5
-6.3
-5.9
-5.4
-6.4
-2.9
-6.9
CO2H
-4.2
CMe2OH
-4.8
CMe2F
-4.9
γgSCS
Scheme 4
4'
4'
.
.
.
.
9'
10'
9'
10'
H
Y
8'
8'
CH3
CH3
OH
Y
Me
CN
N3
NH2 NMe2
-7.4
NHAc
-6.3
OMe
-6.9
OAc
-6.4
F
Cl
γgSCS -6.3 -8.8 -6.0 -6.4
-6.4
-6.4 -6.4
4'
4'
.
.
.
.
9'
10'
9'
10'
H
HO
8'
8'
A
A
A
Me
Ph
-6.4
t-Bu
-6.9
γgSCS
-6.5

ACCEPTED MANUSCRIPT
Scheme 5
4'
4'
9'
9'
10'
10'
.
Y
.
Y
.
.
8'
8'
CH3
H
Y
Me
CN
NH2
+1.9
NMe2
+0.5
NH-CO-Me
+0.6
OH
O-Me
+1.1
O-CO-Me
+1.2
F
Cl
γaSCS
+2.0
-2.4
+1.6
+1.6
-1.9
8′,10′-C resonances: In the 2-monosubstituted adamantanes 1
−
13, 32 35, carbons 8′,10′-C
−
experience the γ-anti effect (γa SCS) of the Yeq group (Y = NR2, OH, F, N3, CN, OCOR, NHCOR,
Cl etc). A polar group Y causes a small negative γa SCS (upfield shift) to the carbon atom situated
in the γ-anti position, when 1,3-diaxial positions are free,11h,k and this structural issue is present in
the 2-substituted adamantanes (Scheme 6); the γa SCS magnitude raises as electronegativity
increases and the values for Y = NH2, OH, F are ~ - 0.4, -1, and -2 ppm and respectively. An alkyl
substituent causes a downfield effect. A second row heteroatom like Cl or SH exerted a small
positive γa SCS (downfield shift).
Scheme 6
4'
4'
9'
9'
10'
10'
.
.
8'
H
Y
.
.
8'
Hα
Hα
H
γ
Hγ
Y
Me
CN
NH2
-0.3
NMe2
-0.4
NH-CO-Me
-0.5
NO2
-0.5
OH
O-Me O-CO-Me
-1.2 -1.3
F
Cl
SH
γaSCS
+1.6
-0.7
-1.1
-2.1
+0.4
+1.0
The γSCS values depend on conformation, branching and substituent pattern.3b It has been
reported that the γ-anti effect of a second row polar group changes sign in systems having the
heteroatom attached to a bridghead atom.11k Thus, when the α-hydrogen in the 2-monosubstituted
adamantane is replaced by the axial alkyl substituent, γaSCS increases by 3-6 ppm, so the shielding
contribution from substituent Yeq on the γ-anti carbon signals disappear and 8′,10′-C carbons

ACCEPTED MANUSCRIPT
experience a downfield (positive) γaSCS in compounds 14
−
31, 36 38 (Scheme 7). The magnitude
−
of this downfield effect is smaller for the related 1-substituted adamantanes, being ~ +2.2 ppm for
1-adamantanol and +0.8 ppm for 1-adamantanamine. It is obvious from Scheme 10 that the
magnitude of the downfield γa SCS increases with the electronegativity of the substituent, and the
values for the amino, hydroxy and fluoro groups are ~ + 3.5, + 4.0 and + 4.4 ppm respectively.11k
Scheme 7
4'
4'
9'
9'
10'
10'
.
.
8'
H
Y
.
.
8'
CH3
CH3
Y
Me
CN
N3
NH2
+3.5
NMe2
+3.0
NH-CO-Me
+2.1
OH
O-Me
+3.5
O-CO-Me
+3.2
F
Cl
γaSCS
+2.0
+4.1
+2.8
+4.0
+4.4 +4.4
The resonances of 8′,10′-C should be affected from the upfield γ-gauche effect of the alkyl Aax
substituent, but its magnitude is expected to be seriously diminished when a first row atom
substituent is already present at the same carbon, as it is shown for some examples in Schemes 8
and 9.
Scheme 8
4'
4'
9'
9'
10'
10'
.
Y
.
Y
.
.
8'
8'
CH3
H
Y
NH2 NMe2
NH-CO-Me
-4.0
OH
O-Me
-1.9
O-CO-Me
-2.1
F
Cl
γ
gSCS -2.9
-3.4
-1.6
-0.3 -3.0
Scheme 9
4'
4'
9'
9'
10'
10'
.
.
HO
HO
.
.
8'
8'
A
H
A
Me
C2H
+0.1
Ph
t-Bu
γ
gSCS
-1.7
-1.9 -1.9

ACCEPTED MANUSCRIPT
Finally, the SCS effected from a pair of substituents Y,A attached at 2-position on the
resonances of γ-carbons were compared; two pairs of γ-carbons exist, that is, the carbons 4′,9′-C and
8′,10′-C (Scheme 10). Carbons 4′,9′-C experienced the effect of the Yax,Aeq arrangement in
cyclohexane ring sub-unit 1′-2′-3′-4′-5′-9′ and 8′,10′-C experienced the effect of the Aax,Yeq
arrangement in cyclohexane ring sub-unit 1′-2′-3′-10′-7′-8 (see Scheme 1). Data for 2,2-
disubstituted adamantane derivatives 14
−
31 and 36
−
38 were analyzed.
Scheme 10
4'
4'
9'
9'
10'
10'
.
.
H
H
Y
.
.
8'
8'
A
+
Y
A
Me
Me
CN
Me
N3
NHMe2
Me
NH2
Me
NMe2
Me
NH-Ac
Me
OH
Me
OSiMe3
Me
O-Ac
Me
OCOtBu
Me
OH
Ph
OH
C2H
-4.8
-0.9
OH
F
Me
t-Bu Me
-4.5 -7.2 -4.4
-4.5 -2.6 -3.9
-7.3
-4.8
-3.2
-5.8
-3.7
-4.7
-4.8
-2.7
-6.8
-4.8
-3.5
-4.8
-4.9
-2.9
-2.3 -4.8
-2.9 -2.3
γ
(4′,9′)SCS
-3.6
-4.6
-2.9
-3.3
γ
(8′,10′)SCS
Y
A
Cl
C=O
C=O
C=O
Me
-4.8
-2.6
(CH2)2
-4.2
(CH2)3
-5.6
(CH2)4
-5.8
γ
(4′,9′)SCS
-4.1
-3.9
-3.4
γ
(8′,10′)SCS
It becomes clear from the above discussion that both pairs of γ-carbons experience a total
upfield shift effect compared to the carbons of the parent adamantane. The upfield shift is larger in
magnitude for 4′,9′-C, effected from heteroatom substituents Y, resulting in the downfield shift of
8′,10′-C relative to 4′,9′-C resonances. Τhe downfield shift of the γ-carbons in the (Yeq, Meax)
conformer relative to (Yax, Meeq) has been observed in 1-Y-1-methylcyclohexanes and 4-tert-butyl-
1-Y-1-methylcyclohexanes using DNMR spectroscopy.11a,22
2.3 C-Hax···Yax contacts

ACCEPTED MANUSCRIPT
It has been suggested that the identification of a delocalization interaction n(Y) → σ*(C-H or
σ(C-H) → σ*(C-H) assures the presence of a hydrogen bonded contact.23-26 In a preceding paper,
the calculations predicted the improper H-bonding character of C-HaxꢀꢀꢀYax contacts in common
cyclohexane derivatives, due to the presence of n(Y) → σ*(C-H or σ(C-H) → σ*(C-H)
hyperconjugative interactions, and the variation of its strength according to the nature of contact
atom in group Yax.6 By increasing the strength of the contact the electronic redistribution inside the
γ-methylene is affected consistently raising the relevant chemical shift separation between the γ-
methylene protons, ꢁδ(γ-CH2).7 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–H···O hydrogen bonds in solution.27
An attempt was sought to analyze the interactions between axial substituents and C-Hax
groups using natural bond orbital (NBO) analysis24a - which analyzes the molecular wave function
to a set of localized bond and lone pair orbitals – applied in the B3LYP/6-31+G**geometry
optimized structures of the global minima at the same level of theory. Selected calculated
parameters are included in Table 3. The NBO analysis revealed that in all molecules the C-HaxꢀꢀꢀY
contacts cause an increase in % s-character and a contraction of the C-Hax bonds relative to the
equatorial bonds, and an increase in proton positive charge of axial relative to equatorial hydrogens
in the cyclohexane-subunit of the adamantane ring (the corresponding values of ꢁ% s-char. = (% s-
char. C4′-Hax − % s-char C4′-Heq), ꢁr4′ = r(C4′-Hax) − r(C4′-Heq), ꢁr9′ = r(C9′-Hax) − r(C9′-Heq) and ꢁq
= q(H4′ax) − q(H4′eq) or q(H9′ax) − q(H9′eq) respectively are included in Table 3). In compounds 2
−
38,
the C-HaxꢀꢀꢀY contact distances were smaller than the sum of the van der Waals radii.28 The
existence of hyperconjugative interactions n(Y) → σ*(C-Hax) in molecules 2 38 was examined by
−
the NBO method at the B3LYP/6-31+G**; second order perturbative energies are shown in Table 3
and the energy difference between the interacting orbitals and the matrix elements are included in
Table S2 in the Supporting Information. The calculations located overlap interactions in most of
compounds 2–38 (see Table 3). Although the first effects, i.e., the inequality rHꢀꢀꢀY < rvdw,H + rvdw,Y
,

ACCEPTED MANUSCRIPT
the increase in the % s-character and the contraction of the C-H bond, are common in improper H-
bonded contacts,29 the identification of a covalent component in a C-HꢀꢀꢀY contact, i.e., the
calculation of a hyperconjugative interaction n(Y) → σ*(C-H) is diagnostic for the presence of
improper hydrogen bonding.24 The resonance structures, Cδ--H δ+ + :Y ↔ C‾ + H-Y+ for a neutral
H-bonded complex describe qualitatively this electron transfer. However, the degree of
hyperconjugative electron transfer is only one of the effects contributing to improper hydrogen
bonding, the strength of which is also reflected by the increase in the % s-character and the
contraction of the C-Hax bond length.

ACCEPTED MANUSCRIPT
Table 3. Structural parametersa-c calculated and hyperconjugative energies for the C-HaxꢀꢀꢀYax contacts included in the adamantane derivatives 1
−
38
1
calculated at the B3LYP/6-31G+** level of theory; in addition H chemical shift separation of the γ-CΗ2 pairsd of adamantane cyclohexane ring subunits
for molecules 1 38.
−
a
c
e
System
C4-Hax, C9-Hax
C4-Heq, C9-Heq
Å
C8-Hax, C10-Hax
C8-Heq, C10-Heq
Å
hyperconjugative interaction
kcal mol-1
rC4′Hax···Y, rC9′Hax···Y θC4′Hax···Y, θC9′Hax···Y ꢁr4′,ꢁr9′
ꢁq4′,ꢁq9′
ꢁ% s-char 4′,9'
ꢁδ4′,9′-H
ꢁδ8′,10′-H
b
d
f
rC8′Hax···Y, rC10′Hax···Y θC8′Hax···Y, θC10′Hax···Y ꢁr8′,ꢁr10′
ꢁq8′,ꢁq10′ ꢁ% s-char 8′,10'
me
.
Å
deg
mÅ
E[na or σ(Y) → σ*(C4′-Hax)]
E[na or σ(Y) → σ*(C9′-Hax)]
1 (Y = H, A = H)c
2 (Y = CH3, A = H)
3 (Y = C(CH3)3, A = H)
4 (Y = CN, A = H)
5 (Y = OH, A = H)
6 (Y = OMe, A = H)
7 (Y = NH2, A = H)
8 (Y = NMe2, A = H)
9 (Y = NHAc, A = H)
10(Y = NO2, A = H)
11 (Y = F, A = H)
1.0986, 1.0986
1.0986, 1.0986
1.0972, 1.0972
1.0986,1.0986
1.0931, 1.0956
1.0990, 1.0990
1.0968, 1.0968
1.0976, 1.0976
1.0954, 1.0959
1.0984, 1.0985
1.0954, 1.0960
1.0985, 1.0985
1.0949, 1.0949
1.0987, 1.0987
1.0958, 1.0958
1.0987, 1.0987
1.0981, 1.0997
1.0979, 1.0980
1.0973, 1.0974
1.0976, 1.0976
1.0957, 1.0957
1.0980, 1.0980
1.0956, 1.0956
1.0978, 1.0978
1.0986, 1.0986
1.0986, 1.0986
1.0986, 1.0986
1.0987, 1.0987
1.0983, 1.0988
1.0988, 1.0987
1.0985, 1.0985
1.0976, 1.0976
1.0988, 1.0986
1.0980, 1.0978
1.0989, 1.0987
1.0982, 1.0979
1.0987, 1.0987
1.0981, 1.0981
1.0985, 1.0985
1.0983, 1.0983
1.0979, 1.0979
1.0981, 1.0980
1.0986, 1.0986
1.0974, 1.0974
1.0987, 1.0987
1.0976, 1.0975
1.0984, 1.0984
1.0977, 1.0977
2.56, 2.56
2.56, 2.56
2.29, 2.29
2.44, 2.44
2.10, 2.10
2.30, 2.32
2.93, 2.93
2.48, 2.48
2.62, 2.68
2.46, 2.47
2.60, 2.68
2.50, 2.49
2.67, 2.67
2.43, 2.43
2.71, 2.71
2.48, 2.48
2.16, 2.67
2.47, 2.46
2.81, 2.81
89, 89
0, 0
0, 0
-1.4, -1.4
0, 0
-5.9, -3.4
-0.5, 0.1
-0.8, -0.8
0.9, 0.9
-3.0, -2.6
0.8, 0.8
-3.1, -2.5
-0.7, -0.8
-3.8, -3.8
0.6, 0.6
-2.9, -2.9
0.2, 0.2
0, 0
0, 0
-2, 0
0, 0
2, -3
0
0
-
0.0
0.0
-0.09
0.10
0.16
0.16
0.19
0.12
0.17
0.15
0.15
-0.19
-0.15
88.8, 88.8
95.8, 95.8
113.4, 113.4
117.1, 120.2
89.6, 89.4
107.0, 107.0
89.3, 89.4
96.0, 96.0
89.8, 89.3
96.1, 95.9
91.3, 91.4
96.7, 96.7
89.4, 89.4
97.2, 97.2
89.6, 89.6
93.8, 95.3
89.5, 89.5
95.67, 95.78
0.31, 0.31
-0.01, 0.01
0.97, 0.61
0.13, 0.13
0.37, 0.37
-0.02, -0.02
0.59, 0.37
-0.24, -0.09
0.65, 0.46
-0.06, -0.02
0.71, 0.71
-0.03, -0.03
0.64, 0.64
0, 0
-0.01, -0.30
0.11, 0.09
1.06, 0.38
0.02, 0.03
0.44, 0.44
-0.03, -0.03
0.55, 0.55
0.11, 0.11
E[σ(C-H) → σ*(C4′-Hax)] = 0.21
E[σ(C-H) → σ*(C9′-Hax)] = 0.21
E[σ(C-H)g → σ*(C4′-Hax)] = 0.63
E[σ(C-H)g → σ*(C9′-Hax)] = 0.60
E[π(C≡N) → σ*(C4′-Hax)] = 0.13
E[π(C≡N) → σ*(C9′-Hax)] = 0.11
E[na(O) → σ*(C4′-Hax)] = 0.21, α = sp1.1
E[nβ(O) → σ*(C9′-Hax)] = 0.25, β = p
E[na(O) → σ*(C4′-Hax)] = 0.25, α = sp1.4
E[nβ(O) → σ*(C9′-Hax)] = 0.18, β = p
E[na(N) → σ*(C4′-Hax)] = 0.40, α = sp4.3
E[na(N) → σ*(C9′-Hax)] = 0.40
E[na(N) → σ*(C4′-Hax)] = 0.23, α = sp6.2
E[na(N) → σ*(C9′-Hax)] = 0.23
E[nα(N) → σ*(C4′-Hax)]=0.21, α = p
E[na(N-H) → σ*(C4′-Hax)] = 0.15
E[nα(N) → σ*(C4′-Hax)]=0.21
α = p
0.45
0.50
0.41
0.54
0.54
0.45
0.87
0.27
0.49
0.53
0.70
-2, 0
9, 9
-6, -6
16, 16
-4, -4
20, 14
-3, -4
22, 22
-3, -3
14, 14
-2, -2
-5, -26
3, 4
0.2, 1.7
-0.2, -0.1
-0.3, -0.2
1.2, 1.2
-2.3, -2.3
1.1, 1.2
6, 6
-8, -8
16, 16
-5, -5
14, 14
-5, -5
2.61, 2.61
2.54, 2.54
2.88, 2.88
2.48, 2.48
95.3, 95.3
88.9, 88.9
102.2, 102.2
89.3, 89.3
-
12 (Y = Cl, A = H)
-2.2, -2.2
0.7, 0.7
E[na(Cl) → σ*(C4′-Hax)] = 0.37
E[na(Cl) → σ*(C9′-Hax)] = 0.37, α = p
E[nβ(Cl) → σ*(C4′-Hax)] = 0.15
E[nβ(Cl) → σ*(C9′-Hax)] = 0.15, β = p
E[na(S) → σ*(C4′-Hax)] = 0.30
13 (Y = SH, A = H)
1.0970, 1.0962
1.0983, 1.0984
1.0984, 1.0987
1.0983, 1.0984
2.88. 2.93
2.46, 2.46
102.3, 102.7
89.3, 89.5
-1.3, -2.2
0.1, 0.3
16, 14
-5, -3
0.46, 0.99
0.12, 0.05
0.68
-0.10
E[nα(S) → σ*(C9′-Hax)] = 0.10, α = sp0.5
E[na(S) → σ*(C4′-Hax)] = 0.11
E[nα(S) → σ*(C9′-Hax)] = 0.73, α = p
E[na(O) → σ*(C4′-Hax)] = 0.40, α = sp1.1
E[nβ(O) → σ*(C9′-Hax)] = 0.37, β = p
E[na(O) → σ*(C4′-Hax)] = 0.54, α = sp1.1
E[nβ(O) → σ*(C9′-Hax)] = 0.38, β = p
E[na(O) → σ*(C4′-Hax)] = 0.39, α = sp1.1
E[nβ(O) → σ*(C9′-Hax)] = 0.42, β = p
E[na(O) → σ*(C4′-Hax)] = 0.33, α = sp1.2
E[nβ(O) → σ*(C9′-Hax)] = 0.41, β = p
E[na(O) → σ*(C4′-Hax)] = 0.33, α = sp1.2
E[nβ(O) → σ*(C9′-Hax)] = 0.41, β = p
14 (Y = OH, A = CH3)
1.0939, 1.0945
1.0984, 1.0984
1.0919, 1.0935
1.0988, 1.0985
1.0942, 1.0945
1.0984, 1.0983
1.0943, 1.0946
1.0982, 1.0981
1.0942, 1.0946
1.0977, 1.0978
1.0965, 1.0966
1.0981, 1.0979
1.0902, 1.0941
1.0985, 1.0984
1.0962, 1.0965
1.0983, 1.0980
1.0963, 1.0965
1.0979, 1.0978
1.0966, 1.0967
1.0974, 1.0973
2.46, 2.53
2.21, 2.22
2.34, 2.44
1.96, 2.04
2.47, 2.53
3.55, 3.56
2.49, 2.53
2.91, 2.89
2.52, 2.60
2.85,2.83
97.2, 96.9
113.3, 113.2
97.3, 96.5
117.7, 121.6
97.4, 97.2
119.4, 119.5
97.1, 97.0
108.0, 108.1
96.7, 96.4
-4.5, -3.9
-1.6, -3.3
-6.9, -5.0
-8.3, -4.3
-4.0, -3.8
-2.1, -1.5
-3.9, -3.5
-1.6, -1.3
-3.5, -3.2
-0.8, -0.6
26, 19
-3, -5
30, 14
3, -8
25, 21
5, 4
22, 17
8, 7
17, 10
6, 6
0.94, 0.70
0.36, 0.40
1.42, 0.91
1.37, 0.87
0.96, 0.79
0.45, 0.54
0.90, 0.82
0.53, 0.53
0.84, 0.60
0.50, 0.51
0.63
0.79
0.68
0.62
0.51
0.13
0.49
0.02
0.36
0.19
15 (Y = OH, A = C(CH3)3)
16 (Y = OH, A = Ph)
17 (Y = OH, A = C2H)
18 (Y = OH, A = CN)
107.9, 108.1

ACCEPTED MANUSCRIPT
19(Y = OTMS, A = CN)
20 (Y= OAc, A = CH3)
1.0944, 1.0958
1.0981, 1.0979
1.0944, 1.0958
1.0981, 1.0979
1.0962, 1.0960
1.0978, 1.0978
1.0962, 1.0960
1.0978, 1.0978
2.56, 2.52
2.81, 2.81
2.45, 2.58
2.17, 2.23
96.6, 96.9
108.2, 108.1
97.3, 96.3
-3.5, -3.2
-1.6, -1.8
-3.7, -2.1
-1.6, -1.8
16, 12
6, 6
3, 15
-5, -3
0.79, 0.66
0.51, 0.51
0.40, 0.71
0.50, 0.50
E[na(O) → σ*(C4′-Hax)] = 0.24, α = sp1.2
E[nβ(O) → σ*(C9′-Hax)] = 0.33, β = p
E[na(O)→σ*(C4′-Hax)] =0.49
E[nβ(O)→σ*(C4′-Hax)] =1.09
α = sp0.7, β = p
0.55
0.46
0.21
0.15
113.2, 112.7
21 (Y = OCOtBu, A= CH3)
22 (Y = NH2, A = CH3)
23 (Y = NMe2, A = CH3)
1.0941, 1.0955
1.0982, 1.0979
1.0935, 1.0935
1.0987, 1.0987
1.0939, 1.0939
1.0988, 1.0988
1.1016, 1.1015
1.0955, 1.0955
1.0937, 1.0938
1.0988, 1.0988
1.0939, 1.0943
1.0988, 1.0988
1.0956, 1.0969
1.0978, 1.0982
1.0968, 1.0956
1.0982, 1.0979
1.0959, 1.0962
1.0978, 1.0978
1.0959, 1.0959
1.0982, 1.0982
1.0960, 1.0960
1.0983, 1.0983
1.0946, 1.0947
1.0960, 1.0960
1.0961, 1.0959
1.0983, 1.0982
1.0961, 1.0961
1.0984, 1.0984
1.0954, 1.0956
1.0980, 1.0980
1.0956, 1.0952
1.0979, 1.0980
2.47, 2.59
2.16, 2.23
2.54, 2.54
2.17, 2.17
2.55, 2.55
2.15, 2.15
1.96, 1.97
2.16, 2.14
2.55, 2.54
2.12, 2.18
2.56, 2.60
2.14, 2.14
2.18, 3.07
2.18, 2.14
2.16, 3.05
97.1, 96.2
113.1, 112.6
97.6, 97.6
113.4, 113.4
98.2, 98.2
113.0, 113.0
105.6, 105.4
112.1, 112.4
98.2, 97.4
113.2, 112.5
98.9, 96.7
-4.1, -2.4
-1.9, -1.6
-5.2, -5.2
-2.3, -2.3
-4.9, -4.9
-2.3, -2.3
6.1, 6.0
-1.4, -1.3
-5.1, -5.0
-2.2, -2.3
-4.9, -4.5
-2.3, -2.3
-2.2, -1.3
-2.6, -2.4
-1.4, -2.3
-2.3, -2.8
12, 7
1, -1
0.48, 0.32
0.12, 0.09
1.0, 1.0
E[na(O) → σ*(C4′-Hax)] = 0.27,α=sp1.83
0.46
0.48
0.15
0.31
26, 26
-3, -3
17, 17
-3, -3
-55, -55
-14, -14
20, 24
-4, -3
19, 20
-5, -3
4, -9
E[na(N) → σ*(C4′-Hax)] = 0.63, α = sp4.2
E[na(N) → σ*(C9′-Hax)] = 0.63
0.52, 0.52
0.97, 0.97
0.53, 0.53
-0.85, -0.80
0.44, 0.44
0.96, 0.97
0.53, 0.54
-0.96, -0.97
0.53, 0.54
0.50, 0.23
0.60, 0.58
0.26, 0.49
0.56, 0.58
E[na(N) → σ*(C4′-Hax)] = 0.28, α = sp7.4
E[na(N) → σ*(C9′-Hax)] = 0.28
0.88
0.21
+
24 (Y = NHMe2 , A = CH3)
Ε[σ(C4′-Hax) → σ*(Ν-Η)]=2.06
0.46
0.10
Ε[σ(C9′-Hax) → σ*(Ν-Η)]=1.92
25 (Y,A = NH(CH2)4)
26 (Y,A = NMe(CH2)4)d
27 (Y = NHAc, A = CH3)
28 (Y = NHCOtBu, A = CH3)
E[nα(N)→σ*(C4′-Hax)]=0.50, α=sp3.33
0.48
0.34
-
0.81;0.71
0.36
0.13;0.22
0.29
112.9, 112.9
108.8, 96.9
113.2, 113.3
E[nα(N) → σ*(C4′-Hax)]=0.21
α = p
1, -2
-9, 4
-2, 1
E[nα(N)→σ*(C4′-Hax)]=0.11, α = sp1.83
E[σ(N-H) → σ*(C4΄-Hax)] =0.11
E[nβ(N) → σ*(C9′-Hax)]=0.15, β =p
E[nα(N)→σ*(C4′-Hax)]=0.57, α =sp1.2
0.32
0.29
113.3, 113.2
29 (Y = N3, A = CH3)
30 (Y = F, A = CH3)
1.0946, 1.0952
1.0980, 1.0978
1.0945, 1.0946
1.0981, 1.0980
1.0940, 1.0940
1.0980, 1.0979
1.0933, 1.0933
1.0993, 1.0993
1.0959, 1.0961
1.0978, 1.0976
1.0967, 1.0967
1.0977, 1.0977
1.0956, 1.0956
1.0977, 1.0977
1.0989, 1.0989
1.0986, 1.0986
2.49, 2.60
2.19, 2.19
2.48, 2.48
2.28, 2.28
2.73, 2.73
98.3, 97.0
113.0, 113.2
96.4, 96.4
113.2, 113.2
104.0, 104.1
-3.4, -2.6
-1.9, -1.5
-3.6, -3.4
-1.0, -1.0
-4.0, -3.9
-2.1, -2.1
-6.0, -6.0
0.3, 0.3
8, 18
-6, -5
20, 20
-5, -5
18, 18
-6, -6
31, 31
-4, -4
0.51, 0.76
0.45, 0.43
0.73, 0.73
0, 0
0.90, 0.91
0.63, 0.63
1.39, 1.38
0.03, 0.03
0.55
0.61
0.63
0.65
0.19
0.13
0.13
0.13
-
31 (Y = Cl, A = CH3)
32 (Y = CMe2OH, A = H)
E[nβ(Cl) → σ*(C4′-Hax)]=0.64, β =p
E[nβ(Cl) → σ*(C9′-Hax)]=0.63
2.41, 2.41
118.9, 118.9
E[na(O) → σ*(C4′-Hax)] = 1.34
E[na(O) → σ*(C9′-Hax)] = 0.98, α = sp1.2
E[nβ(O) → σ*(C4′-Hax)] = 0.66
E[nβ(O) → σ*(C9′-Hax)] = 0.98, β = p
E[na(F) → σ*(C4′-Hax)] = 0.43
33 (Y = CMe2F, A = H)
1.0939, 1.0939
1.0990, 1.0990
1.0989, 1.0989
1.0984, 1.0984
2.39, 2.39
118.78,117.88
-5.1, -5.1
0.5, 0.5
33, 33
-5, -5
1.18, 1.17
0, 0
0.54
0.13
E[na(F) → σ*(C9′-Hax)] = 0.30, α = sp0.5
E[nβ(F) → σ*(C4′-Hax)] = 0.32
E[nβ(F) → σ*(C9′-Hax)] = 0.29, β = p
E[nγ(F) → σ*(C4′-Hax)] = 0.41
E[nγ(F) → σ*(C9′-Hax)] = 0.27, γ = p
34 (Y = COMe, A = H)
35 (Y = CO2H, A = H)
1.0924, 1.0963
1.0988, 1.0985
1.0981, 1.0958
1.0980, 1.0981
1.0984, 1.0989
1.0983, 1.0980
1.0988, 1.0986
1.0978, 1.0980
2.40, 2.77
2.82, 2.84
119.0, 115.0
96.11, 96.22
-6.4, -2.2
0.1, 0.9
0.1, -2.3
1.0, 0.6
34, 13
-5, -7
11, -1
-5, -4
1.5, 0.64
0.03, -0.04
0.65, 0.12
-0.08, -0.01
E[na(O) → σ*(C4′-Hax)] = 0.49, α = sp0.7
0.13
0.12
0.27

ACCEPTED MANUSCRIPT
36 (Y, A = CO(CH2)2
1.0952, 1.0952
1.0985, 1.0985
1.0978, 1.0978
1.0982, 1.0982
2.63, 2.63
2.42, 2.42
121.1, 121.2
97.7, 97.7
-3.3, -3.3
-0.4, -0.4
22, 22
-5, -4
0.88, 0.87
-0.08, -0.01
E[na(O)→σ*(C4′-Hax)]=0.10
E[na(O)→σ*(C9′-Hax)]=0.11
0.56
0.12
E[nβ(O)→σ*(C4′-Hax)]=0.38
E[nβ(O)→σ*(C9′-Hax)]=0.39
α = sp0.8, β = p
E[π(C=O→σ*(C4′-Hax)]=0.13
E[π(C=O→σ*(C9′-Hax)]=0.13
E[na(O) → σ*(C4′-Hax)] = 0.10
E[na(O) → σ*(C9′-Hax)] = 0.11, α = sp0.8
E[nβ(O) → σ*(C4′-Hax)] = 0.38
E[nβ(O) → σ*(C9′-Hax)] = 0.39, β = p
E[na(O) → σ*(C4′-Hax)] = 0.20
E[na(O) → σ*(C9′-Hax)] = 0.60, α = sp0.8
E[nβ(O) → σ*(C4′-Hax)] = 0.26
E[nβ(O) → σ*(C9′-Hax)] = 1.17, β = p
E[π(C=O→σ*(C9′-Hax)] = 0.43
E[na(O) → σ*(C4′-Hax)] = 0.42, α = sp0.8
E[nβ(O) → σ*(C4′-Hax)] = 0.58, β = p
E[π(C=O→σ*(C9′-Hax)] = 0.37
37 (Y, A = CO(CH2)3
38 (Y, A = CO(CH2)4
1.0918, 1.0939
1.0988, 1.0985
1.0956, 1.0968
1.0983, 1.0981
2.33, 2.46
2.03, 2.64
120.7, 119.2
98.4, 96.5
-7.0, -4.6
-2.7, -1.3
20, 22
-8, -5
1.59, 1.10
0.55, 0.37
1.04
0.44
0.33
0.25
1.0920, 1.0983
1.0985, 1.0983
1.0964, 1.0959
1.0985, 1.0985
2.35, 3.17
2.11, 2.14
117.6, 109.9
96.7, 97.0
-6.5, 0.0
-2.1, -2.6
26, -1
-5, -6
1.46, 0.18
0.48, 0.47
aꢁr4′ = r(C4′-Hax) − r(C4′-Heq)], ꢁr9′ = r(C9′-Hax) − r(C9′-Heq)], bꢁr8′ = r(C8′-Hax) − r(C8′-Heq)], bꢁr10′ = r(C10′-Hax) − r(C10′-Heq)], cꢁq4′ = (qH4′ax − qH4′eq), cꢁq9′ = (qH9′ax − qH9′eq), dꢁq8′ = (qH8′ax − qH8′eq), dꢁq4′ = (qH10′ax − qH10′eq), eꢁ% s-char.4′
=
(% s-char. C4′-Hax − % s-char. C4′-Heq), eꢁ% s-char.9′ = (% s-char. C9′-Hax − % s-char. C9′-Heq), fꢁ% s-char.8′ = (% s-char. C8′-Hax − % s-char. C8′-Heq); fꢁ% s-char.10′ = (% s-char. C10′-Hax − % s-char. C10′-Heq); g1H NMR chemical
shift separation within γ-CΗ2, [ꢁδ(γ-CH2) 4′,9′ = ꢁδ4′,9′ = δ(H4′,9′ax) − δ(H4′,9′eq)], [ꢁδ(γ-CH2) 8′,10′ = ꢁδ8′,10′ = δ(H8′,10′ax) − δ(H8′,10′eq)]; gcorrespond to different C-H bonds included by the same methyl or by different
methyl groups inside a t-Bu group.

When an axial substituent is attached to a cyclohexane ring sub-unit of adamantane 1 in derivatives
ACCEPTED MANUSCRIPT
2
−
38, the calculations locate hyperconjugative interactions in all compounds 2
presence of improper hydrogen bonding in C-HaxꢀꢀꢀY contacts, for example n(N or O or F or Cl) → σ*(C-
H) in 5 23, 25 38 or/and σ(C-H) → σ*(C-H) in 2, 3, 20 31, 36 38, π(C≡N or C≡C) → σ*(C-H) in 4, 17-
−
38, suggesting the
−
−
−
−
19. In an improper H-bonded contact, the major C-H bond shortening contributors are steric compression
between C-Hax and Yax together with electrostatic attraction between positive H and negative C; these
prevail the major lengthening contributors of the weak H-bonded C-HaxꢀꢀꢀYax contact which are the
electrostatic attraction (or dispersion) between the positive H of C-H dipole, and the Lewis base Y and the
hyperconjugative electron donation n(Y) → σ*(C-H).25,26 The relative strength of the improper H-bonded
contacts included by compounds 2 38 in Table 3, is reflected by the changes on the contraction of the C-
−
Hax bonds, the increase in the % s-character of the C-Hax bonds relative to the equatorial bonds of the
cyclohexane-subunit of adamantane ring, and the relevant energy values of hyperconjugative interactions.
The effect of a stronger contact is to increase the contraction and the % s-character of C-Hax bonds, and
the postive charge of Hax protons compared to adamantane 1; the observed increased difference between
1
the H chemical shifts of the axial and equatorial protons within the γ-methylene group, ꢁδ(γ-CH2), can
likely represent an experimental parameter reflecting the strength of the contact.27
When the acceptor group is Y = OR, NR2 and the second row lone-pair bearing heteroatom is
directly connected to the cyclohexane ring-subunit, the weak interaction [n(Yax) → σ*(C-Hax), E ≤ 0.63
kcal mol-1] is located; the hyperconjugative interaction efficiency was increased on going from Y = F and
OH or OMe to NH2 or NMe2, which is consistent with the basicity order of these groups. The contact
angle for the 1,4-C-HaxꢀꢀꢀYax contacts in compounds 2, 4-23, 25-31 is larger than 90° permitting weak
overlap interactions for these contacts.30
When the interacting atom of the Y group in C-HaxꢀꢀꢀY contacts changes from a second row to a
third row lone-pair bearing heteroatom31 (Y = SR, Cl in compounds 12, 13), a substantial elongation of
contact distances by 0.2-0.5 Å and an increase in contact angles by 5-6° is calculated (for example θ(C-
HaxꢀꢀꢀYax) is 95° in compounds 11 and 5 and changes to 102-103° in 12, 13). The interaction energy
E[n(Υax) → σ*(C-Hax)] increases by 0.2 – 0.7 kcal mol-1 because of a more effective orbital overlap. The

% s-character and the contraction of the C-Hax bonds relative to the equatorial bonds is also increased.
ACCEPTED MANUSCRIPT
Recent comparative studies of the hydrogen bonded dimers Me2OꢀꢀꢀHOMe, Me2SꢀꢀꢀHOMe and SꢀꢀꢀHN
showed that sulfur can be an almost equally good hydrogen bond acceptor as oxygen.32 In agreement with
these observations, the calculations predicted the stronger hyperconjugative interactions for the C-HꢀꢀꢀS
contact in compound 13, where the contact atom of the axial substituent is tetrahedral sulfur, compared to
its oxygen analog 5, and for the C-HꢀꢀꢀCl contact in compounds 12, 31 compared to 11, 30. The examined
experimental value of ꢁδ(γ-CH2) increases consistently from 0.53, 0.54, 0.54 ppm in 11 (Y = F), 5, 6 (Y =
OH, OMe respectively), to 0.70 in 12 (Y = Cl) and 0.68 ppm in 13 (Y = SH ).
The geminal equatorial alkyl group, methyl and tert-butyl, in compounds 14 and 15 respectively
forces the corresponding axial group to approach C-Hax bonds and reduces the contact distance C-
HaxꢀꢀꢀYax, resulting in the enhancement of the hyperconjugative energy and the other characteristic
improper hydrogen bonding interaction parameters (ꢁ% s char., ꢁr). Thus, the interaction energy
E[n(Υax) → σ*(C-Hax)] and the value of ꢁδ(γ-CH2) increases consistently from 0.24 kcal mol-1 and 0.54
ppm in 7 (Y = OH, A = H) to 0.24 kcal mol-1 and 0.63 in 14 (Y = OH, A = Me) and 0.54 kcal mol-1 and
0.79 ppm in 15 (Y = OH, A = t-Bu) respectively; in the last compound t-Bu reduced the C-HaxꢀꢀꢀY contact
distance by ~ 0.3 Å, increases the contact angle by 6° and raised the value by 0.25 ppm. Upon capping
heteroatom lone pair in the acetylated derivatives 9, 20, 21, 27, 28 (Y = OAc or NHAc) the strength of the
contact is seriously reduced and the relevant values of ꢁδ(γ-CH2) are 0.27, 0.46, 0.46, 0.36, 0.32 ppm,
respectively, compared to the parent lone pair bearing compounds having values 0.54, 0.63 in 5, 14 (Y =
OH) and 0.45 or 0.48, 0.87 or 0.88 in 7, 8, 22, 23 (Y = NH2, NMe2).
The relative strength of the effect from different substituents on the C-HaxꢀꢀꢀYax contact and the
ꢁδ(γ-CH2) values can be obtained from the data of the monosubstituted compounds 2 13. The
−
disubstituted derivatives, including those mentioned in the previous paragraph, can be also used to
compare the relative strength of the effect from different substituents on the C-HaxꢀꢀꢀY contact and the
ꢁδ(γ-CH2) values. For example in disubstituted derivatives 14
or Cl) and is axial in the cyclohexane ring sub-unit 1′-2′-3′-4′-5′-9′. Also A is an alkyl group in
compounds 14, 15 and 20 31 or Ph or C≡CH or C≡N groups in compounds 16, 17, 18, 19, respectively,
−
19 and 20
−
31, Y is an heteroatom (N, O, F
−

and is axial in the cyclohexane ring sub-unit 1′-2′-3′-10′-7′-8. For example, the stronger effect of Yax
ACCEPTED MANUSCRIPT
compared to that of Aax in the chemical shift separation within the γ-cyclohexane CH2 was observed in the
case of compound 15 (Y = OH, A = t-Bu) where OH group antagonizes the large t-Bu group. Thus, in
compound 15, 8′ax,10′ax-H are sterically compressed by the syn axial t-butyl group and the observed
separation for the 8′,10′-H pairs was 0.49 ppm and the 8′ax,10′ax-H doublet resonance appeared at 2.17
ppm, whereas the values for the γ-CH2 of 4′ax,9′ax-H indicated a more significant interaction; the
electronic distribution within the 4′,9′ γ-CH2 was affected to a greater effect by the hydroxyl group in the
axial position and the 4′ax,9′ax-H signal appeared more downfield at 2.26 ppm, that is, 0.79 ppm from the
4′eq,9′eq-H signal.
It is interesting to note that when the NMe2 group of compound 23 was protonated, upon addition of
a drop of TFA inside the NMR tube resulting in 24, ꢁδ4′,9′-H was reduced from 0.88 to 0.46 ppm. The
calculations suggested that the N+-H proton strongly repels the 4′ax proton, since the distance between
these protons was calculated to be ~ 1.99 Å. This can explain why protonation was so slow, the time
required in order to obtain sharp signals in the 1H NMR spectrum being several weeks!
Of considerable interest are the structures 32 38 and 3 and 24 with contacts in which the improper
−
hydrogen bonding character can be enhanced because of a linker group between adamantane C-2 and Y
group; in these compounds Xax-Y bond vector bisects the cyclohexane ring sub-unit (allowing the
formation of a six-membered ring) and interacts more effectively with both the C-Hax bonds of
cyclohexane ring 1′-2′-3′-4′-5′-9′; 1,5-C-HaxꢀꢀꢀYax contacts are formed between atoms Hax and O for 32 38
−
and Hax and C-Ht-Bu for 3. The transition from compound 5 to compound 32 results in increased contact
C-HaxꢀꢀꢀOax-C angles (θC-ΗaxꢀꢀꢀO = 96° in 5 to θC-ΗaxꢀꢀꢀO = 119° in 32) and reduced contact distances (by ~
0.2-0.3 Å, Scheme 6) giving rise to increased hyperconjugative energies by ~ 1 kcal mol-1 when the
stronger orbital interactions n(O) → σ*(C-Hax) for each compound are compared. The improper H-
bonding interactions strengthen considerably, since the CMe2-OH group is conformationally homogenous
and the C-OH bond bisects cyclohexane ring, resulting in a significant contraction and increase of the %
s-character of the C-Hax bonds relative to the equatorial bonds; the axial proton positive charge changes
also increase (the values of the ꢁ% s-char. and ꢁq and of the C-Hax bond contraction changes from C-Hax