# Density Functional Theory Study on Conformers of Benzoylcholine Chloride

Authors: Mustafa Karakaya; Fatih Ucun; Ahmet Tokatlı
Journal: Journal of Spectroscopy
 (2013)

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## Abstract

The optimized molecular structures and vibrational frequencies and also gauge including atomic orbital (GIAO)1H and 13C NMR shift values of benzoylcholine chloride [(2-benzoyloxyethyl) trimethyl ammonium chloride] have been calculated using density functional theory (B3LYP) method with 6-31++G(d) basis set. The comparison of the experimental and calculated infrared (IR), Raman, and nuclear magnetic resonance (NMR) spectra has indicated that the experimental spectra are formed from the superposition of the spectra of two lowest energy conformers of the compound. So, it was concluded that the compound simultaneously exists in two optimized conformers in the ground state.  Also the natural bond orbital (NBO) analysis has supported the simultaneous exiting of two conformers in the ground state. The calculated optimized geometric parameters (bond lengths and bond angles) and vibrational frequencies for both the lowest energy conformers were seen to be in a well agreement with the corresponding experimental data.


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## Body

## 1. Introduction

The determination of the minimum energy conformers of acetylcholine has been subject by many theoretical works [1–3]. Marino et al. have investigated the conformational behavior and molecular motion of acetylcholine in vacuum and aqueous solution [4]. They have calculated five low lying conformers by molecular mechanics computing. The ab initio data of acetylcholine has indicated that the most stable conformer is the transgauche arrangement of the two essential torsion angles (τ1; C-C-O-C and τ2; N-C-C-O) [5, 6]. The observed conformer of acetylcholine is transgauche (τ1 = −166.9 and τ2 = 84.7°) in the crystal of its chloride [7, 8], gauche-gauche (τ1=78.9 and τ2 = 78.4°) in the crystal of its bromide [9], and gauche-gauche (τ1 = ±83 and τ2=±89°) in the crystal of its iodide [10].In this study we wish to report the IR, Raman (R), NMR, and NBO analysis of benzoylcholine chloride (BzChCl) to obtain the lowest energy conformer in the ground state by means of density functional theory (B3LYP) method.


## 2. Computational Details

The optimized structure parameters and vibrational frequencies of BzChCl were calculated by density functional theory B3LYP method at 6-31++G(d) basis set level. All the computations were performed by using Gaussian 03 package [11] and Gauss-View molecular visualization programs [12] on the personal computer. The calculated vibration frequencies have been scaled with a scale factor of 0.9614 [13]. The chemical shifts of 1H and 13C NMR in vacuum for all the conformers of the compound were calculated by GIAO method [14] using the same set level of the theory which is routinely used for NMR chemical shift calculations on fairly large molecules [15, 16]. In the chemical shift calculations tetramethylsilane (TMS) was used as reference molecule.


## 3. Results and Discussion

### 3.1. Ground State Conformers

The molecular structures of all the calculated optimized conformers of BzChCl can be seen in Figure1. In calculations firstly the potential energy surface (PES) of the compound was scanned around the torsion angle of Cl(34)-C(11)-N(19)-C(4) from −180° to 180° at increments of 20° with an Cl…N distance of around 3.60 Å at B3LYP/6-31 G(d,p). The PES showed four minimum-energy structures (Figure 2). The barrier height between the conformer I and II is 9.6 kcal/mol while those between the conformer I and III or I and IV is bigger than 13 kcal/mol. These structures were chosen as initial geometry to obtain the further ones. The conformers of the compound are defined by five essential torsion angles as given in Table 1. For comparison, the experimental data being available for a similar molecule, acetylcholine chloride, are also shown in the table.Table 1
Five essential torsion angles for all the conformers of BzChCl.
Torsion Angles (°)
Exp. [6]
Conformer I
Conformer II
Conformer III
Conformer IV
τ
1[C(21)-O(20)-C(1)-C(4)]
167.9
115.02
83.64
−179.64
136.13
τ
2[O(20)-C(1)-C(4)-N(19)]
84.7
−81.83
−153.87
−179.83
−87.70
τ
3[C(1)-C(4)-N(19)-C(11)]
171.4
−172.97
−49.28
−61.10
174.13
τ
4[C(1)-C(4)-N(19)-Cl(34)]
—
−112.83
−105.05
−179.75
−166.48
τ
5[O(22)-C(21)-O(20)-C(1)]
5.2
−9.68
−0.87
0.00
−3.70Optimized molecular structures of four conformers of BzChCl.
(a)
(b)
(c)
(d)Figure 2
Potential energy surface (PES) scan of BzChCl.The electronic energies, relative energies, and mean vibrational deviations for all the conformers of the compound are given in Table2. The relative energy values and calculated mean vibrational deviations in the table are respect to the lowest energy conformer I of the compound. As seen the mean vibrational deviation increases while the relative energy increases. Therefore, we state that the more different the molecular structures of the two conformers are the higher the relative energy is between them, and so, a bigger mean vibrational deviation occurs. This comment has also been given for pyridine carboxaldehyde and difluorobenzaldehyde molecules in our previous studies [17, 18]. From Table 2 we also see that the relative energies and mean vibrational deviations between the conformers I and II are fairly low while the others are fairly high. Therefore, we take into account only the conformers I and II after this part of the study.Table 2
Electronic energies, and relative energies and mean calculated vibrational deviations between the conformers of BzChCl.
Conformer I
Conformer II
Conformer III
Conformer IV
Energy  (Hartree/part.)
−1133.243575
−1133.242015
−1133.239145
−1133.238584
Relative energy (kcal/mol)
0.00
0.978
2.778
3.130
Vib. deviations|Δν|ave
0.00
6.219688
9.875208
6.393542


### 3.2. Vibrational Frequencies

The calculated vibrational frequencies and proposed vibrational assignments for the two lowest energy conformers I and II of BzChCl are given in Table3. In the table are also given the experimental vibrational frequencies (IR and R) of the compound [19]. The linear correlation coefficients (R2), mean absolute error (MAE) and the root mean square errors (RMSE) were also given in the last lines of the table. The RMSE is defined by the following
(1)RMSE(wi)=∑(δicalc-δiexp)2n,
where δicalc and δiexp are the calculated and experimental chemical shifts of atom i, respectively, and n denotes the number of atoms. According to these values it can be stated that the calculated vibrational frequencies are in a good agreement with the experiment data. The calculated vibrational frequencies are slightly higher than the observable values for the majority of the normal modes. Two factors may be responsible for this discrepancy. The first is the environmental change of the molecule in the experimental medium and the second is that the calculated frequencies are harmonic while the experimental ones are anharmonic.Table 3
Experimental and calculated vibrational frequencies of two lower-energy conformers of BzChCl.ν shows stretching, δ bending, γ out of plane bending, ρr rocking, t twisting, τ torsion, and w wagging modes.
Mode no.
Assignments
Experimental frequencies
Calculated frequencies
(cm−1) BzChCl [19]
(cm−1) B3LYP 6-31++G(d)
IR
R
Conformer I
Conformer II
96
Ringν(CH)sym
3107
3109
95
Ringν(CH)sym
3091vw
3100
3098
94
Ringν(CH)asym
3086
3086
93
Ringν(CH)asym
3085
3078
92
ν(CH3)asym
3073s
3077
3076
91
Ringν(CH)asym
3068sh
3066
3065
90
ν(CH3)asym
3065w
3065
3058
89
ν(CH3)asym
3053
3053
88
ν(CH3)asym
3050
3048
87
ν(CH3)asym + ν(CH2)asym
3037w
3046
3044
86
ν(CH2)asym + ν(CH3)asym
3034vw
3023m
3026
3024
85
ν(CH3)asym + ν(CH2)asym
3018
3018
84
ν(CH2)asym
2994sh
2997m
2998
3015
83
ν(CH3)sym + ν(CH2)sym
2979m
2988
2980
82
ν(CH2)sym + ν(CH3)sym
2956.2927vs
2951m
2972
2975
81
ν(CH3)sym + ν(CH2)sym
2932m
2919
2920
80
ν(CH3)sym + ν(CH2)sym
2871sh
2892w
2906
2904
79
ν(CH2)sym + ν(CH3)sym
2855vs
2836vw
2809
2887
78
ν (C=O)
1725vs
1726vs
1687
1688
77
Ringν (C=C) + Ring δ(CH)
1598m
1601s
1588
1589
76
Ringν (C=C) + Ring δ(CH)
1583w
1584w
1569
1569
75
γ(CH3) + δ(CH2)
1498
1493
74
γ(CH3) + δ(CH2)
1486m
1489vw
1485
1479
73
δ(CH2) + γ(CH3) + Ring δ(CCH)
1481
1476
72
Ringδ(CCH) + δ(CH2) + γ(CH3)
1471sh
1475
1474
71
γ(CH3) + δ(CH2)
1466
1464
70
γ(CH3) + δ(CH2)
1464
1458
69
δ(CH3) + δ(CH2)
1459, 1451s
1455m
1458
1455
68
Ringδ(CH) + γ(CH3) + δ(C–CH2) + δ(CH2)
1443w
1445
1448
67
δ(CH2) + γ(CH3)
1437
1444
66
γ(CH3) + δ(CH3)
1435
1434
65
Ringδ(CH) + ν(Ring) + δ(CCC)
1434sh
1434
1434
64
δ(CH3) + δ(C–CH2)
1411w
1413vw
1413
1412
63
δ(CH3) + δ(C–CH2)
1404vw
1402
1402
62
δ(CH3) + δ(C–CH2)
1385vw
1394
1391
61
δ(C–CH2) + δ(CH3)
1381ms
1374
1362
60
δ(C–CH2) + δ(CH3) + δ(CH) + ν(Ring)
1341w
1346w
1338
1319
59
δ(C–CH2) + δ(CH3) + δ(CH)
1311m
1311w
1314
1314
58
δ(CH) + δ(CCC)
1283m
1299
1300
57
δ(N–CH3) + δ(C–CH2) + ν(N–CH2)
1280.1261s
1269sh
1272
1281
56
δ(C–CH2) +  δ(N–CH3)
1249sh
1261m
1259
1262
55
δ(C–CH2) +  δ(CH) + ν(C–O) + Ring ν(C–C) +  δ(CC=O)
1249sh
1239
1246
54
δ(N–CH3) + δ(C–CH2) + ν(N–CH3)
1219vw
1221w
1231
1227
53
δ(N–CH3) + δ(C–CH2)
1206
1209
52
δ(CH)
1172m
1163m
1160
1162
51
δ(CH)
1161w
1143vw
1148
1148
50
δ(NCH)
1141vw
1135
1139
49
δ(NCH)
1118s
1121vw
1115
1119
48
δ(CCC) + ν(CO) + δ(NCH)
1103w
1089vw
1093
1094
47
δ(CCH)
1076m
1067
1066
46
τ(HCCH) + δ(NCH)
1041vw
1058
1060
45
δ(NCH)
1033w
1042w
1055
1051
44
δ(NCH) + Ring ν(CC)
1018m
1011
1026
43
δ(CCH) + ν(O–C)
1002s
1003
1012
42
δ(Ring) + ν(O–CH2) + δ(NCH)
992vw
983
979
41
τ(HCCH)
979
978
40
τ(HCCH)
978
976
39
τ(HCCH)
951ms
959, 953w
961
961
38
ν(N–CH3) + δ(NCH)
929
940
37
τ(Ring)
927
927
36
δ(CCH) + ν(N–CH3)
902m
903w
906
924
35
ν(N–CH3) + δ(NCH)
869w
871w
861
883
34
Ringγ(CH)
836m
835
835
33
δ(N–CH3) + δ(Ring) + δ(OC=O)
812vw
811vw
828
825
32
τ(HCCH) + Ring γ(CH) + γ(OC=O)
793
788
31
τ(HCCH) + Ring γ(CH) + γ(OCC)
785
778
30
Breathing (choline)
714s
724m
698
717
29
Ringγ(CH) + γ(CC=O)
688vw
680m
673
699
28
γ(Ring)
679w
671
670
27
δ(Ring) + δ(COC)
657
663
26
δ(Ring)
619vw
619m
606
606
25
δ(N–CH3) + δ(NCC) + δ(OCC)
544w
544vw
526
516
24
δ(N–CH3) + δ(NCC) + δ(OCC)
474w
495vw
471
465
23
δ(N–CH3) + δ(N–CH2)
476w
454
459
22
δ(N–CH3)
455vw
440
441
21
γ(Ring) + γ(OC=O)
423w
431
434
20
γ(Ring)
409
399
19
δ(N–CH3)
399
390
18
δ(N–CH3) + ρr (CH2)
369w
369
374
17
ρ
r (CH2) + ρr (CH3)
356
357
16
ρ
r (CH3) out of plane
344
329
15
ρ
r (CH3) out of plane
324
322
14
w(CH3)
303
293
13
ρ
r (CH3) out of plane
261w
266
266
12
ρ
r (Ring) + w(CH3)
255
236
11
ρ
r (CH2) + w(Ring)
209m
236
226
10
ν(N–Cl) + ρr (CH3) out of plane
185
177
9
w(Ring) + ν(N–Cl)
166w
166
161
8
ρ
r (CH3) + ρr (CH2)
138
149
7
ρ
r (CH2) + w(Ring)
132
130
6
ρ
r (CH2) + ρr (CH3)
111w
106
114
5
w(CH2) + w(C=O)
84
72
4
ρ
r (Ring) + w(CH2) + ρr (CH3)
63
54
3
w(Ring) + w(C=O) + w(Cl)
38
33
2
w(Ring) + ρr (CH3) out of plane
25
26
1
ρ
r (Ring) out of plane + w(CH3)
19
20
R2
0.9998
0.9998
RMSE
12.8726
12.6161
MAE
8.8888
9.6111
w: weak, m: medium, s: strong, v: very, sh: shoulder, and br: broad.The assignments in the table are similar those done for a choline derivative molecule, acetylcholine bromide, which is available in literature [21].


### 3.3. Geometric Structures

BzChCl consists of a benzene ring and a choline group. The calculated optimized structure parameters for the lowest energy conformers I and II of BzChCl are summarized in Table4, in accordance with the atom numbers in Figure 1. Since the X-ray analysis of the compound could not be reached the theoretical optimized structures were compared with those of acetylcholine chloride for which the crystal structure has been solved [5]. The R2, MEA, and RMSE values between the calculated and experimental geometric parameters are given in the last lines of the table and they show a well agreement for the two conformers.Table 4
Calculated optimized geometric parameters for two lower-energy conformers of BzChCl.
Parameters
Experimental [6]
Calculated B3LYP [6-31++G(d)]
Bond lengths (Å)
Conformer I
Conformer II
N(19)-C(7)
1.52
1.513
1.500
N(19)-C(11)
1.50
1.514
1.513
N(19)-C(15)
1.49
1.499
1.512
N(19)-C(4)
1.49
1.532
1.528
C(1)-C(4)
1.47
1.516
1.535
C(1)-O(20)
1.45
1.451
1.439
O(20)⋯N(19)
3.26
3.324
3.760
O(20)⋯C(15)
3.17
3.252
4.862
C(21)-C(23)
1.49
1.487
1.486
C(21)-O(20)
1.38
1.356
1.358
C(21)-O(22)
1.18
1.221
1.221
C(11)-H(12)
—
1.092
1.092
C(11)-H(13)
—
1.092
1.100
C(11)-H(14)
—
1.097
1.091
C(7)-H(8)
—
1.092
1.092
C(7)-H(9)
—
1.097
1.089
C(7)-H(10)
—
1.090
1.091
C(15)-H(16)
—
1.092
1.092
C(15)-H(17)
—
1.089
1.092
C(15)-H(18)
—
1.092
1.097
C(1)-H(2)
—
1.093
1.091
C(1)-H(3)
—
1.090
1.093
C(4)-H(5)
—
1.094
1.092
C(4)-H(6)
—
1.105
1.098
C(23)-C(24)
—
1.404
1.404
C(23)-C(28)
—
1.404
1.404
Cl(34)⋯N(19)
—
3.616
3.593
Cl(34)⋯C(4)
—
3.317
3.33850
Cl(34)⋯H(6)
—
2.281
—
Cl(34)⋯H(9)
—
2.467
—
Cl(34)⋯H(14)
—
2.463
—
Cl(34)⋯H(6)
—
—
2.377
Cl(34)⋯H(13)
—
—
2.381
Cl(34)⋯H(18)
—
—
2.486
R2
0.999
0.9414
RMSE
0.0397
0.5327
MAE
0.0303
0.2207
C(7)-N(19)-C(11)
109
108.2
110.2
C(7)-N(19)-C(15)
108
109.8
109.5
C(4)-N(19)-C(7)
111
110.8
110.9
C(4)-N(19)-C(11)
111
106.2
111.0
C(4)-N(19)-C(15)
107
112.4
107.1
N(19)-C(4)-C(1)
119
118.2
114.3
N(19)-C(7)-H(9)
—
107.3
109.9
C(1)-O(20)-C(21)
115
118.5
116.4
C(11)-N(19)-C(15)
111
109.3
108.1
O(20)-C(21)-O(22)
123
122.9
122.4
O(22)-C(21)-C(23)
129
124.4
124.9
O(20)-C(1)-C(4)
111
113.8
109.2
O(20)-C(21)-C(23)
108
112.8
112.8
H(2)-C(1)-H(3)
—
108.4
110.2
H(6)-C(4)-H(5)
—
110.0
111.3
H(6)-C(4)-N(19)
—
104.0
105.4
H(14)-C(11)-N(19)
—
107.5
109.0
H(13)-C(11)-N(19)
—
108.4
107.3
H(12)-C(11)-N(19)
—
108.2
107.9
H(12)-C(11)-H(13)
—
110.1
111.1
H(12)-C(11)-H(14)
—
111.3
109.6
H(16)-C(15)-H(17)
—
109.5
110.2
H(8)-C(7)-H(9)
—
110.8
110.3
H(8)-C(7)-N(19)
—
107.6
108.5
N(19)-C(7)-H(10)
—
108.8
108.9
N(19)-C(15)-H(16)
—
108.4
108.3
H(17)-C(15)-H(18)
—
110.7
111.1
C(4)-C(1)-H(3)
—
113.5
113.4
O(20)-C(1)-H(2)
—
104.9
104.9
C(21)-C(23)-C(24)
—
117.9
118.0
C(21)-C(23)-C(28)
—
122.2
122.1
C(23)-C(24)-H(29)
—
119.0
119.0
C(23)-C(28)-H(33)
—
119.8
119.8
C(23)-C(24)-C(25)
—
120.1
120.0
C(23)-C(28)-C(27)
—
119.9
119.8
R2
0.7623
0.8597
RMSE
3.2139
2.5758
MAE
2.6083
1.9333


### 3.4. Chemical Shifts

The experimental and calculated1H and 13C NMR chemical shifts (with respect to TMS) for the lowest energy conformers I and II of BzChCl are given in Table 5. The experimental chemical shifts have been obtained from Spectral Database for Organic Compounds Web Page [20]. Since the experimental 1H chemical shift values of individual hydrogens are not available we have found the average values of 1H chemical shifts for the CH2 and CH3 hydrogen atoms. These are shown as bold in the table. For comparison the average chemical shift values of the two conformers are also given in the table. The R2, MEA, and RMSE values between the experimental and theoretical chemical shifts are obtained, and given in the last two lines of Table 5. According to these values one important observation is that the calculated results for the average chemical shifts values of the two conformers have a better agreement with the experimental data relative to the individual conformers.Table 5
Theoretical and experimental13C and 1H isotropic chemical shift (with respect to TMS, all values in ppm) for two lower-energy conformers of BzChCl.
Atom
Experimental (ppm) (in DMSO-d6) [20]
Calculated B3LYP/6-31++G(d) GIAO
Conformer I
Conformer II
Average
C1
58.680
60.411
58.651
59.531
C4
63.810
64.922
59.722
62.322
C7
52.810
47.663
52.414
50.039
C11
52.810
54.922
48.123
51.523
C15
52.810
51.758
53.989
52.874
C21
165.100
163.479
163.453
163.466
C23
126.700
123.718
125.209
C24
129.270
127.056
126.633
126.845
C28
129.270
124.849
126.745
125.797
C25
128.750
125.041
122.853
123.947
C27
128.750
124.475
123.381
123.928
C26
133.540
127.651
128.555
128.103
R2
0.9967
0.9973
0.9985
RMSE
3.4388
3.6272
3.1446
MAE
3.0257
3.0399
2.6414
H2
4.013
4.612
4.313
H3
5.452
4.477
4.965
H(O–CH2)
4.752
4.733
4.545
4.639
H5
2.491
2.123
2.307
H6
7.794
7.291
7.543
H(N–CH2)
3.973
5.142
4.707
4.925
H8
2.011
2.328
2.170
H9
6.254
3.733
4.994
H10
3.113
2.535
2.824
H(N–CH3)
3.309
3.793
2.865
3.329
H12
1.930
1.820
1.875
H13
2.071
6.906
4.489
H14
6.429
1.981
4.205
H(N–CH3)
3.309
3.477
3.569
3.523
H16
2.140
1.991
2.066
H17
2.887
2.100
2.494
H18
2.152
6.384
4.268
H(N–CH3)
3.309
2.393
3.492
2.943
H29
8.373
8.257
8.315
H33
8.140
8.230
8.185
H(Benzene)
8.037
8.257
8.244
8.251
H30
7.458
7.468
7.463
H32
7.435
7.482
7.459
H(Benzene)
7.578
7.447
7.475
7.461
H31
7.761
7.554
7.658
H(Benzene)
7.711
7.761
7.554
7.658
R2
0.9290
0.9713
0.9665
RMSE
0.5631
0.3460
0.3810
MAE
0.3946
0.2869
0.2561


### 3.5. NBO Analysis

The role of hyperconjugative interactions in the stabilization of the conformers of the compound was investigated by NBO analysis [22–25]. Here, the hyperconjugative represents the transfer of an electron from the lone pair (LP Cl) to an antibonding orbital since the molecular structures of the conformers are only changed by the location of the Cl anion. Table 6 consists of hyperconjugative interactions (kcal mol−1) for the two lowest energy conformers of the compound calculated by using the B3LYP/LANL2DZ method. As seen the total hyperconjugative energies determined relative to only the location of the Cl anion for the two conformers are very near. This supports that the two conformers of the compound should have close optimized energies.Table 6
Calculated hyperconjugative interactions (kcal mol−1) for two lower-energy conformers of BzChCl.
Donor NBO
Acceptor NBO
Calculated B3LYP/6-31++G(d)
Conformer I
Conformer II
LP (Cl)
σ
* C1–H2
—
0.09
σ
* C4–H5
0.12
0.20
σ
* C4–H6
15.03
10.26
σ
* C7–H9
7.54
—
σ
* C11–H13
—
10.07
σ
* C11–H14
7.51
—
σ
* C11–N19
—
0.08
σ
* C15–H18
—
6.92
Total
30.20
27.62
Relative energy
2.58
0.00


### 3.6. Spectral Analysis

The calculated IR and R spectra of the lowest energy conformers I and II of the compound are given in Figures3(a) and 3(b), respectively. The powder experimental spectra of the compound are also given in the figures, as labeled (d). As seen the experimental IR or R spectrum does fit well to none of the calculated spectra for the two conformers, individually. The experimental spectra show the peaks splinted doublets or triplets, and thus, have more spectral lines than the calculated ones. Since the relative energy values and barrier height between the two conformers of the compound are very low we think that the spectra of these two conformers can simultaneously exist in one experimental spectrum. So, we have drawn the sum of the calculated spectra (IR or R) of these conformers, and obtained the spectra in Figure 3(c). By confronting them to the experimental ones (Figure 3(d)) it can be seen that they fit very well to each other. Therefore, we state that the title compound simultaneously contain these two optimized lowest energy conformers of the compound in the ground state.Figure 3
Calculated IR and R spectra of conformers I and II of BzChCl as labeled (a) and (b), respectively. (c) shows the sum of (a) and (b); (d) shows experimental spectrum [19].When we investigate the relationship of the experimental and calculated chemical shifts by taking into consideration theR2, MAE, and RMSE values we see from Table 5 the agreement between them are better for the average chemical shift values of the two conformers. This also confirms the simultaneous presence of the two conformers, regarding one experimental NMR spectrum for the two conformers since of their fast motions in the solution phase. Since of these, we state that the title compound simultaneously contains the two optimized energy conformers in the ground state. This is maybe because of highly deliquescent of choline compounds.


## 3.1. Ground State Conformers

The molecular structures of all the calculated optimized conformers of BzChCl can be seen in Figure1. In calculations firstly the potential energy surface (PES) of the compound was scanned around the torsion angle of Cl(34)-C(11)-N(19)-C(4) from −180° to 180° at increments of 20° with an Cl…N distance of around 3.60 Å at B3LYP/6-31 G(d,p). The PES showed four minimum-energy structures (Figure 2). The barrier height between the conformer I and II is 9.6 kcal/mol while those between the conformer I and III or I and IV is bigger than 13 kcal/mol. These structures were chosen as initial geometry to obtain the further ones. The conformers of the compound are defined by five essential torsion angles as given in Table 1. For comparison, the experimental data being available for a similar molecule, acetylcholine chloride, are also shown in the table.Table 1
Five essential torsion angles for all the conformers of BzChCl.
Torsion Angles (°)
Exp. [6]
Conformer I
Conformer II
Conformer III
Conformer IV
τ
1[C(21)-O(20)-C(1)-C(4)]
167.9
115.02
83.64
−179.64
136.13
τ
2[O(20)-C(1)-C(4)-N(19)]
84.7
−81.83
−153.87
−179.83
−87.70
τ
3[C(1)-C(4)-N(19)-C(11)]
171.4
−172.97
−49.28
−61.10
174.13
τ
4[C(1)-C(4)-N(19)-Cl(34)]
—
−112.83
−105.05
−179.75
−166.48
τ
5[O(22)-C(21)-O(20)-C(1)]
5.2
−9.68
−0.87
0.00
−3.70Optimized molecular structures of four conformers of BzChCl.
(a)
(b)
(c)
(d)Figure 2
Potential energy surface (PES) scan of BzChCl.The electronic energies, relative energies, and mean vibrational deviations for all the conformers of the compound are given in Table2. The relative energy values and calculated mean vibrational deviations in the table are respect to the lowest energy conformer I of the compound. As seen the mean vibrational deviation increases while the relative energy increases. Therefore, we state that the more different the molecular structures of the two conformers are the higher the relative energy is between them, and so, a bigger mean vibrational deviation occurs. This comment has also been given for pyridine carboxaldehyde and difluorobenzaldehyde molecules in our previous studies [17, 18]. From Table 2 we also see that the relative energies and mean vibrational deviations between the conformers I and II are fairly low while the others are fairly high. Therefore, we take into account only the conformers I and II after this part of the study.Table 2
Electronic energies, and relative energies and mean calculated vibrational deviations between the conformers of BzChCl.
Conformer I
Conformer II
Conformer III
Conformer IV
Energy  (Hartree/part.)
−1133.243575
−1133.242015
−1133.239145
−1133.238584
Relative energy (kcal/mol)
0.00
0.978
2.778
3.130
Vib. deviations|Δν|ave
0.00
6.219688
9.875208
6.393542


## 3.2. Vibrational Frequencies

The calculated vibrational frequencies and proposed vibrational assignments for the two lowest energy conformers I and II of BzChCl are given in Table3. In the table are also given the experimental vibrational frequencies (IR and R) of the compound [19]. The linear correlation coefficients (R2), mean absolute error (MAE) and the root mean square errors (RMSE) were also given in the last lines of the table. The RMSE is defined by the following
(1)RMSE(wi)=∑(δicalc-δiexp)2n,
where δicalc and δiexp are the calculated and experimental chemical shifts of atom i, respectively, and n denotes the number of atoms. According to these values it can be stated that the calculated vibrational frequencies are in a good agreement with the experiment data. The calculated vibrational frequencies are slightly higher than the observable values for the majority of the normal modes. Two factors may be responsible for this discrepancy. The first is the environmental change of the molecule in the experimental medium and the second is that the calculated frequencies are harmonic while the experimental ones are anharmonic.Table 3
Experimental and calculated vibrational frequencies of two lower-energy conformers of BzChCl.ν shows stretching, δ bending, γ out of plane bending, ρr rocking, t twisting, τ torsion, and w wagging modes.
Mode no.
Assignments
Experimental frequencies
Calculated frequencies
(cm−1) BzChCl [19]
(cm−1) B3LYP 6-31++G(d)
IR
R
Conformer I
Conformer II
96
Ringν(CH)sym
3107
3109
95
Ringν(CH)sym
3091vw
3100
3098
94
Ringν(CH)asym
3086
3086
93
Ringν(CH)asym
3085
3078
92
ν(CH3)asym
3073s
3077
3076
91
Ringν(CH)asym
3068sh
3066
3065
90
ν(CH3)asym
3065w
3065
3058
89
ν(CH3)asym
3053
3053
88
ν(CH3)asym
3050
3048
87
ν(CH3)asym + ν(CH2)asym
3037w
3046
3044
86
ν(CH2)asym + ν(CH3)asym
3034vw
3023m
3026
3024
85
ν(CH3)asym + ν(CH2)asym
3018
3018
84
ν(CH2)asym
2994sh
2997m
2998
3015
83
ν(CH3)sym + ν(CH2)sym
2979m
2988
2980
82
ν(CH2)sym + ν(CH3)sym
2956.2927vs
2951m
2972
2975
81
ν(CH3)sym + ν(CH2)sym
2932m
2919
2920
80
ν(CH3)sym + ν(CH2)sym
2871sh
2892w
2906
2904
79
ν(CH2)sym + ν(CH3)sym
2855vs
2836vw
2809
2887
78
ν (C=O)
1725vs
1726vs
1687
1688
77
Ringν (C=C) + Ring δ(CH)
1598m
1601s
1588
1589
76
Ringν (C=C) + Ring δ(CH)
1583w
1584w
1569
1569
75
γ(CH3) + δ(CH2)
1498
1493
74
γ(CH3) + δ(CH2)
1486m
1489vw
1485
1479
73
δ(CH2) + γ(CH3) + Ring δ(CCH)
1481
1476
72
Ringδ(CCH) + δ(CH2) + γ(CH3)
1471sh
1475
1474
71
γ(CH3) + δ(CH2)
1466
1464
70
γ(CH3) + δ(CH2)
1464
1458
69
δ(CH3) + δ(CH2)
1459, 1451s
1455m
1458
1455
68
Ringδ(CH) + γ(CH3) + δ(C–CH2) + δ(CH2)
1443w
1445
1448
67
δ(CH2) + γ(CH3)
1437
1444
66
γ(CH3) + δ(CH3)
1435
1434
65
Ringδ(CH) + ν(Ring) + δ(CCC)
1434sh
1434
1434
64
δ(CH3) + δ(C–CH2)
1411w
1413vw
1413
1412
63
δ(CH3) + δ(C–CH2)
1404vw
1402
1402
62
δ(CH3) + δ(C–CH2)
1385vw
1394
1391
61
δ(C–CH2) + δ(CH3)
1381ms
1374
1362
60
δ(C–CH2) + δ(CH3) + δ(CH) + ν(Ring)
1341w
1346w
1338
1319
59
δ(C–CH2) + δ(CH3) + δ(CH)
1311m
1311w
1314
1314
58
δ(CH) + δ(CCC)
1283m
1299
1300
57
δ(N–CH3) + δ(C–CH2) + ν(N–CH2)
1280.1261s
1269sh
1272
1281
56
δ(C–CH2) +  δ(N–CH3)
1249sh
1261m
1259
1262
55
δ(C–CH2) +  δ(CH) + ν(C–O) + Ring ν(C–C) +  δ(CC=O)
1249sh
1239
1246
54
δ(N–CH3) + δ(C–CH2) + ν(N–CH3)
1219vw
1221w
1231
1227
53
δ(N–CH3) + δ(C–CH2)
1206
1209
52
δ(CH)
1172m
1163m
1160
1162
51
δ(CH)
1161w
1143vw
1148
1148
50
δ(NCH)
1141vw
1135
1139
49
δ(NCH)
1118s
1121vw
1115
1119
48
δ(CCC) + ν(CO) + δ(NCH)
1103w
1089vw
1093
1094
47
δ(CCH)
1076m
1067
1066
46
τ(HCCH) + δ(NCH)
1041vw
1058
1060
45
δ(NCH)
1033w
1042w
1055
1051
44
δ(NCH) + Ring ν(CC)
1018m
1011
1026
43
δ(CCH) + ν(O–C)
1002s
1003
1012
42
δ(Ring) + ν(O–CH2) + δ(NCH)
992vw
983
979
41
τ(HCCH)
979
978
40
τ(HCCH)
978
976
39
τ(HCCH)
951ms
959, 953w
961
961
38
ν(N–CH3) + δ(NCH)
929
940
37
τ(Ring)
927
927
36
δ(CCH) + ν(N–CH3)
902m
903w
906
924
35
ν(N–CH3) + δ(NCH)
869w
871w
861
883
34
Ringγ(CH)
836m
835
835
33
δ(N–CH3) + δ(Ring) + δ(OC=O)
812vw
811vw
828
825
32
τ(HCCH) + Ring γ(CH) + γ(OC=O)
793
788
31
τ(HCCH) + Ring γ(CH) + γ(OCC)
785
778
30
Breathing (choline)
714s
724m
698
717
29
Ringγ(CH) + γ(CC=O)
688vw
680m
673
699
28
γ(Ring)
679w
671
670
27
δ(Ring) + δ(COC)
657
663
26
δ(Ring)
619vw
619m
606
606
25
δ(N–CH3) + δ(NCC) + δ(OCC)
544w
544vw
526
516
24
δ(N–CH3) + δ(NCC) + δ(OCC)
474w
495vw
471
465
23
δ(N–CH3) + δ(N–CH2)
476w
454
459
22
δ(N–CH3)
455vw
440
441
21
γ(Ring) + γ(OC=O)
423w
431
434
20
γ(Ring)
409
399
19
δ(N–CH3)
399
390
18
δ(N–CH3) + ρr (CH2)
369w
369
374
17
ρ
r (CH2) + ρr (CH3)
356
357
16
ρ
r (CH3) out of plane
344
329
15
ρ
r (CH3) out of plane
324
322
14
w(CH3)
303
293
13
ρ
r (CH3) out of plane
261w
266
266
12
ρ
r (Ring) + w(CH3)
255
236
11
ρ
r (CH2) + w(Ring)
209m
236
226
10
ν(N–Cl) + ρr (CH3) out of plane
185
177
9
w(Ring) + ν(N–Cl)
166w
166
161
8
ρ
r (CH3) + ρr (CH2)
138
149
7
ρ
r (CH2) + w(Ring)
132
130
6
ρ
r (CH2) + ρr (CH3)
111w
106
114
5
w(CH2) + w(C=O)
84
72
4
ρ
r (Ring) + w(CH2) + ρr (CH3)
63
54
3
w(Ring) + w(C=O) + w(Cl)
38
33
2
w(Ring) + ρr (CH3) out of plane
25
26
1
ρ
r (Ring) out of plane + w(CH3)
19
20
R2
0.9998
0.9998
RMSE
12.8726
12.6161
MAE
8.8888
9.6111
w: weak, m: medium, s: strong, v: very, sh: shoulder, and br: broad.The assignments in the table are similar those done for a choline derivative molecule, acetylcholine bromide, which is available in literature [21].


## 3.3. Geometric Structures

BzChCl consists of a benzene ring and a choline group. The calculated optimized structure parameters for the lowest energy conformers I and II of BzChCl are summarized in Table4, in accordance with the atom numbers in Figure 1. Since the X-ray analysis of the compound could not be reached the theoretical optimized structures were compared with those of acetylcholine chloride for which the crystal structure has been solved [5]. The R2, MEA, and RMSE values between the calculated and experimental geometric parameters are given in the last lines of the table and they show a well agreement for the two conformers.Table 4
Calculated optimized geometric parameters for two lower-energy conformers of BzChCl.
Parameters
Experimental [6]
Calculated B3LYP [6-31++G(d)]
Bond lengths (Å)
Conformer I
Conformer II
N(19)-C(7)
1.52
1.513
1.500
N(19)-C(11)
1.50
1.514
1.513
N(19)-C(15)
1.49
1.499
1.512
N(19)-C(4)
1.49
1.532
1.528
C(1)-C(4)
1.47
1.516
1.535
C(1)-O(20)
1.45
1.451
1.439
O(20)⋯N(19)
3.26
3.324
3.760
O(20)⋯C(15)
3.17
3.252
4.862
C(21)-C(23)
1.49
1.487
1.486
C(21)-O(20)
1.38
1.356
1.358
C(21)-O(22)
1.18
1.221
1.221
C(11)-H(12)
—
1.092
1.092
C(11)-H(13)
—
1.092
1.100
C(11)-H(14)
—
1.097
1.091
C(7)-H(8)
—
1.092
1.092
C(7)-H(9)
—
1.097
1.089
C(7)-H(10)
—
1.090
1.091
C(15)-H(16)
—
1.092
1.092
C(15)-H(17)
—
1.089
1.092
C(15)-H(18)
—
1.092
1.097
C(1)-H(2)
—
1.093
1.091
C(1)-H(3)
—
1.090
1.093
C(4)-H(5)
—
1.094
1.092
C(4)-H(6)
—
1.105
1.098
C(23)-C(24)
—
1.404
1.404
C(23)-C(28)
—
1.404
1.404
Cl(34)⋯N(19)
—
3.616
3.593
Cl(34)⋯C(4)
—
3.317
3.33850
Cl(34)⋯H(6)
—
2.281
—
Cl(34)⋯H(9)
—
2.467
—
Cl(34)⋯H(14)
—
2.463
—
Cl(34)⋯H(6)
—
—
2.377
Cl(34)⋯H(13)
—
—
2.381
Cl(34)⋯H(18)
—
—
2.486
R2
0.999
0.9414
RMSE
0.0397
0.5327
MAE
0.0303
0.2207
C(7)-N(19)-C(11)
109
108.2
110.2
C(7)-N(19)-C(15)
108
109.8
109.5
C(4)-N(19)-C(7)
111
110.8
110.9
C(4)-N(19)-C(11)
111
106.2
111.0
C(4)-N(19)-C(15)
107
112.4
107.1
N(19)-C(4)-C(1)
119
118.2
114.3
N(19)-C(7)-H(9)
—
107.3
109.9
C(1)-O(20)-C(21)
115
118.5
116.4
C(11)-N(19)-C(15)
111
109.3
108.1
O(20)-C(21)-O(22)
123
122.9
122.4
O(22)-C(21)-C(23)
129
124.4
124.9
O(20)-C(1)-C(4)
111
113.8
109.2
O(20)-C(21)-C(23)
108
112.8
112.8
H(2)-C(1)-H(3)
—
108.4
110.2
H(6)-C(4)-H(5)
—
110.0
111.3
H(6)-C(4)-N(19)
—
104.0
105.4
H(14)-C(11)-N(19)
—
107.5
109.0
H(13)-C(11)-N(19)
—
108.4
107.3
H(12)-C(11)-N(19)
—
108.2
107.9
H(12)-C(11)-H(13)
—
110.1
111.1
H(12)-C(11)-H(14)
—
111.3
109.6
H(16)-C(15)-H(17)
—
109.5
110.2
H(8)-C(7)-H(9)
—
110.8
110.3
H(8)-C(7)-N(19)
—
107.6
108.5
N(19)-C(7)-H(10)
—
108.8
108.9
N(19)-C(15)-H(16)
—
108.4
108.3
H(17)-C(15)-H(18)
—
110.7
111.1
C(4)-C(1)-H(3)
—
113.5
113.4
O(20)-C(1)-H(2)
—
104.9
104.9
C(21)-C(23)-C(24)
—
117.9
118.0
C(21)-C(23)-C(28)
—
122.2
122.1
C(23)-C(24)-H(29)
—
119.0
119.0
C(23)-C(28)-H(33)
—
119.8
119.8
C(23)-C(24)-C(25)
—
120.1
120.0
C(23)-C(28)-C(27)
—
119.9
119.8
R2
0.7623
0.8597
RMSE
3.2139
2.5758
MAE
2.6083
1.9333


## 3.4. Chemical Shifts

The experimental and calculated1H and 13C NMR chemical shifts (with respect to TMS) for the lowest energy conformers I and II of BzChCl are given in Table 5. The experimental chemical shifts have been obtained from Spectral Database for Organic Compounds Web Page [20]. Since the experimental 1H chemical shift values of individual hydrogens are not available we have found the average values of 1H chemical shifts for the CH2 and CH3 hydrogen atoms. These are shown as bold in the table. For comparison the average chemical shift values of the two conformers are also given in the table. The R2, MEA, and RMSE values between the experimental and theoretical chemical shifts are obtained, and given in the last two lines of Table 5. According to these values one important observation is that the calculated results for the average chemical shifts values of the two conformers have a better agreement with the experimental data relative to the individual conformers.Table 5
Theoretical and experimental13C and 1H isotropic chemical shift (with respect to TMS, all values in ppm) for two lower-energy conformers of BzChCl.
Atom
Experimental (ppm) (in DMSO-d6) [20]
Calculated B3LYP/6-31++G(d) GIAO
Conformer I
Conformer II
Average
C1
58.680
60.411
58.651
59.531
C4
63.810
64.922
59.722
62.322
C7
52.810
47.663
52.414
50.039
C11
52.810
54.922
48.123
51.523
C15
52.810
51.758
53.989
52.874
C21
165.100
163.479
163.453
163.466
C23
126.700
123.718
125.209
C24
129.270
127.056
126.633
126.845
C28
129.270
124.849
126.745
125.797
C25
128.750
125.041
122.853
123.947
C27
128.750
124.475
123.381
123.928
C26
133.540
127.651
128.555
128.103
R2
0.9967
0.9973
0.9985
RMSE
3.4388
3.6272
3.1446
MAE
3.0257
3.0399
2.6414
H2
4.013
4.612
4.313
H3
5.452
4.477
4.965
H(O–CH2)
4.752
4.733
4.545
4.639
H5
2.491
2.123
2.307
H6
7.794
7.291
7.543
H(N–CH2)
3.973
5.142
4.707
4.925
H8
2.011
2.328
2.170
H9
6.254
3.733
4.994
H10
3.113
2.535
2.824
H(N–CH3)
3.309
3.793
2.865
3.329
H12
1.930
1.820
1.875
H13
2.071
6.906
4.489
H14
6.429
1.981
4.205
H(N–CH3)
3.309
3.477
3.569
3.523
H16
2.140
1.991
2.066
H17
2.887
2.100
2.494
H18
2.152
6.384
4.268
H(N–CH3)
3.309
2.393
3.492
2.943
H29
8.373
8.257
8.315
H33
8.140
8.230
8.185
H(Benzene)
8.037
8.257
8.244
8.251
H30
7.458
7.468
7.463
H32
7.435
7.482
7.459
H(Benzene)
7.578
7.447
7.475
7.461
H31
7.761
7.554
7.658
H(Benzene)
7.711
7.761
7.554
7.658
R2
0.9290
0.9713
0.9665
RMSE
0.5631
0.3460
0.3810
MAE
0.3946
0.2869
0.2561


## 3.5. NBO Analysis

The role of hyperconjugative interactions in the stabilization of the conformers of the compound was investigated by NBO analysis [22–25]. Here, the hyperconjugative represents the transfer of an electron from the lone pair (LP Cl) to an antibonding orbital since the molecular structures of the conformers are only changed by the location of the Cl anion. Table 6 consists of hyperconjugative interactions (kcal mol−1) for the two lowest energy conformers of the compound calculated by using the B3LYP/LANL2DZ method. As seen the total hyperconjugative energies determined relative to only the location of the Cl anion for the two conformers are very near. This supports that the two conformers of the compound should have close optimized energies.Table 6
Calculated hyperconjugative interactions (kcal mol−1) for two lower-energy conformers of BzChCl.
Donor NBO
Acceptor NBO
Calculated B3LYP/6-31++G(d)
Conformer I
Conformer II
LP (Cl)
σ
* C1–H2
—
0.09
σ
* C4–H5
0.12
0.20
σ
* C4–H6
15.03
10.26
σ
* C7–H9
7.54
—
σ
* C11–H13
—
10.07
σ
* C11–H14
7.51
—
σ
* C11–N19
—
0.08
σ
* C15–H18
—
6.92
Total
30.20
27.62
Relative energy
2.58
0.00


## 3.6. Spectral Analysis

The calculated IR and R spectra of the lowest energy conformers I and II of the compound are given in Figures3(a) and 3(b), respectively. The powder experimental spectra of the compound are also given in the figures, as labeled (d). As seen the experimental IR or R spectrum does fit well to none of the calculated spectra for the two conformers, individually. The experimental spectra show the peaks splinted doublets or triplets, and thus, have more spectral lines than the calculated ones. Since the relative energy values and barrier height between the two conformers of the compound are very low we think that the spectra of these two conformers can simultaneously exist in one experimental spectrum. So, we have drawn the sum of the calculated spectra (IR or R) of these conformers, and obtained the spectra in Figure 3(c). By confronting them to the experimental ones (Figure 3(d)) it can be seen that they fit very well to each other. Therefore, we state that the title compound simultaneously contain these two optimized lowest energy conformers of the compound in the ground state.Figure 3
Calculated IR and R spectra of conformers I and II of BzChCl as labeled (a) and (b), respectively. (c) shows the sum of (a) and (b); (d) shows experimental spectrum [19].When we investigate the relationship of the experimental and calculated chemical shifts by taking into consideration theR2, MAE, and RMSE values we see from Table 5 the agreement between them are better for the average chemical shift values of the two conformers. This also confirms the simultaneous presence of the two conformers, regarding one experimental NMR spectrum for the two conformers since of their fast motions in the solution phase. Since of these, we state that the title compound simultaneously contains the two optimized energy conformers in the ground state. This is maybe because of highly deliquescent of choline compounds.


## 4. Conclusion

The optimized molecular structures (bond lengths and bond angles), vibrational frequencies, and chemical shifts of all the conformers of benzoylcholine chloride have been calculated using B3LYP method at 6-31++G(d) basis set level. The comparison of the experimental and calculated IR, R, and NMR spectra of the compound have shown that the experimental spectra are formed from the superposition of the spectra of two optimized energy conformers of the compound. So it was concluded the compound simultaneously exits in two optimized energy conformers in the ground state.



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*Source: 369342-2012-09-13.xml*