Synthesis and NMR spectral studies of N-chloroacetyl-2,6-diarylpiperidin-4-ones

Article abstract of DOI:10.1016/j.saa.2007.01.013

A series of 2,6-diarylpiperidin-4-ones having electron withdrawing chloroacetyl group at the heterocyclic nitrogen were synthesized. Unambiguous characterizations of the synthesized compounds were achieved by one-dimensional (¹H NMR and ¹³

Full text of DOI:10.1016/j.saa.2007.01.013

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Spectrochimica Acta Part A 68 (2007) 1153–1163
Synthesis and NMR spectral studies of
N-chloroacetyl-2,6-diarylpiperidin-4-ones
G. Aridoss, S. Balasubramanian1, P. Parthiban, S. Kabilan∗
Department of Chemistry, Annamalai University, Annamalainagar 608002, Tamil Nadu, India
Received 5 April 2006; accepted 15 January 2007
Abstract
A series of 2,6-diarylpiperidin-4-ones having electron withdrawing chloroacetyl group at the heterocyclic nitrogen were synthesized. Unam-
biguous characterizations of the synthesized compounds were achieved by one-dimensional (1H NMR and 13C NMR) and two-dimensional
(HOMOCOSY, NOESY and HSQC spectra for compounds 8 and 9 and HOMOCOSY spectrum only for 10) NMR spectroscopic data. The
conformational preferences of N-chloroacetyl-2,6-diarylpiperidin-4-ones with and without alkyl substituent at C-3 and C-5 (8–14) have also been
discussed using the spectral studies. The spectral data and extracted coupling constant values suggest that the compounds 8, 12 and 14 adopt
flattened boat conformation whereas the remaining compounds exist in twist-boat conformations in solution with coplanar orientation of the
chloroacetyl moiety present at the heterocyclic nitrogen. The substituent parameters for the chloroacetyl moiety on the heterocyclic ring carbons
have also been derived and discussed elaborately on the basis of their steric, electronic and ␥-eclipsing interaction. This substituent at the nitrogen
causes a substantial change on the chemical shifts of ring carbons and the associated protons.
© 2007 Elsevier B.V. All rights reserved.
Keywords: 1H NMR; 13C NMR; 2D techniques; Conformation; Substituent effect; 2,6-Diarylpiperidin-4-ones; Chloroacetylation
1. Introduction
introduction of certain heteroconjugate groups such as –NO,
–CHO, –COCH3, –COC6H5, etc., at the ring nitrogen of 2,6-
disubstituted piperidine ring system have reported to cause a
major change in ring conformation, chemical shifts of carbons
and associated protons and also orientation of the substituents
[9–13]. Further it has also been well documented by Johnson
and Malhotra [14] that in N–NO, N-acyl, N-sulphonyl deriva-
tives of 2-methylpiperidine and r-2, c-6-dimethylpiperidine,
the methyl groups occupy axial position due to A1,3 strain
operated by the various type of substituents present at nitro-
gen on the equatorial methyl group (at both the ␣-positions).
Hence, the change in ring conformation is mainly ascribed
to an extensive delocalization of the lone pair of electrons
on the nitrogen with the ␲-electron orbital of –COR func-
tion [9–13,15]. Owing to this, –N–CO acquires partial double
bond character, which in turn leads to restricted rotation
around this bond and consequently affects the conformation
of the ring and chemical shifts of carbons and the attached
protons.
NMR spectroscopy is a versatile tool for providing informa-
tion about the structural diagnosis of most of the heterocyclic
compounds. It also finds its frequent use in the conforma-
tional analysis and in understanding the influence of electronic
and conformational effects on chemical shifts and coupling
constants. 1H and 13C NMR technique have been exten-
sively applied in deriving stereochemical information about
a wide variety of systems. Vicinal coupling constant values
have been used in conformational analysis as it can give clue
about the orientation of the substituent [1,2]. Substituted 2,6-
diarylpiperidin-4-ones synthesized by Noller and Baliah [3]
have been subjected to quite a large number of synthetic [4]
and physico-chemical studies [5–8].
2,6-Diarylpiperidin-4-ones normally adopt chair conforma-
tion with equatorial orientation of all the substituents. However,
∗
Corresponding author. Tel.: +91 4144 238641.
In six-membered heterocyclic compounds, 13C chemical
shifts are very much affected by electronic effects due to het-
eroatom, ␥-eclipsing effect operated by the substituent at ‘N’
and conformation of the ring [16].
E-mail address: skabilan@rediffmail.com (S. Kabilan).
Present address: Department of Chemistry, Bowman Oddy Laboratories, The
1
University of Toledo, 2801, W. Bancroft Street, MS 602, Toledo, OH 43606,
USA.
1386-1425/$ – see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.saa.2007.01.013

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G. Aridoss et al. / Spectrochimica Acta Part A 68 (2007) 1153–1163
Though conformational analyses of 2,6-diarylpiperidin-4-
2. Results and discussion
ones having some electron withdrawing groups, viz. N–NO,
N–COR, etc., at the heterocyclic nitrogen have been made
already, no extensive study has been carried out on the
NMR studies and conformational analysis of N-chloroacetyl-
2,6-diarylpiperidin-4-ones. This prompted us to undertake a
detailed NMR study on a series of synthesized compounds
8–14, and to understand the change in ring conformation
and its consequences on the chemical shift of ring carbons
and attached protons due to the replacement of hydrogen
by relatively bulkier chloroacetyl moiety at the heteroatom
site.
In continuation of our earlier work on the spectral [17]
and biological [18] studies of variously substituted 2,6-
diarylpiperidin-4-ones, we report herein the synthesis and
spectral studies of N-chloroacetyl-2,6-diarylpiperidin-4-ones
with a view to assign its 1H and 13C NMR signals unam-
biguously and compare its stereochemical aspects with that
of its parent compounds. Besides the effect of chloroacetyl
substituent on the ring carbons resonances is also studied
extensively.
Variously substituted N-chloroacetyl-2,6-diarylpiperidin-4-
ones were synthesized by electrophilic substitution reaction
of chloroacetyl chloride with the corresponding parent piperi-
dones in the presence of NEt3 as base and benzene as solvent
(Scheme 1). The yields, melting points and elemental analysis
are furnished in Table 1. 1H NMR chemical shifts of the synthe-
sized compounds 8–14 are furnished in Table 2, while coupling
constant values are given in Table 3. For the complete analy-
1
sis of the compounds 8–14, H NMR and 13C NMR spectra
were recorded at 400 MHz and 100 MHz, respectively. Besides,
HOMOCOSY, NOESY and HSQC spectra were also recorded
for compounds 8 and 9 while for compound 10, HOMOCOSY
spectrum only was recorded.
IR spectra of all the compounds 8–14 (Table 4) reveal that
the stretching band due to NH group disappeared while a new
signal significant for the amide carbonyl stretching appeared at
around 1660–1633 cm−1. This confirms the complete conver-
sion of NH into N-COCH2Cl. Furthermore, it is obvious from
Table 1 that chemical ionization mass spectrum of the compound
Scheme 1.
Compound
R
R1
R2
1
2
3
4
5
6
7
H
H
H
Cl
Cl
OMe
OMe
H
H
H
H
H
Me
H
Me
Me
i-Pr
Me
Me
Me
Me

G. Aridoss et al. / Spectrochimica Acta Part A 68 (2007) 1153–1163
1155
Table 1
Physical data for compounds 1–9
Compound
mp (◦C)
Yield (%)
Elemental analysis
Calculated (%)
C
Found (%)
C
H
N
H
N
8
9a
120–122
131
102
169
159
84
94
89
82
80
83
80
69.59
70.25
71.41
58.45
59.34
65.72
66.39
5.54
5.90
6.54
4.42
4.75
6.02
6.30
4.27
4.09
3.79
3.41
3.29
3.49
3.37
69.60
70.28
71.41
58.46
59.32
65.73
66.40
5.52
5.91
6.55
4.42
4.74
6.01
6.30
4.27
4.1
3.8
3.4
3.29
3.5
10
11
12
13
14
128
108–110
3.37
a
From the mass spectrum, molecular mass was found to be 342 (M + H)+ for 2, which is consistent with the proposed molecular formula.
Table 2
Proton chemical shifts (δ, ppm) of compounds 8–14 and their parent compounds 1–3 and 5
Compound H2 (s)
H3a (m)
H3e (dd) H5a (dd)
H5e (dd) H6 (s)
Aromatic (m) p-OCH3 (s) CH3 (d)
CH (m)
CH2Cl (m)
8
9
5.88
5.39
6.45
5.35
5.42
5.30
5.39
4.09 (dd)
3.63 (d)
3.99 (d)
3.63 (d)
3.08 (dd)
3.04–3.07
2.82
2.95–2.98
3.03–3.09
3.00–3.04
3.09–3.13
2.78
–
–
–
–
3.08
3.17
2.85
3.11
3.03–3.09 (m)
3.15
3.12 (m)
2.78
2.83
2.72
2.87
–
5.88
5.92
5.43
5.86
5.42
5.87
5.39
4.09 (dd)
4.10 (dd)
4.09 (dd)
3.63 (d)
6.99–7.30
7.11–7.36
6.98–7.30
7.02–7.33
7.11–7.35
7.01–7.16
6.84–7.10
7.26–7.49
7.24–7.48
7.22–7.47
7.26–7.38
–
–
–
–
–
1.06
–
–
3.90 (s)
3.86–3.95
10
11
12
13
14
1
2
3
5
1.13/1.07 2.08–2.16 3.89–4.05
1.06
1.09
1.03
1.08
–
–
–
–
–
–
–
1.66
–
3.91–3.97
3.89 (s)
3.87–3.96
3.90 (s)
–
–
–
–
–
–
–
2.80
–
3.78/3.81
3.81
–
–
–
–
2.35–2.75 (m)
2.68
2.67
2.69
–
–
–
2.74
2.67
2.69
2.83
2.55
–
0.84
0.8/1.02
a
a
Not available.
9 shows (M + H)+ ion at 342 and also peaks characteristic for
the fragmentation pattern are obtained.
and a sharp singlet with maximum intensity at 3.93 ppm. Apart
from this, there is also a broad singlet centered at 5.88 ppm.
The double doublets centered at 3.08 ppm and 2.78 ppm has one
large and one small couplings respectively at 17.44/6.24 Hz and
17.64/5.52 Hz. From the magnitude of coupling constants and
on the basis of HOMOCOSY correlations (these two have cross
peaks with each other Table 5) we can assign these two double
doublets to methylene protons at C-3 and C-5. Here the large
coupling constant is due to geminal coupling of H-3a/H-5a pro-
tons with H-3e/H-5e protons while the small coupling constant
is due to the coupling of each of the methylene protons at C-3
and C-5 (H-3a/H-5a and H-3e/H-5e) with benzylic protons at
C-2 and C-6.
2.1. 1H NMR spectra of symmetrically substituted
N-chloroacetyl-2,6-diarylpiperidin-4-ones 8, 12 and 14
1H NMR spectrum of symmetrically substituted compound
8 shows a multiplet in the most downfield region of about
6.99–7.30 ppm. This is due to aromatic protons at C-2 and C-
6 positions of heterocyclic ring. Further, there are two double
doublets each resonating at 3.08 ppm and 2.78 ppm respectively
Table 3
NOE spectrum of compound 8 (Table 5) gives useful infor-
mation about the assignments of ring protons and side chain
methylene protons. Among the two double doublets, the one at
3.08 ppm has strong NOE with aromatic protons ortho to the
phenyl ipso carbon than the other at 2.78 ppm. From this, it is
concluded that the former one is due to H-3a and H-5a protons
since these are spatially close to ortho protons while the later
one is due to H-3e and H-5e protons. It has also been previously
reported by Pandiarajan et al. [19] that the aromatic protons
ortho to the ipso carbons show strong NOE with the adjacent
axial proton.
Vicinal and geminal coupling constants (Hz) of compounds (8–14) and parent
piperidones (1–5)
Compound
3J2a,3a
3J2a,3e
2J3a,3e
2J5a,5e
3J5a,6a
3J5e,6a
8
9
6.24
7.01
1.50
6.90
6.71
6.99
6.78
9.96
5.52
–
–
–
–
–
–
4.47
–
17.54
17.54
18.22
17.02
18.15
6.24
6.10
9.50
5.46
6.71
5.59
6.78
9.96
5.52
5.91
6.00
6.02
–
6.01
–
4.47
2.83
3.03
–
–
–
–
–
–
–
–
–
–
–
10
11
12
13
14
1
2
3
5
–
18.35
–
–
–
–
–
10.36
10.51
10.36
11.85
11.67
10.36
A broad singlet centered at 5.88 ppm is unambiguously
assigned for benzylic protons at C-2 and C-6. This assignment is
evident from the NOESY spectrum of 8, wherein this broad sin-
–
–

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G. Aridoss et al. / Spectrochimica Acta Part A 68 (2007) 1153–1163
Table 4
IR and mass spectroscopic data 8–14
Compound
IR (cm−1
)
M.S. m/z
8
3059; 3028; 2949; 2912; 2853(C–H stretching); 1723 (C O stretching); 1633(N–C O stretching); 1569; 1497;
1453; 1391; 1358; 1247; 1119; 1023; 947; 781; 702; 596; 480; 424
9
3077; 3057; 3028; 2971; 2937; 2886(C–H stretching); 1721 (C O stretching); 1651 (N–C O stretching); 1495;
1453; 1386; 1323; 1253; 1199; 1116; 1079; 1027; 931; 855; 784; 744; 704; 607; 529; 405
(M + H)+ 342 (base peak);
249; 238; 182; 149; 131;
119; 105; 91; 77
10
11
12
13
14
3082; 3044; 3028; 2984; 2962; 2924; 2897; 2869 (C–H stretching); 1718 (C O stretching); 1648 (N–C
stretching); 1494; 1454; 1383; 1263; 1216; 1137; 1105; 1031; 993; 931; 764; 701; 627; 518
3071; 3044; 2981; 2929; 2869 (C–H stretching); 1723 (C O stretching); 1658 (N–C O stretching); 1492; 1433;
1401; 1342; 1302; 1263; 1130; 1093; 1013; 942; 834; 735; 670; 585; 543; 499; 448
3010; 2983; 2938; 2872 (C–H stretching); 1717 (C O stretching); 1652 (N–C O stretching); 1492; 1386; 1335;
1258; 1206; 1091; 1014; 836; 788; 652
3060; 3006; 2968; 2831 (C–H stretching); 1714 (C O stretching); 1646 (N–C O stretching); 1610; 1512; 1463;
1389; 1306; 1252; 1179; 1116; 1029; 930; 870; 848; 787; 662; 553; 411
3021; 3015; 3000; 2973; 2962; 2935; 2902; 2836 (C–H stretching); 1713 (C O stretching); 1658 (N–C
stretching); 1609; 1513; 1458; 1388; 1289; 1252; 1180; 1110; 1029; 974; 886; 838; 809; 722; 586; 542
O
O
Table 5
Correlations in the HOMOCOSY and NOESY spectra of compounds 8–10 [δ (ppm)]
Compound
Signal
Correlations in the HOMOCOSY spectrum
Correlations in the NOESY spectrum
8
7.19 (s, 4H)
5.88 (bs, 2H)
3.93 (s, 2H)
3.08 (dd, 2H)
2.78 (dd, 2H)
No
2.78
No
2.78
5.88, 3.93, 3.08, 2.78
7.19, 3.93, 3.08, 2.78
7.19, 5.88, 2.78
7.19, 5.88, 2.78
7.19, 5.88, 3.08
5.88, 3.08
9
7.24 (d, 2H)
7.12 (d, 2H)
5.92 (bs, 1H)
5.39 (bs, 1H)
3.93, 3.88 (2d, 2H)
3.17 (dd, 1H)
3.06 (t, 1H)
No
No
3.17, 2.83
3.06
No
5.92
5.39, 1.06
5.92
5.92, 3.93, 3.88, 3.17, 3.06
5.39, 3.93, 3.88, 3.17,1.06
7.24, 3.93, 3.88, 3.17, 2.83,
7.12, 3.93, 3.88, 3.06, 1.06
7.24, 7.12, 5.92, 5.39
7.24, 7.12, 5.92, 3.06
7.24, 7.12, 5.39, 1.06
7.24, 5.92, 2.83
2.83 (dd, 1H)
1.06 (d 3H)
3.06
7.12, 3.06
10
5.51 (bs, 1H)
2.91; 2.69
2.69
5.51; 2.91
1.66–1.75
3.02–3.04
1.66–1.75
–
–
–
–
–
2.91 (dd, 1H)
2.69 (dd, 1H)
3.02–3.04 (m, 1H)
1.66–1.75 (m, 2H)
1.05 (t, 3H)
glet shows strong NOE with the signals for methylene protons
at C-3/C-5 and aromatic protons ortho to the ipso carbon. A
more intense signal centered at 3.93 ppm shows strong NOE
with the signals due to H-3e/H-5e, H-2a/H-6a and aromatic
ortho protons. Hence, it can be conveniently assigned to methy-
lene protons of chloroacetyl moiety at the heterocyclic nitrogen
site. Since methylene protons of chloroacetyl moiety have strong
NOE with the benzylic protons at C-2 and C-6, there is a possi-
bility for the existence of two rotamers 2A and 2B (Scheme 2)
arising out of restricted rotation of N–CO bond. However, only
1
an average H NMR spectrum was obtained in our case. This
indicates that the two rotamers undergo interconversion at a
faster rate on NMR time-scale.
1H NMR spectrum of compounds 12 (having p-chloro phenyl
at C-2 and at C-6) and 14 (having p-methoxy phenyl at C-2 and
at C-6) having equatorial methyl substituent at C-3 and C-5
Scheme 2.

G. Aridoss et al. / Spectrochimica Acta Part A 68 (2007) 1153–1163
1157
positions shows multiplet for the methine proton at the corre-
2.3. Conformational analysis based on the coupling
constant values
sponding positions in the region of 3.03–3.18 ppm. Furthermore,
a doublet in the region of about 1.09 ppm is assigned to methyl
protons at C-3 and C-5. Unlike 8, in 12 and 14, two sets of
signals were observed corresponding to two kind of aromatic
protons (ortho and meta protons with respect to substituent at the
para position). An additional sharp singlet appears at 3.81 ppm
in 14 is due to methoxy protons present at the para position of
phenyl groups at C-2 and C-6. The 1H NMR assignments for the
remaining signals are similar to that of corresponding signals in
compound 8.
It is pertinent to note that the introduced chloroacetyl moiety
at heterocyclic nitrogen can adopt either a coplanar or perpendic-
ular orientation with respect to reference plane of the piperidone
ring system. If chloroacetyl moiety is in energy minimum of pla-
nar conformation, the ␲-electron orbital of the amide carbonyl
group overlaps with the orbital of the lone pair of electrons on
the nitrogen there by stabilizes the planar conformation [20].
Further the signal due to benzylic protons is broadened instead
of getting multiplicities in their signal (as observed for parent
piperidones). Hence, the broadening of benzylic signal at room
temperature strongly suggests the existence of restricted rotation
about N-CO bond in the molecule due to high-energy barrier
[20]. Furthermore, it is also obvious from the NMR study that
suchlinebroadeningispossibleonlyifwevisualizecoplanarori-
entation of chloroacetyl moiety to that of dynamically averaged
plane of piperidone ring and is also confirmed by X-ray studies
in the case of N-phenylcarbamoyl [11a] and N-benzoyl [11c]
derivatives. Thus the prediction of coplanarity of chloroacetyl
moiety is also supported by Lunazzi et al. [21] who have stated
that perpendicular orientation does not bring about the said line
broadening. Despite the restricted rotation of N-CO group in
the molecules, we get only one set of signals for the ring pro-
tons instead of getting two set of signals corresponding to two
rotamers 2A and 2B (Scheme 2) arising out of restricted rotation.
Thus, the obtained one is only an average 1H NMR spectrum for
the compounds 8–14. This may be due to the fact that the two
rotomers undergo interconversion at a faster rate on NMR time
scale.
2.2. 1H NMR spectral analysis of unsymmetrically
substituted N-chloroacetyl-2,6-diarylpiperidin-4-ones 9, 10,
11 and 13
In compound 9 having equatorial methyl group at C-
3, there are two double doublets centered respectively at
2
3.17 ppm (3J5a,6a = 6.10 Hz, J5a,5e = 18.22 Hz) and 2.83 ppm
(3J5a,6a = 5.91 Hz, J5a,5e = 18.22 Hz). These are assigned
2
1
respectively to H-5a and H-5e on the basis of its H NMR,
HOMOCOSY and NOESY spectra.
From the NOE (Table 5), it is pertinent to note that a triplet
centered at 3.06 ppm has strong NOE with methyl protons sig-
nal at 1.06 ppm. Hence, the triplet is due to methine proton
at C-3. Two broad singlets are observed for the benzylic pro-
tons H-2 and H-6 at 5.39 ppm and 5.92 ppm, respectively. A
striking observation from NOE is that among the two, the
upfield signal shows strong NOE with methyl protons signal
at 1.06 ppm, methine proton signal at 3.06 ppm and aromatic
protons ortho to the phenyl ipso carbon at 7.12 ppm whereas
downfield one to two double doublets centered at 3.17 ppm
and 2.83 ppm and also aromatic protons ortho to the phenyl
ipso carbon at 7.24 ppm. Therefore two singlets at 5.39 ppm
and 5.92 ppm are unambiguously assigned to H-2 and H-6 pro-
tons, respectively. Akin to compound 8, the upfield double
doublet at 2.83 ppm is assigned to H-5e while the downfield
one at 3.17 ppm to H-5a by considering HOMOCOSY and
NOESY correlations (Table 5). It is very interesting to note
that the methylene protons of chloroacetyl moiety appears as
two sets of closely spaced doublet at 3.88 ppm and 3.93 ppm
unlike in compound 8 due to its anisochronous nature rather
than isochronous, i.e. these protons become diastereotopic in
nature due to the loss of symmetry by the methyl group
introduction at C-3. In a similar manner, assignments of
the ring and side chain protons are also made for 11 and
13.
In all the cases, the benzylic protons appear as a broad singlet
while the ring methylene protons (at C-3 and C-5 in 8 and C-5
in 9, 10, 11 and 13) appear as double doublet. A close survey of
Table 2 reveals that incorporation of chloroacetyl moiety at the
heterocyclic nitrogen makes the ring protons to deshield signif-
icantly compared to the corresponding parent piperidones. The
deshielding magnitude of benzylic protons at C-2 and C-6 is in
the range of 1.34–2.46 ppm. By comparing the coupling con-
stant values of parent piperidones [7] a rigid chair conformation
could not be offered for these molecules 8–14, since the coupling
constant values are abruptly changed from the parent com-
pounds 1–7. As reported earlier by Johnsons and Malhotra [14],
in the case of N-substituted-2,6-dimethylpiperidines, the pre-
ferred conformation was found to be the one with axial methyl
groups in order to avoid the severe 1,3 diaxial interaction (A1,3
)
between the methyl groups. Hence, in this series of molecules
also, there may be allylic (A1,3) strain between the carbonyl
group of chloroacetyl moiety with the ␣-phenyl groups. In order
to avoid this, the normal conformation for these compounds
8–14 is ruled out and a non-chair conformation is proposed. To
support this, the vicinal coupling constant values are also very
much reduced in compounds 8–14 compared to their parents
1–7. Therefore, it is more appropriate to note that the decrease
in coupling constant values in these compounds may be due to
increased electronegativity of ‘N’ owing to the existence of con-
jugation between nitrogen lone pair and p-electrons of carbonyl
In the case of compound 10, among the two benzylic proton
signals, the one in the downfield region is assigned unambigu-
ously to H-6 proton whereas the upfield one to H-2 proton on
the basis of its HOMOCOSY correlations (Table 5) and with
the supports of the magnitude of observed coupling constants.
The HOMOCOSY spectrum of 10 correlates the broad singlet
at 5.43 ppm with the two double doublets for C-5 protons at
2.72 ppm and 2.82 ppm thereby rendering the distinct assign-
ment of this signal to H-6 proton. Hence, the other singlet at
6.45 ppm is due to H-2 proton.

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G. Aridoss et al. / Spectrochimica Acta Part A 68 (2007) 1153–1163
Scheme 3.
Compound
R1
R2
R
8
12
14
H
CH3
CH3
H
CH3
CH3
Ph
Ph (p-Cl)
Ph (p-OCH3)
group. Also as the extracted coupling constant values are in close
proximity with the one reported earlier for N-phenylcarbamoyl
[11a] and N-benzoyl [11c] derivatives of 2,6-diarylpiperidin-4-
ones, we may also propose similar kind of conformation for
the chloroacetyl derivatives too, wherein the said A1,3 strain is
very minimum. Thus the compound 8 may exist in equilibrium
between half boat conformations 3A and 3B (Scheme 3). In this
proposed conformation, the ring becomes flattened appreciably
at the nitrogen end and consequently the benzylic protons get
into the planar region of chloroacetyl moiety. Inspite of this, the
benzylic protons are deshielded by about 1.79 ppm compared to
the parent piperidone 1 as they lie in the deshielding region of
the amide plane (on the basis of the model proposed by Paulson
and Todt [22] for the anisotropic effect of amides) [23]. Since the
compounds 12 and 14 are symmetrically substituted by methyl
group at C-3 and C-5, we may offer similar kind of conformation
3A and 3B for these compounds also. However, the benzylic pro-
tons are shielded by about 0.46 ppm and 0.49 ppm respectively
compared to 8. Also a striking observation in this molecule is
that the vicinal coupling values are increased by about 0.8 Hz
compared to the compound without methyl substitution at C-3
and C-5 (compound 7). This reveals that flattening of the ring
at the nitrogen is lowered slightly in conformations 3A and 3B
for 12 and 14 thereby decreases their “in plane” nature of the
benzylicprotons. ThisconsequentlyshieldstheH-2andH-6pro-
tons of 12 and 14 by about 0.46 ppm and 0.49 ppm respectively
compared to 8.
In the case of compound 9 having equatorial methyl group at
C-3 position, the benzylic protons H-2 and H-6 are deshielded
by about 1.76 ppm and 1.82 ppm respectively compared to its
parent compound 2. However, the magnitude of deshielding is
3
not changed appreciably from compound 8 but, J2a,3a value
is higher than that of 8. Thus, in order to account for the
observed difference in chemical shift and coupling constant val-
ues, an equilibrium mixture of twist-boat conformers 4A and
4B (Scheme 4) is proposed for compound 2. In this conforma-
tion, the ring of 9 is puckering about C(2)-C(3) and C(5)-C(6)
bonds compared to 8. Similarly compounds 11 and 13 respec-
tively bearing p-chloro and p-methoxy phenyl groups at C-2 and
C-6 instead of phenyl groups also adopt similar conformation
(i.e. 4A and 4B) as the difference in chemical shift and coupling
constant value are not significant from 9.
In the case of compound 10 having bulkier isopropyl group
at C-3 deshields the C-2 benzylic proton significantly (H-
2 = 6.45 ppm) compared to 9 (H-2 = 5.39 ppm). This may be
due to the increased bulkiness of the substituent at C-3 which
forced the C-2 benzylic proton more to lie “in plane” with
chloroacetyl moiety. As a result of this C-2 benzylic proton
is deshielded greatly than C-6 proton. Furthermore, there is a
substantial decrease in 3J2a,3a value in 10 compared to 9. Thus
in 10, the ring is further flattened about C(2)–C(3) bond and
prefers to be in equilibrium mixture of the conformations 5A and
5B. In all the cases (8–14), the benzylic protons are deshielded
significantly compared to their parents. Due to coplanarity of
Scheme 4.
Compound
R
9
11
13
Ph
Ph (p-Cl)
Ph (p-OCH3)

G. Aridoss et al. / Spectrochimica Acta Part A 68 (2007) 1153–1163
1159
Scheme 5.
Compound
R
10
i-Pr
chloroacetyl moiety, the C–H(2)/C–H(6) bonds get polarized
by amide carbonyl group, which in turn develops fractional pos-
itive charge over protons and negative charge over the carbon,
which bears the corresponding proton. As a result of this, res-
onances of carbons are shielded while the attached protons are
deshielded (Scheme 5).
HSQC spectra recorded for compounds 1 and 2. The chemi-
cal shift values of compounds 8–14 and their parent compounds
1–7 are listed in Tables 6 and 7, respectively.
From the HSQC spectrum of compound 8 (Table 8), it is evi-
dent that benzylic protons at C-2 and C-6 have cross peaks with
the low intensity signal at 55.36 ppm. Thus, it is due to benzylic
carbons at C-2 and C-6. Similarly, as the signal at 44.06 ppm
shows cross peaks with methylenic protons at C-3 and C-5, it
corresponds to methylenic carbons at C-3 and C-5. A signal with
double the intensity to that of C-3 and C-5 signal is ascribed to
methylenic carbon of side chain chloroacetyl moiety, since it has
cross peak with –CH2Cl protons signal. It is pertinent to note
that, shielding of C-2 and C-6 carbons may perhaps be due to
flattening of the ring at the ‘N’ site and also due to the known
electronic and ␥-eclipsing interaction.
2.4. 13C NMR spectral analysis of
N-chloroacetyl-2,6-diarylpiperidin-4-ones
In the 13C NMR spectrum of this series of compounds, there
are two signals in the region of 206–210 ppm and 168–169 ppm.
These are characteristic for ring carbonyl group at C-4 and amide
carbonyl carbon at the heterocyclic nitrogen respectively. The
signals in the region of 114–159 ppm are due to aromatic car-
bons. Among this, the less intense signals with higher chemical
shift values in the region of 132–159 ppm are characteristic for
ipso carbons. In compounds 11 and 12, the chlorine bearing
ipso carbons show resonance at around 134 ppm while in 13 and
14 the methoxy bearing ipso carbons appear at about 159 ppm
due to the effect of substituent present at the corresponding
carbons.
Fromthe13CNMRspectrumofcompound9, theassignments
for the C-2, C-6 and C-3 carbons are made and are further con-
firmed from its HSQC (Table 8) spectrum. However, there are
two signals resonating very closely at 42.98 ppm and 42.73 ppm
in 9. The assignment of this signal is made unambiguously with
the help of HSQC, wherein the signal at 42.98 ppm has cross
peak with methylene protons at C-5 while the other at 42.73 ppm
with side chain –CH2Cl protons. Therefore, among the two, the
former one is assigned more precisely to C-5 carbon and the
The heterocyclic ring carbon signals appear in the range of
42–62 ppm can be assigned more precisely with the help of
Table 6
13C chemical shifts (δ, ppm) of compounds 8–14
Compound
C-2
C-3
C-4
C-5
C-6
CH3
–
CH
–
N–C
0
CH2Cl
42.68
Aromatic
8
55.36
44.06
206.33
44.06
55.36
168.66
168.94
168.64
168.71
140.79 (C-2ꢀ,C-6ꢀ), 126.57–129.11 (other
aryl carbons)
9
10
11
61.85
57.77
61.26
46.14
54.94
46.12
208.61
208.37
207.69
42.98
44.64
42.48
54.73
57.19
54.34
13.63
–
42.73
42.41
42.33
140.65 (C-2ꢀ), 140.92 (C-6ꢀ), 126.66–129.21
(other aryl carbons)
20.40/21.28
13.75
28.56
–
140.89 (C-2ꢀ,C-6ꢀ), 125.894–128.99 (other
aryl carbons).
138.82 (C-2ꢀ), 138.99 (C-6ꢀ), 134.31
(C-6ꢀꢀꢀꢀ), 134.19 (C-2ꢀꢀꢀꢀ), 128.05–129.40
(other aryl carbons)
12
13
60.73
61.44
45.51
46.35
209.76
208.77
45.51
43.06
60.73
54.19
14.14
13.59
–
–
169.30
168.76
42.38
42.67
139.20 (C-2ꢀ, C-6ꢀ), 134.35 (C-2ꢀꢀꢀꢀ,C-6ꢀꢀꢀꢀ),
128.81 and 129.32 (other aryl carbons)
159.35 (C-6ꢀꢀꢀꢀ), 159.28 (C-2ꢀꢀꢀꢀ), 132.78
(C-2ꢀ), 132.98 (C-6ꢀ), 114.25-128.73 (other
aryl carbons)
159.24 (C-2ꢀꢀꢀꢀ, C-6ꢀꢀꢀꢀ), 132.92 (C-2ꢀ, C-6ꢀ),
114.24–128.59 (other aryl carbons)
14
60.68
45.64
210.81
45.64
60.68
14.03
–
169.17
42.59

1160
G. Aridoss et al. / Spectrochimica Acta Part A 68 (2007) 1153–1163
Table 7
13C chemical shifts of parent piperidin-4-ones 1–3 and 5
Compound
C-2
C-3
C-4
C-5
C-6
CH3
CH2
CH
Aromatic
1
2
3
5
61.0
68.4
66.6
68.0
50.2
51.6
58.1
51.9
207.8
209.50
209.0
210.1
50.2
50.90
51.1
51.9
61.5
61.50
61.7
68.0
–
–
–
–
–
–
–
17.8
–
142.60 (C-2ꢀ, C-6ꢀ), 126.40–128.60 (other aryl carbons)
141.80 (C-2ꢀ), 142.7(C-6ꢀ), 126.50–128.60 (other aryl carbons)
141.9 (C2ꢀ), 142.9 (C6ꢀ), 126.4-128.5 (others)
10.10
12.0
a
140.3 (C-2ꢀ, C-6ꢀ), 133.6 (C-2ꢀꢀꢀꢀ, C-6ꢀꢀꢀꢀ), 128.6, 128.9 (other carbons)
a
Not available.
Table 8
Correlations in the HSQC spectra of compounds 1 and 2 [δ (ppm)]
different charge densities at ␣, ␤ and ␥ carbons in the proposed
conformations and consequently shield or deshields the same
differently. However, the marked shielding effect observed with
the ring carbon chemical shifts may not be explained on the
basis of electronic effect only. Instead, it would have also been
explained on the basis of the steric interactions and conforma-
tional distortions arising out of the substituent at the nitrogen
site.
Earlier reports [11a,c] stated that remarkable shielding of ␣, ␤
and ␥ carbons of the heterocyclic ring are primarily controlled
by the orientation of substituent at the ‘N’ site. The observed
shielding of ring carbons resonances by chloroacetyl introduc-
tion is explained primarily on the basis of steric and ␥-eclipsing
effect as it has been made for N-phenylcarbamoyl [11a] and
N-benzoyl [11c] derivatives of 2,6-diarylpiperidin-4-ones.
Compound
Signal
Correlations in the HSQC spectrum
8
126.11–140.79
55.36
6.99–7.30 (aromatic protons)
5.88 (H-2a, H-6a)
44.06
42.68
2.78 (H-3a,H-5a and H-3e, H-5e)
3.93 (chloroacetyl)
9
126.66–140.92
61.85
7.11–7.36 (aromatic protons)
5.39 (H-2a)
54.73
5.92 (H-2a)
46.14
3.06 (H-3a)
42.98
42.73
13.63
2.83 and 3.17 (H-5a, H-5e)
3.88, 3.93 (chloroacetyl)
1.06 (methyl)
latter one to –CH2Cl carbons. However, these two protons are
interchangeable.
2.5.1. α-Effect
Similarly assignments for rest of the compounds 10–14 are
also made unambiguously by comparing the assignments made
for 8 and 9.
In all the N-chloroacetyl derivatives (compounds 8–14), ␣
carbons (C-2 and C-6) are shielded significantly over a wide
range, i.e. about 6–10 ppm compared to their parent piperidones
due to the substitution of chloroacetyl moiety.
2.5. Effect of chloroacetyl substituent on the ring carbons
chemical shifts
Coplanarity of chloroacetyl moiety in 8–14 with the plane
of the ring is established well by H NMR studies. As stated
1
already such situation arises only if ␲ electrons of chloroacetyl
carbonyl group delocalize with p-electrons of ‘N’ and effecting
rehybridisation with diminished electron density at the nitrogen.
Thus, irrespective of the various conformations, which the hete-
rocyclic ring adopts in order to avoid various strain energies, the
atoms such as N, C-2, C-6 and CO of chloroacetyl moiety lie in
the same plane. Therefore, in all the cases ␥-eclipsing interac-
tion exists between C–O (of N-substituent) and N–C(2)/N–C(6).
Owing to this ␥-eclipsing interaction, C-2 and C-6 carbons are
shielded to a greater extent in all the compounds compared to
their parent compounds. However, in compound 9, an additional
shielding of about 0.91 ppm and 1.13 ppm are observed for C-2
and C-6 carbons respectively compared to 8. Though this shield-
ing magnitude is not significant, it warrants explanation. If we
closely look at its conformations 3A and 3B (Scheme 3), the
In order to study the effect of chloroacetyl substituent on the
heterocyclic ring carbons chemical shift, the substituent param-
eters are derived and discussed here. The substituent parameters
furnished in Table 9 are obtained by subtracting the chemical
shifts of 1–3 and 5 from the corresponding shifts in compounds
8–10 and 12 and are discussed in terms of ␣, ␤ and ␥ effects.
A perusal of the data in Table 9 reveals that the magnitude of
␣ and ␤ effects are much higher than the expected value. Pople-
Gordon [23] have suggested that through-bond inductive effect
exhibit an alteration in magnitude of polarity in saturated hete-
rocyclic systems having different groups at the heteroatom site
and consequently exert different effect on the ring carbon chem-
ical shifts. Further, due to coplanar orientation of chloroacetyl
moiety at ‘N’ site with the plane of the ring, it would induce
Table 9
Chloroacetyl substituent parameters for compounds 8–10 and 12
Compound
C-2(␣)
C-3(␤)
C-4(␥)
C-5(␤)
C-6(␣)
C-2ꢀ(␤)
C-6ꢀ(␤)
CH3(␥)
CH2(␥)
CH(␥)
8–1
9–2
10–4
12–5
−5.64
−6.55
−8.83
−7.27
−6.14
−5.46
−3.16
−6.39
−1.47
−0.89
−0.63
−0.34
−6.14
−7.92
−6.46
−6.39
−5.64
−6.77
−4.51
−7.27
−1.81
−1.15
−1.01
−1.1
−1.81
−0.78
−2.01
−1.1
–
–
–
–
–
–
+3.53
–
+3.74
–
+10.76
–
+: denotes deshielding; –: denotes shielding.

G. Aridoss et al. / Spectrochimica Acta Part A 68 (2007) 1153–1163
1161
C(6)–C(5) and C(4)–C(3) bonds are comparatively eclipsed.
Hence, it explains the slight increase in shielding magnitude
of C(2) and C(6) carbons.
Due to chloroacetyl substitution, chemical shifts for the
phenyl ipso carbons (C-2ꢀ and C-6ꢀ) of 8–10 and 12 are also
moved to upfield magnitude (shielding) of about 1–2 ppm com-
pared to their parent compounds 1–3 and 5.
In compound 10, C-2 (8.83 ppm) and C-6 (4.51 ppm) carbons
are shielded markedly than the corresponding carbons in its par-
ent 3. However, the shielding magnitude of C-2 carbon in 10 is
increased by about 3.19 ppm than the corresponding carbon in
8. This can be explained satisfactorily by considering again ␥-
eclipsing interaction between C(2)–C(3) and C(4)–C(5) bonds
in the molecule. Therefore, C-2 carbon is shielded markedly
than rest of the carbons in the molecule 10.
Among the two symmetrically substituted compounds 8 and
12, the shielding effect experienced by the ␣-carbons (C-2 and
C-6) of 12 is relatively high. This can be explained by the fact
that in addition to ␥-eclipsing interaction, there is a considerable
non-bonded interaction between benzylic protons at C-2 and C-6
and methyl groups at C-3 and C-5. This in turn may increase the
electron density around C-2 and C-6 and consequently shields
more. This may be the reason for the shielding of C-2 and C-6
carbons in 12 by 1.63 ppm compared to 8.
It is interesting to point out here that there also exist electronic
interaction between amide carbonyl group and benzylic C–H
bond. In the preferred conformations of all the compounds, the
amide carbonyl N, C-2 and C-6 are “in plane” with each other.
Hence, the amide carbonyl function may polarize the C–H bond
at C-2 and C-6. In spite of this, carbons of C-2 and C-6 acquire a
fractional negative charge there by shield much. It is known from
the NMR studies that in 10, the ring is flattened about C(2)–C(6)
bond which in turn may increases the extent of polarization there
by shields C-2 carbon significantly than C-6 carbon. It is also in
corroboration with the earlier studies on piperidones [16].
2.5.3. γ-Effect
The shielding of carbonyl carbon has been noticed in
most of the heterocyclic compounds bearing substituent at the
N. In compounds such as N–Cl, N–CH3 and N-SO2Ph-2,6-
diarylpiperidin-4-ones, the carbonyl carbon is shielded in the
range of 4–6 ppm compared to the corresponding parent com-
pounds [24] whereas in N–COCH3, N–COPh [25], N–CONHPh
[11a], the shielding magnitude is very negligible. However in
the present set of compounds, the ␥-carbonyl carbon in 9, 10
and 12 is shielded by less than 1 ppm, while for 8, it is about
1.47 ppm compared to the corresponding carbon in their parents.
The magnitude of shielding indicates that it is not a significant
one when compared to 4–6 ppm observed in the analogues com-
pounds. The decreased ␥-effect may perhaps be due to increase
in electronegativity at the ‘N’ site by the chloroacetyl incorpo-
ration. The ␥-anti carbon of 9 (methyl) and 10 (methine carbon
of isopropyl group) are deshielded by 3.53 ppm and 10.76 ppm
respectively compared to their parents 2 and 3. Hence, deshield-
ing of anti carbon in these molecules may be owing to the fact
that, if nitrogen has lone pair of electrons it can shield the car-
bons anti periplanar to it through hyperconjugative interaction
as reported by Eliel et al. [26]. But in compounds under study
such interaction is absent due to the loss of lone pair of electrons
by chloroacetyl substitution at ‘N’, which in turn deshields the
anti carbon (alkyl carbon) at C-3 with respect to heterocyclic
‘N’.
Furthermore, the deshielding parameters noticed in 9, 10 and
12 may also be due to the interactions arising out of major
conformational change compared to the corresponding parent
piperidones (2, 3 and 5).
2.5.2. β-Effect
The chloroacetyl group shields ␤ carbons also to a consider-
able extent. But the magnitude of shielding is less in 9–10 but it
is high for compound 8 compared to ␣-effect.
Comparison of 13C chemical shifts of p-chloro and p-
methoxy phenyl substituted compounds 11, 13 and 14 indicates
that replacement of phenyl groups present at C-2 and C-6 of
heterocyclic ring by p-chlorophenyl or p-methoxyphenyl would
not bring about a significant change in chemical shifts of ring
carbons. Therefore, we may expect similar kind of ␣, ␤ and ␥
effects from these set of compounds too.
C-3andC-5carbonsof 8areshieldedby6.14 ppmwhencom-
pared to 1. It is quite obvious from the proposed conformations
3Aand3Bthat␥-eclipsinginteractionsnotedinbetweenC(2)–N
and C(6)–C(5) bonds and between C(6)–N and C(2)–C(3) bonds
may be responsible for the observed shielding effect on C-3
and C-5 carbons. Besides, higher ␤-effect in 8 compared to ␣-
effect may perhaps be due to the electronic interaction prevailing
between the C(3)–H/C(5)–H and the C(4)–O bonds.
In 12, ␤-effect is higher than that of compound 8. This is
explained similar to ␣-effect that the existence of steric interac-
tion between benzylic protons (at C-2/C-6) and methine protons
(at C-3/C-5), will in turn paved a way to perturb the electron
density around C-3 and C-5 in 12 thereby shields it well. In
unsymmetrically substituted compounds 9 and 10, the shielding
characteristic observed with C-3 and C-5 carbons are differ-
ent due to difference in assumed conformation. In this set of
compounds, C-5 carbon is shielded much than C-3 carbon.
This may be explained on the grounds of electronic interaction
between C(5)–H and C(4)–O bonds in addition to steric interac-
tion between the substituents in the assumed conformations of
the molecule.
It is of interesting to note that, the detected ␣, ␤ and ␥
effects strongly agree with our suggestion of coplanarity of the
chloroacetyl moiety at the ‘N’ site and also proposed conforma-
tions for the heterocyclic ring with and without alkyl substituent
at C-3 and C-5 positions.
3. Conclusion
Replacement of ‘H’ by electron withdrawing chloroacetyl
group at the heterocyclic nitrogen is known to exert a major
change in chemical shifts of ring carbons and associated pro-
tons. Besides, the coupling constants values are also affected
markedly by the incorporation of this group. Similarly, ␣ and ␤
carbons are shielded significantly, whereas the shielding mag-
nitude of ␥-carbon (carbonyl carbon) is very less. However, the

1162
G. Aridoss et al. / Spectrochimica Acta Part A 68 (2007) 1153–1163
␥-anti carbon is deshielded remarkably due to increase in elec-
tronegativity of the heterocyclic nitrogen by the introduction
of chloroacetyl moiety. Therefore, in order to substantiate the
abruptchangeincouplingconstantvaluesandchemicalshiftval-
uesfromthecorrespondingparentpiperidoneswehaveproposed
different conformations such as flattened boat (for 8, 12 and 14)
and twist-boat forms (for 9, 10, 11 and 13) for the compounds
under study.
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4. Experimental
All the reported melting points were taken in open capillaries
and are uncorrected. IR spectra were recorded in AVATAR-330
FT-IR spectrophotometer (Thermo Nicolet) and only note-
worthy absorption levels (reciprocal centimeters) are listed.
1H NMR spectra were recorded at 400 MHz on BRUKER
AMX 400 MHz spectrophotometer using CDCl3 as solvent and
TMS as internal standard. 13C NMR spectra were recorded at
100 MHz on BRUKER AMX 400 MHz spectrophotometer in
CDCl3. 1H-1H COSY, phase-sensitive NOESY and one-bond
1H–13C correlations spectra were recorded on BRUKER DRX
500 NMR spectrometer using standard parameters. 0.05 M solu-
tions of the sample prepared in CDCl3 were used for recording
2D NMR spectra. The tubes used for recording NMR spectra are
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(EI) and microanalyses were performed on Heraeus Carlo Erba
1108 CHN analyzer. Unless otherwise stated, all the reagents
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4.1. Synthesis of N-chloroacetyl-2,6-diphenylpiperidin-
4-one 8
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To a well-stirred solution of respective 2,6-diphenyl-
piperidin-4-one (1) (0.005 mol) and triethylamine (0.005 mol)
in benzene, chloroacetyl chloride (0.005 mol) in benzene was
added in drop wise for about half an hour. Stirring was continued
with mild heating (30–35 ◦C) using a magnetic stirrer. After the
completion of reaction, it was poured into water and extracted
with ether. The collected ether extracts were then washed well
with 3% sodium bicarbonate solution and dried over anhydrous
sodium sulphate. This upon evaporation afforded the compound
(8) in good yield. The obtained compound is recrystalized from
ethanol. The compounds 9–14 were also synthesized similarly.
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Acknowledgements
We are thankful to Prof. K. Pandiarajan, Head, Department of
Chemistry, AnnamalaiUniversityforthefacilitiesprovided. One
of the authors SK is grateful to University Grants Commission,
New Delhi, India for financial support in the form of Major
Research Project. We also thank NMR Research Centre, IISc,
Bangalore for providing all the NMR facilities to record NMR
spectra.
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