Original Article
Phys Chem Ind J, Volume: 13( 2)

1H and 13C NMR Investigation of Quinoline Pharmaceutical Derivatives: Interpretation of Chemical Shifts and their Comparison with the Experimental Value

*Correspondence:
Zakiyeh Bayat , Department of Chemistry, Quchan Branch, Islamic Azad University, Quchan, Iran, Tel: +989151811750; E-Mail: [email protected]

Received: June 5, 2018; Accepted: June 26, 2018; Published: June 28, 2018

Citation: Z.Bayat, M Shir Mohammadi, and E Mohammadi Nasab. 1H and 13C NMR Investigation of Quinoline Pharmaceutical Derivatives: Interpretation of chemical shifts and their comparison with the experimental value. Phys Chem Ind J. 2018;13(2):122.

Abstract

In this paper, 1H and 13C chemical shift values have been calculated for the optimized structures of the quinoline pharmaceutical derivatives of compounds by theoretically method and compared to the experimental chemical shift values. Theoretically chemical shifts values were determined at GIAO HF/6-31++G(d,p) level of theory by Gaussian 09 program and are fully interpreted. Highest frequency are observed for the nitrogen, Oxygen and chlorine substitutions occurring in ipso carbons and also on nitrogen heteroatom occur at ortho and para positions in heterocyclic carbons and Hydrogen attached to them. The aliphatic Hydrogen at high frequency for the Hydrogen attached on Carbon adjacent to Oxygen, Nitrogen and carbons include double bond. The correlation analysis of the calculation and experimental data was performed in order to quantify the disagreement.

Keywords

NMR; Quinoline; Computational; Comparison; Chemical shift

Introduction

The use of heterocyclic compounds in our lives is irrefutable. So there is a growing request for heterocyclic compounds, and this has incited research activities in the field of heterocyclic compound chemistry. Amongst the wide diversity of heterocyclic compounds, those containing the nitrogen atom are usual in nature, and their biological usage distinguishes them [1]. Quinoline and its derivatives have evermore engrossed both biological and synthetic chemist due to its various pharmacological and chemical attributes [2]. 1,10-Phenanthroline (FIG. 1) has been widely used for decades as a chemically Multipurpose module displaying a good combination of structural and chemical attributes. 1,10-phenanthroline derivatives provided the development of sophisticated synthetic strategies that have yielded fascinating molecular architectures. Remarkable, some of these systems can be designed to work as molecular-level machines. Another capacity of 1,10- phenanthroline is connected to its Flat structure, that prompts intercalation or binding with DNA or RNA [3]. Chloroquine (FIG. 2) was introduced in the 1940s and quickly became the mainstay of treatment and prevention because it was inexpensive and nontoxic and malaria parasites were generally susceptible to it [4]. Cinchocaine (FIG. 3) is a member of a category of drugs known as local anesthetics [5]. Imiquimod (FIG. 4) have been shown to have attributes as immune response modifiers in vitro and in vivo, and display antiviral and antitumor activity via endogenous cytokine production [6]. Nitroxoline (FIG. 5) is an antibiotic, which does not belong to any known antimicrobial class and is used as a urinary antibacterial agent, active against oversensitive Gram-positive and Gram-negative bacterial strains that generally exist in urinary tracts and cause infections [7]. Primaquine (FIG. 6) is the only 8-aminoquinoline which is extensively employed as an antimalarial drug [8]. Proflavine (FIG. 7) is the prototype of DNA-intercalating aminoacridines and is a planar polyaromatic chromophore that is mono-protonated in the physiological situation [9]. Quinine and quinidine, two cinchona alkaloids so freely provided by Nature, are not only important pharmacological drugs,' but their contribution to chemistry certainly deserves respect [10]. Quinine (FIG. 8) and quinidine (FIG. 9) have been used widely in the medical profession as antimalarial and antiarrhythmic drugs, respectively [11]. Tacrine (FIG. 10) is the first factor approved by the Food and Drug Administration for the treatment of Alzheimer's disease and has been extensively employed in the infirmary. Tacrine acts as an acetylcholinesterase inhibitor blocking the degradation of acetylcholine in neurons of the cerebral cortex thereby increasing cholinergic transmission [12]. Of the specific importance of NMR studies has been the use of various multidimensional sequences of NMR programs to define the detailed molecular structure. The standard NMR experiences are enough to obtain a perfect assignment of organic compounds, and efficient to obtain molecular structure information [13]. NMR chemical shifts, however, depend on the electronic environment of the nucleus studied. This gives us the unique leisure to quantify the effect of the packing on the chemical shifts in such a complex system [14]. This Presentation is a theoretical study of NMR magnetic shielding spectra of quinoline pharmaceutical derivatives. Presented here is calculated 13C and 1H isotropic NMR chemical shifts for 1,10-Phenanthroline, Chloroquine, cinchocaine, Imiquimod, Nitroxoline, Primaquine, Proflavine, Quinine, quinidine, and Tacrine. The optimized geometrical parameters of quinoline pharmaceutical derivatives which are calculated by HF methods with 6-31++G(d,p) basis sets are consistent with the atom numbering scheme.1H and 13C chemical shift values have been calculated for the optimized structures of the quinoline pharmaceutical derivatives of compounds and compared to the experimental chemical shift values.

physical-chemistry-Phenanthroline

Figure 1: The structure of optimized 1,10 Phenanthroline.

physical-chemistry-chloroquine

Figure 2: The structure of optimized chloroquine.

physical-chemistry-cinchocaine

Figure 3: The structure of optimized cinchocaine.

physical-chemistry-imiquimod

Figure 4: The structure of optimized imiquimod.

physical-chemistry-nitroxoline

Figure 5: The structure of optimized Nitroxoline.

physical-chemistry-primaquine

Figure 6: The structure of optimized Primaquine.

physical-chemistry-proflavine

Figure 7: The structure of optimized Proflavine.

physical-chemistry-quinidine

Figure 8: The structure of optimized Quinidine.

physical-chemistry-quinine

Figure 9: The structure of optimized Quinine.

physical-chemistry-tacrine

Figure 10: The structure of optimized Tacrine.

Materials and Methods

Ab initio NMR calculations are now attainable and accurate enough to be useful in exploring the relationship between chemical shift and molecular structure. Study on quinoline derivatives the structural formula of the drug. Using the structure molecules were using the software Gauss view drawing. The program Gaussian optimized structures at the beginning of the Gauss view software structure was obtained as a Gaussian input. In general, studies on 10 cases of selected derivatives of quinolines that the computational method ab initio with the level of computational HF calculations with 6-31++G(d,p) basis sets. This basis set was chosen since it had been successfully used in the study of NMR chemical shielding tensors. The term, σ is a second rank tensor called NMR chemical shielding tensor whose elements describe the size of chemical shielding as a function of molecular orientation with respect to the external magnetic field. The isotropic chemical shielding σiso parameters can be related to the principal components by the following equation:

equation

and the chemical shift to note is the Isotropic value. To convert the shifts to ppm subtract the isotropic value from the isotropic chemical shift of the protons in TMS:

equation

Results and Discussion

In this work, we study magnetic properties of atomic nuclei to determine properties of atoms in the titled compound by NMR spectroscopy. Ab initio calculation of nu0063lear magnetic shielding has become an aid for the analysis of molecular structure. So, NMR is based on the quantum mechanical property of nuclei. Based on NMR study, calculated magnetic shielding tensor (σ, ppm), magnetic shielding anisotropy (σaniso ppm), and chemical shift (δ) were calculated. These results are, listed in TABLES 1-20. On the other hand, experimental 13C and 1H NMR data have been extracted from previous research and Along with referrals are presented in TABLES 1-20 too. Experimental and computational data were compared and full explanations were given on NMR shifts. As can be seen in FIG. 1, the molecular structure of the 1, 10-phenanthroline includes tree aromatic ring. It is a heterocyclic compound with five carbon and one nitrogen atoms in the hetero rings. The study of Chloroquine shows 13 different carbon atoms, which is consistent with the structure on the basis of molecular symmetry. It includes two aromatic rings. The molecular structure of the Cinchocaine includes two aromatic ring, the studied molecule shows 20 different carbon atoms, which is consistent with the structure on the basis of molecular symmetry. So the study of Imiquimod shows 14 different carbon atoms, which is consistent with the structure on the basis of molecular symmetry. it includes three aromatic rings. The molecular structure of the Nitroxoline includes two aromatic ring and molecular structure of the Primaquine includes two aromatic ring and the molecular structure of the Proflavine includes tree aromatic ring. it is a heterocyclic compound with 13 carbon, two NH2 and substitutions and one nitrogen atoms in the hetero rings. The molecular structure of the Quinidine includes two aromatic ring and molecular structure of the Quinine includes two aromatic rings. The study of molecule shows 13 different carbon atoms, which is consistent with the structure on the basis of molecular symmetry. The molecular structure of the Tacrine includes two aromatic and one aliphatic rings. Results of all of the compounds show the calculated and experimental values are comparable. There is an excellent agreement between the experimental and theoretical data. We present here the chemical shifts for each compound and we try to present a complete interpretation based on its structure. Let's start with 1, 10-phenanthroline. Chemical shifts of it are given in TABLE 1 and 2.

Atom δtheo δExp Δδ
1 129.52 147.42 17.9
3 130.48 151.24 20.76
4 100.45 124.43 23.98
5 117.97 137.24 19.27
6 108.16 130.12 21.96
7 104.88 127.96 23.08
8 104.91 127.96 23.05
9 108.14 130.12 21.98
10 129.63 147.42 17.79
11 117.97 137.24 19.27
12 100.46 124.43 23.97
13 130.35 151.24 20.89

Table 1: Theoretical and experimental values of chemical shift)13c NMR( and the difference between of 1,10 phenanthroline [15].

Atom δtheo δExp Δδ
15,22 9.0762 9.17 0.0938
17,20 8.2974 8.45 0.1526
19,18 7.62435 7.98 0.35565
16,21 7.4327 7.77 0.3373

Table 2: Theoretical and experimental values of chemical shift)1H NMR( and the difference between of 1,10 Phenanthroline [15].

Atom δtheo δExp Δδ
8 138.6032 154.8 16.1968
12 134.3873 142 7.6127
3 133.5483 138.9 5.3517
1 121.2667 137.6 16.3333
2 109.704 126.9 17.196
5 107.3318 118.5 11.1682
6 103.6583 123.8 20.1417
4 101.777 114.6 12.823
11 89.2534 98.5 9.2466
19 30.8767 47.1 16.2233
29 30.7723 51.1 20.3277
42 23.2405 49.4 26.1595
35 18.7263 49.4 30.6737
25 13.1495 31.8 18.6505
26 6.3769 20.2 13.8231
20 2.3083 18.6 16.2917
36 -3.8914 8 11.8914
43 -11.5089 8 19.5089

Table 3: Theoretical and experimental values of chemical shift)13C NMR( and the difference between of chloroquine [16].

Atom δtheo δExp Δδ
14 8.4867 8.1 -0.3867
7 8.1724 7.4 -0.7724
9 8.0405 7.8 -0.2405
10 7.2674 7.3 0.0326
13 6.4088 6.7 0.2912
21 2.5185 3.9 1.3815
45 2.3429 3 0.6571
18 1.8943 3 1.1057
44,37 1.6919 3 1.3081
38,45 1.6023 3 1.3977
33,23 1.36795 3 1.63205
28 1.0591 1.7 0.6409
22,23,24 0.9238 1.1 0.1762
41,31 0.8503 1.1 0.2497
27 0.7654 1.1 0.3346
48,40 0.62775 1.1 0.47225
24,39 0.5492 1.1 0.5508
47 0.36 1.1 0.74
46,30 -0.01655 1.1 1.11655

Table 4: Theoretical and experimental values of chemical shift)1H NMR ( and the difference between of chloroquine [16].

Atom δtheo δExp Δδ
30 147.3312 167 19.6688
13 140.3558 161.5 21.1442
9 132.7935 147.2 14.4065
3 130.1242 145.1 14.9758
1 112.5122 129.8 17.2878
5 108.9804 125.3 16.3196
2 107.0759 127.5 20.4241
6 101.823 124.5 22.677
4 100.0413 121.5 21.4587
12 89.1233 111.2 22.0767
17 41.7184 65.9 24.1816
35 30.3526 51.2 20.8474
41 26.5909 46.6 20.0091
48 24.5595 46.6 22.0405
34 19.8895 37.4 17.5105
18 11.6443 31 19.3557
21 0.1684 19.3 19.1316
42 -2.484 11.8 14.284
49 -2.5654 11.8 14.3654
24 -3.3412 13.9 17.2412

Table 5: Theoretical and experimental values of chemical shift)13C NMR( and the difference between of cinchocaine [5].

Atom δtheo δExp Δδ
10 8.4281 8.1 -0.3281
8 7.9361 7.84 -0.0961
7 7.6519 7.63 -0.0219
11 7.2681 7.39 0.1219
14 6.6085 6.95 0.3415
19, 20 3.6027 4.47 0.8673
36 3.4563 3.55 0.0937
38 2.4875 2.66 0.1725
37 2.082 3.55 1.468
50 1.7692 2.54 0.7708
43, 44 1.61465 2.54 0.92535
51 1.4526 2.54 1.0874
39 1.3442 2.66 1.3158
22, 23 1.3442 1.81 0.4658
54 1.1522 0.99 -0.1622
25,26 0.82554 1.51 0.68446
27 0.82554 0.99 0.16446
47,53 0.82554 0.99 0.16446
46 0.7245 0.99 0.2655
29,28 0.60515 0.99 0.38485
52,45 0.43865 0.99 0.55135

Table 6: Theoretical and experimental values of chemical shift)1H NMR( and the difference between of Cinchocaine [5].

Atom δtheo δExp Δδ
12 135.2619 148.2 12.9381
4 129.821 137.13 7.309
16 121.3296 145.85 24.5204
9 116.3767 138.74 22.3633
5 109.7951 124.47 14.6749
6 109.0687 130.41 21.3413
13 106.0072 118.89 12.8828
2 102.0309 121.68 19.6491
1 99.7642 136.19 36.4258
3 93.6592 113.34 19.6808
18 30.8647 60.52 29.6553
19 7.4717 30.63 23.1583
22 0.6284 20.07 19.4416
27 -0.3664 20.07 20.4364

Table 7: Theoretical and experimental values of chemical shift)13C NMR( and the difference between of imiquimod [17].

Atom δtheo δExp Δδ
8.33 8.0206 8.33 0.3094
7.94 7.7768 7.94 0.1632
7.9 7.518 7.9 0.382
9.48 7.3779 9.48 2.1021
7 7.145 8.05 0.905
33 4.8524 5 0.1476
34 4.2008 5 0.7992
20 3.9512 4.8 0.8488
21 3.0832 4.8 1.7168
23 1.7307 2.54 0.8093
24,26 0.8805 1.23 0.3495
25,28,30 0.5252 1.23 0.7048
29 0.2506 1.23 0.9794

Table 8: Theoretical and experimental values of chemical shift)1H NMR( and the difference between of imiquimod [17].

Atom δtheo δExp Δδ
6 141.5031 159.9 18.3969
9 129.4509 148.5 19.0491
5 118.6535 136.7 18.0465
7 115.7548 131.7 15.9452
2 114.3525 128.4 14.0475
3 113.2211 122.0 8.7789
4 107.9696 124.4 16.4304
8 104.2444 124.6 20.3556
1 81.4541 109.4 27.9459

Table 9: Theoretical and experimental values of chemical shift)13C NMR( and the difference between of Nitroxolin [18].

Atom δtheo δExp Δδ
17 9.7063 9.14 -0.5663
16 8.9323 8.53 -0.4023
19 8.8514 9.025 0.1736
18 7.596 7.87 0.274
15 6.3845 7.2 0.8155
20 4.5302 4.93 0.4

Table 10: Theoretical and experimental values of chemical shift)1H NMR( and the difference between of Nitroxolin [18].

Atom δtheo δExp Δδ
13 137.0734 159.6 22.5266
10 132.1573 145.2 13.0427
5 126.219 144.3 18.081
4 121.1624 135.5 14.3376
2 118.2818 134.8 16.5182
3 112.4115 130 17.5885
1 100.4469 121.8 21.3531
12 91.5396 98.9 7.3604
9 87.3098 91.9 4.5902
19 37.8414 55.2 17.3586
23 27.2771 48.1 20.8229
33 21.541 41.7 20.159
29 13.9052 34.1 20.1948
30 10.5073 29.3 18.7927
25 2.0535 20.5 18.4465

Table 11: Theoretical and experimental values of chemical shift)1c NMR( and the difference between of Primaquine [8].

Atom δtheo δExp Δδ
11 8.6757 8.45 -0.2257
8 8.0959 7.8 -0.2959
7 7.2151 7.15 -0.0651
6 6.8982 6.25 -0.6482
14 6.5108 6.25 -0.2608
24 4.2927 3.5 -0.7927
21 3.5456 3.75 0.2044
20 3.1717 3.75 0.5783
22 2.9055 3.75 0.8445
17 1.8816 6 4.1184
36 1.8816 2.55 0.6684
37 1.5463 2.55 1.0037
28 1.4396 1.2 -0.2396
27 0.9474 1.2 0.2526
31 0.76985 1.6 0.83015
34 0.76985 1.5 0.73015
35 0.6117 1.5 0.8883
26 0.2443 1.2 0.9557
32 0.2443 1.6 1.3557
40 -0.0197 1.8 1.8197
39 -0.4114 1.8 2.2114

Table 12: Theoretical and experimental values of chemical shift)1H NMR( and the difference between of Primaquine [8].

Atom δtheo δExp Δδ
5,9 136.7097 149.66 12.9503
14,1 131.5815 140.85 9.2685
7 121.625 134.87 13.245
12 113.5437 128.59 15.0463
3 113.4859 128.59 15.1041
8,4 96.93065 122.47 25.53935
2,13 94.6209 121.00 26.3791
15 84.3246 115.13 30.8054
6 84.1013 115.13 31.0287

Table 13: Theoretical and experimental values of chemical shift)13c NMR( and the difference between of proflavine [19].

Atom δtheo δExp Δδ
20 8.5304 8.731 0.2006
18,23 7.7528 7.811 0.0582
19,25 7.1074 6.78 -0.3274
17,24 6.63095 7.019 0.38805
21,26 3.1124 7.2 4.0876
22,27 2.7359 7.2 4.4641

Table 14: Theoretical and experimental values of chemical shift)1H NMR( and the difference between of Proflavine[19].

Atom δtheo δExp Δδ
33 8.5971 8.474 -0.1231
29 8.4089 7.864 -0.5449
34 7.5363 7.495 -0.0413
27 7.3471 7.113 -0.2341
28 7.1686 7.213 0.0444
42 6.4429 6.065 -0.3779
35 4.9705 5.593 0.6225
44 4.8888 5.45 0.5612
43 4.7923 5.04 0.2477
31 3.6708 3.788 0.1172
30,32 3.24495 3.788 0.54305
41 2.9419 3.404 0.4621
48 2.2943 2.969 0.6747
40 2.2229 2.87 0.6471
47 2.0596 2.84 0.7804
24 1.982 2.711 0.729
37 1.7031 2.206 0.5029
39 1.3917 2.07 0.6783
23,45 0.8213 1.73 0.9087
46 152.889 1.039 -151.85

Table 15: Theoretical and experimental values of chemical shift)13C NMR( and the difference between of Quinidine [20].

Atom δtheo δExp Δδ
33 8.5971 8.474 -0.1231
29 8.4089 7.864 -0.5449
34 7.5363 7.495 -0.0413
27 7.3471 7.113 -0.2341
28 7.1686 7.213 0.0444
42 6.4429 6.065 -0.3779
35 4.9705 5.593 0.6225
44 4.8888 5.45 0.5612
43 4.7923 5.04 0.2477
31 3.6708 3.788 0.1172
30,32 3.24495 3.788 0.54305
41 2.9419 3.404 0.4621
48 2.2943 2.969 0.6747
40 2.2229 2.87 0.6471
47 2.0596 2.84 0.7804
24 1.982 2.711 0.729
37 1.7031 2.206 0.5029
39 1.3917 2.07 0.6783
23,45 0.8213 1.73 0.9087
46 152.889 1.039 -151.85

Table 16: Theoretical and experimental values of chemical shift)1H NMR( and the difference between of Quinidine[20].

Atom δtheo δExp Δδ
1,10 133.3377 157.7 24.36235
8 128.0208 147.3 19.2792
4 125.4435 143.8 18.3565
24 123.3287 141.7 18.3713
3 114.7397 131.2 16.4603
5 108.7657 126.2 17.4343
9 99.8936 118.5 18.6064
2 93.9553 121.4 27.4447
25 92.4771 114.4 21.9229
6 90.4357 101.3 10.8643
13 57.0937 71.52 14.4263
15 37.9491 59.94 21.9909
12 29.7441 56.6 26.8559
23 26.0446 56.9 30.8554
22 25.9823 43.24 17.2577
20 20.4145 39.85 19.4355
19 8.724 27.83 19.106
21 6.8739 27.49 20.6161
17 1.2289 21.48 20.2511

Table 17: Theoretical and experimental values of chemical shift)13C NMR( and the difference between of Quinine [21].

Atom δtheo δExp Δδ
29 8.5036 8.67 0.1664
27,28 8.39215 7.82 -0.57215
26 7.2142 7.38 0.1658
30 7.0167 7.5 0.4833
46 6.4852 5.86 -0.6252
48 4.9213 5 0.0787
47 4.8505 5 0.1495
34 4.7449 5.24 0.4951
31 3.6896 3.89 0.2004
32,33 3.2389 3.89 0.6511
44 2.8285 2.85 0.0215
42,45 2.19835 3.19 0.99165
36 2.0644 1.64 -0.4244
43 2.0093 2.43 0.4207
18 1.7185 3.05 1.3315
39 1.3932 2.19 0.7968
38 0.8956 1.72 0.8244
40 0.7941 1.72 0.9259
35,41 0.71795 1.72 1.00205
37 152.7406 1.64 -151.101

Table 18: Theoretical and experimental values of chemical shift)1H NMR( and the difference between of Quinine [21].

Atom δtheo δExp Δδ
4 145.7461 157 11.2539
8 131.007 152 20.993
7 128.8446 138 9.1554
14 111.1168 136 24.8832
13 109.4853 129 19.5147
10 102.0501 124 21.94995
12 102.0501 116 13.94995
9 97.7301 120 22.2699
3 87.8941 115 27.1059
5 11.7331 32 20.2669
2 1.1847 26 24.8153
1 0.9807 24 23.0193
6 -0.6916 23 23.6916

Table 19: Theoretical and experimental values of chemical shift)13C NMR( and the difference between of Tacrine [22].

Atom δtheo δExp Δδ
21 8.0924 7.5 -0.5924
11 7.6334 7.2 -0.4334
20 7.5626 7.2 -0.3626
19 7.2678 6.75 -0.5178
28 3.3913 4.9 1.5087
27 3.1576 4.9 1.7424
17 2.5144 2.3 -0.2144
25 2.1965 2.3 0.1035
16 2.0933 1.9 -0.1933
22 1.9699 1.9 -0.0699
15,18 1.4176 1.7 0.2824
24 1.1499 1.7 0.5501
23 1.0093 1.7 0.6907

Table 20: Theoretical and experimental values of chemical shift)1H NMR( and the difference between of Tacrine[22].

The aromatic carbon in 13C NMR spectra usually locates in the range of 110–135 ppm. As a rule, Ortho-carbon chemical shifts (C1=147.42, C3=151.24, C10=147.42, C13=151.24) oxygen and nitrogen containing rings is further to the left than Meta carbon chemical shifts (C4=124.43, C6=130.12, C9=130.12, C12=124.43) due to Ortho-carbon lower electron density Caused by the high electro-negative of N heteroatom. data for all 12 aromatic carbons for which experimental data are available. It can be seen that the calculated results are comparable. There is excellent agreement with the experimental data. Even though all of the carbons are aromatic, the range of 006Eearly 100 ppm is about half of the total 13C NMR chemical shift range. The prediction of chemical shifts to this accuracy is remarkable, considering that solvent effects were not considered.it can be seen that the aromatic carbons at highest frequency are those in the range of 130-152 ppm for the ortho and para of the N heteroatom (C1, C3, C10, C13, C11 and C5) Calculated results for all carbons are greater by averages of 20 ppm if polarization functions are included. There are also clear trends in the calculated 13C NMR chemical shifts. All of the 13C NMR chemical shifts in TABLE 1 for the Theoretical shift are lesser than those experimental data. calculations underestimate the 13C NMR chemical shifts at ortho and para carbons of N heteroatom.

As in TABLE 2, the presence of four peaks in 1H NMR spectra suggests that there are four distinct types of protons in 1, 10-phenanthroline. Normally, the protons on phenyl ring are expected to yield NMR signals in the 1H NMR range of 6–8 ppm. The electronegative property of the N heteroatom causes a decrease in shielding constants around the ortho protons connected to C3 and C13. The calculated chemical shifts of 9.0762 ppm are ascribed to these two hydrogen atoms. Para protons connected to C5 and C11 behave similarly. The calculated chemical shifts of 8.2974 ppm are ascribed to these two hydrogen atoms. The second drug we are examining is Chloroquine. Chemical shifts of it are given in TABLE 3 and 4.

One of Chloroquine`s (FIG. 2 ) rings includes nitrogen atom which shows the electronegative property. On the other side, nitrogen atom substitute shows more electronegative property than chloride atom substitute. Therefore, it can be seen that the aromatic carbons at highest frequency are those in the range of 142-155 ppm for the ipso and meta (C1, C3, C8, and C12) carbons of the NH group. Also, it can be seen that the aliphatic carbons at highest frequency are those in the range of 49-48 ppm for the attached (C19, C29, C35, and C42) carbons of the N atoms. data for all nine aromatic carbons for which experimental data are available. It can be seen that the calculated results are comparable. There is excellent agreement with the experimental data. Even though all of the carbons are aromatic, the range of nearly 100 ppm is about half of the total 13C NMR chemical shift range. The prediction of chemical shifts to this accuracy is remarkable, considering that solvent effects were not considered.it can be seen that the aromatic carbons at highest frequency are those in the range of 130-160 ppm for the ortho and para of the N heteroatom (C3, C8, and C12) and ipso of Subordinate (C1) carbons. Calculated results for all carbons are greater by averages of 20 ppm if polarization functions are included. There are also clear trends in the calculated 13C NMR chemical shifts. All of the 13C NMR chemical shifts in TABLE 3 for the Theoretical shift are lesser than those experimental data. calculations underestimate the 13C NMR chemical shifts at ortho and para carbons of N heteroatom and the shifts for ipso carbons.

The methyl and methylene protons of –NH–CH2–CH3 group in Chloroquine showed signals at 3.9 ppm and 1.1 ppm (H21, H22, H23, H32 and H24, Respectively) integrating for three and two protons respectively in its 1H NMR spectra. A broad signal at 3.7273 ppm was observed for the – NH– proton of the amino moiety. Presence of singlets at 3.0 ppm and 1.1 ppm integrating for two protons in 1H NMR of N(CH2-CH3)2 (H37, H38, H44, H45 and H39, H40, H41, H46, H47, H48 respectively). The electronegative property of the N heteroatom causes a decrease in shielding constants around the ortho protons connected to C12. The calculated chemical shifts of 8.4867 ppm are attributed to this hydrogen atom. In this study the third drug is Cinchocaine. Chemical shifts of it are given in TABLE 5 and 6.

The structure of cinchocaine (FIG. 3) shows one of two rings include nitrogen atom which has electronegative property. In TABLE 5 it can be seen that the signal at 145.1 ppm is assigned to the C3 on account of the strong electronegative property of the N hetero atom. data for all 13 aromatic carbons for which experimental data are available. It can be seen that the calculated results are comparable. There is excellent agreement with the experimental data. Even though all of the carbons are aromatic, the range of nearly 100 ppm is about half of the total 13C NMR chemical shift range. The prediction of chemical shifts to this accuracy is remarkable, considering that solvent effects were not considered. There are also clear trends in the calculated 13C NMR chemical shifts. All of the 13C NMR chemical shifts in TABLE 5 for the Theoretical shift are lesser than those experimental data. calculations underestimate the 13C NMR chemical shifts at ortho and para carbons of N hetero atom. The carbon of (C=O) group shows the highest chemical shifts, due to carbon lower electron density Caused by the high electro-negative of (=O) and (N-H) attached groups. Also, it can be seen that the aliphatic carbons at high frequency are those in the range of 37- 66 ppm for the attached carbons of the N-H (C34), N(35, 41, 48) and O (C17) atoms.

In TABLE 6 it can be seen that the aliphatic Hydrogen at high frequency for the Hydrogen attached to carbon connected to Oxygen atom (C17) and N atoms (C34 and C35). Normally, the protons on phenyl ring are expected to yield NMR signals in the δHrange of 6–8 ppm. Unlike the frequency calculations, the basis set effect is rather significant for chemical shifts. The correlation analysis of the calculation and experimental data was performed in order to quantify the disagreement, and the result is listed in TABLE 5 and 6. 1H and 13C chemical shift values have been calculated for the optimized structures of the Cinchocaine compound and compared to the experimental chemical shift values. The fourth drug that was studied was Imiquimod. Chemical shifts of it are given in TABLE 7 and 8.

These rings include nitrogen atom which shows the electronegative property. On the other side, NH2 substitute shows the more electronegative property. In FIG. 4 it can be seen that the aromatic carbons at highest frequency are those in the range of 138-149 ppm for the Ipso and Meta (C4, C9, and C12) carbons of the aminopyrimidines and C16 in imidazole ring. Also, it can be seen that the aliphatic carbons at highest frequency are those in the 60.52 ppm for the Attached (C18) carbons to Nitrogen atom. Even though all of the carbons are aromatic, the range of nearly 100 ppm is about half of the total 13C NMR chemical shift range. The prediction of chemical shifts to this accuracy is remarkable, considering that solvent effects were not considered.it can be seen that the aromatic carbons at highest frequency are those in the range of 130-150 ppm for the ortho and para of the N hetero atom (C4, C12, C16 and C9). Calculated results for all carbons are greater by averages of 20 ppm if polarization functions are included. There are also clear trends in the calculated 13C NMR chemical shifts. All of the 13C NMR chemical shifts in TABLE 7 for the Theoretical shift are lesser than those experimental data. calculations underestimate the 13C NMR chemical shifts at ortho and para carbons of N hetero atom.

The methyl and methylene protons of –N–CH2–CH-CH3 group in Imiquimod showed signals at 4.8 ppm, 2.54 ppm and 1.23 ppm (H20, H21, H23 and H24, H25, H26, H28, H29, H30 Respectively) integrating for two, one and six protons respectively in its 1H NMR spectra. The electronegative property of the N heteroatoms causes a decrease in shielding constants around the protons connected to C12 in the imidazole ring (FIG. 4). The fifth drug we are examining is Nitroxoline. Chemical shifts of it are given in TABLE 9 and 10.

Nitroxoline: the studied molecule shows nine different carbon atoms (FIG. 5), which is consistent with the structure on the basis of molecular symmetry. Due to that fact, nine peaks were observed in 13C NMR spectrum.[19] One of two rings includes nitrogen atom which shows the electronegative property. The aromatic carbon in 13C NMR spectra usually locates in the δC range of 110–135 ppm. Due to the conjugation arising from the phenyl ring and the lone-pair electron of an oxygen atom, the signal at 159.9 ppm is assigned to the C6 with high electron density. Equally, the signal at 148.5 and 136.7 ppm is assigned to the C9 and C5 respectively on account of the strong electronegative property of the N hetero atom. Since C1 is located in the meta-position to the NO2, C4 and C8 are located in the meta-position to the N hetero atom, the induction effect is strong. Thus, the peaks at 109.4 ppm, 124.4 ppm, and 124.6 ppm are assigned to C1, C4, and C8, respectively, due to their lower electron density. The relatively high chemical shifts at 129.9 ppm and 129.4 ppm are ascribed to C3 and C5, respectively. Since C3 is Attachment to the NO2. Thus, the peaks at 122.0 ppm are assigned to C2, due to their lower electron density. The relatively high chemical shift at 131.7 ppm is ascribed to C7. Data for all nine aromatic carbons for which experimental data are available. Even though all of the carbons are aromatic, the range of nearly 100 ppm is about half of the total 13C NMR chemical shift range. It can be seen that the aromatic carbons at highest frequency are those in the range of 130-160 ppm for the ortho and para of the N hetero atom (C5, C7, and C9) and ipso of OH Subordinate (C6) carbons. Calculated results for all carbons are greater by averages of 20 ppm if polarization functions are included. There are also clear trends in the calculated 13C NMR chemical shifts. All of the 13C NMR chemical shifts in TABLE 9 for the Theoretical shift are lesser than those experimental data. calculations underestimate the 13C NMR chemical shifts at ortho and para carbons of N hetero atom and overestimate the shifts for ipso carbons.

As in TABLE 10, the presence of other six peaks in 1H NMR spectra suggests that there are six distinct types of protons in Nitroxoline. Normally, the protons on phenyl ring are expected to yield NMR signals in the δHrange of 6–8 ppm. The substitution of the proton for NO2 and nitrogen atom in ring changes the chemical environment of the remaining aryl protons. The strong electronegative property of the N heteroatom and More than that NO2 substitution causes a decrease in shielding constants around the meta-protons connected to C8 and C1 (FIG. 5). The calculated chemical shifts of 7.596 ppm and 6.3845 ppm are attributed to this two hydrogen atom. Unlike the frequency calculations, the basis set effect is rather significant for chemical shifts. The correlation analysis of the calculation and experimental data was performed in order to quantify the disagreement, and the result is listed in TABLE 9 and 10. 1H and 13C chemical shift values have been calculated for the optimized structures of the Nitroxoline compound and compared to the experimental chemical shift values. In this study the sixth drug is Primaquine. Chemical shifts of it are given in TABLE 11 and 12.

As in TABLE 11, the studied molecule (FIG. 6) shows 15 different carbon atoms, which is consistent with the structure on the basis of molecular symmetry. Due to that fact, nine peaks are observed in 13C NMR spectrum. One of two rings includes nitrogen atom which shows the electronegative property. On the other side, NH substitute shows the more electronegative property. The aromatic carbon in 13C NMR spectra usually locates in the δC range of 110–135 ppm. Due to the conjugation arising from the phenyl ring and the lone-pair electron of an oxygen atom, the signal at 159.9 ppm is assigned to the C13 with high electron density. also In TABLE 1 it can be seen that the aromatic carbons at high frequency are those in the range of 130-146 ppm for the ipso (C10=145.2)and meta (C3= 130) carbons of the NH2 groups and the signal at 135.5 and 144.8 ppm is assigned to the C4 (135.5) and C5 (144.3) respectively on account of the strong electronegative property of the N heteroatom. data for all 13 aromatic carbons for which experimental data are available. It can be seen that the calculated results are comparable. There is excellent agreement with the experimental data. Even though all of the carbons are aromatic, the range of nearly 100 ppm is about half of the total 13C NMR chemical shift range. The prediction of chemical shifts to this accuracy is remarkable, considering that solvent effects were not considered. There are also clear trends in the calculated 13C NMR chemical shifts. All of the 13C NMR chemical shifts in TABLE 11 for the Theoretical shift are lesser than those experimental data. calculations underestimate the 13C NMR chemical shifts at ortho and para carbons of N hetero atom and oVerestimate the shifts for ipso carbons. Also, it can be seen that the aliphatic carbons at highest frequency are those in the range of 40-49 ppm for the attached (C23 and C33) carbons of the N atoms.

The methyl and methylene protons of –NH–CH2(CH3)–CH2-CH2-CH2-NH2 group in Primaquine showed signals in the δH range of 1.2-3.5 ppm. In TABLE 12 it can be seen that the aliphatic Hydrogen at high frequency for the Hydrogen attached on carbons connected to the NH and NH2 groups on account of the strong electronegative property of the N atom. A broad signal at 6 and 1.8 ppm was observed for the –NH– and –NH2- protons respectively. Normally, the protons on phenyl ring are expected to yield NMR signals in the δH range of 6–8 ppm. The electronegative property of the N heteroatom causes a decrease in shielding constants around the ortho protons connected to C5 (FIG. 6). The calculated chemical shifts of 8.6757 ppm are attributed to this hydrogen atom. Unlike the frequency calculations, the basis set effect is rather significant for chemical shifts. The Seventh drug that was studied was Proflavine (FIG. 7). Chemical shifts of it are given in TABLE 13 and 14.

As a rule, Ortho (C9 and C5 =149.66) and para (C7= 134.87) carbon chemical shifts oxygen and nitrogen-containing rings are further to the left than Meta carbon chemical shifts (C4 and C8=122.47) due to Ortho-carbon lower electron density Caused by the high electro-negative of N hetero atom also in TABLE 13 it can be seen that the aromatic carbons at high frequency are those in the range of 128-141 ppm for the ipso (C1 and C14=140.85) and meta (C12 and C3= 128.59) carbons of the NH2 groups. data for all nine aromatic carbons for which experimental data are available. It can be seen that the calculated results are comparable. There is excellent agreement with the experimental data. Even though all of the carbons are aromatic, the range of nearly 100 ppm is about half of the total 13C NMR chemical shift range Calculated results for all carbons are greater by averages of 20 ppm, if polarization functions are included. There are also clear trends in the calculated 13C NMR chemical shifts. All of the 13C NMR chemical shifts in TABLE 13 for the Theoretical shift are lesser than those experimental data. calculations underestimate the 13C NMR chemical shifts at ortho and para carbons of N hetero atom and the shifts for ipso carbons.

Regularly, the protons on the aromatic ring are expected to yield NMR signals in the δHrange of 6–8 ppm. The substitution of the proton for NH2 and the presence of nitrogen hetero atom in the ring changes the chemical environment of the remaining aryl protons and consequently protons chemical shift (TABLE 14). The presence of other six peaks in 1H NMR spectra suggests that there are six distinct types of protons in Proflavine. The Eighth drug we are examining is Quinidine. Chemical shifts of it are given in TABLE 15 and 16.

As in TABLE 15, the studied molecule (FIG. 8) shows 19 different carbon atoms, which is consistent with the structure on the basis of molecular symmetry. Due to that fact, 19 peaks are observed in 13C NMR spectrum. One of two rings includes nitrogen atom which shows the electronegative property. The aromatic carbon in 13C NMR spectra usually locates in the δC range of 110–135 ppm. Due to the conjugation arising from the phenyl ring and the lone-pair electron of an oxygen atom, the signal at 157.55 and 147.11 ppm is assigned to the C1 and C10 respectively with high electron density. Also in TABLE 15, it can be seen that the signal at 148.69 and 143.66 ppm is assigned to the C10 and C1 respectively on account of the strong electronegative property of the N hetero atom. data for all 13 aromatic carbons for which experimental data are available. It can be seen that the calculated results are comparable. There is excellent agreement with the experimental data. Even though all of the carbons are aromatic, the range of nearly 100 ppm is about half of the total 13C NMR chemical shift range. The prediction of chemical shifts to this accuracy is remarkable, considering that solvent effects were not considered. There are also clear trends in the calculated 13C NMR chemical shifts. All of the 13C NMR chemical shifts in TABLE 15 for the Theoretical shift are lesser than those experimental data. calculations underestimate the 13C NMR chemical shifts at ortho and para carbons of N hetero atom. In general, the terminal =CH2 group absorbs (C22=114.44) to the right relative to an internal =CH- group (C21=140.78), Also it can be seen that the aliphatic carbons at highest frequency are those in the range of 43-72 ppm for the attached carbons of the N(C14, C20, and C26) and O (C8 and C13) atoms.

In TABLE 16 it can be seen that the aliphatic Hydrogen at high frequency for the Hydrogen attached on carbons include double bond (C21 and C22). Also, Hydrogen attached to carbon connected to Oxygen atom (C8) showed a chemical shift at 3.778. Normally, the protons on phenyl ring are expected to yield NMR signals in the δHrange of 6–8 ppm. The electronegative property of the N heteroatom causes a decrease in shielding constants around the ortho protons connected to C10 (FIG. 8). The calculated chemical shifts of 8.474 ppm are attributed to this hydrogen atom. Unlike the frequency calculations, the basis set effect is rather significant for chemical shifts. In this study the ninth drug is Quinine. Chemical shifts of it are given in TABLE 17 and 18.

As in TABLE 17, the studied molecule (FIG. 9) shows 19 different carbon atoms, which is consistent with the structure on the basis of molecular symmetry. Due to that fact, 19 peaks are observed in 13C NMR spectrum. One of two rings includes nitrogen atom which shows the electronegative property. The aromatic carbon in 13C NMR spectra usually locates in the δC range of 110–135ppm. Due to the conjugation arising from the phenyl ring and the lone-pair electron of an oxygen atom, the signal at 157.7 ppm is assigned to the C1 and C10 with high electron density. Also in TABLE 17, it can be seen that the signal at 143.8 and 147.3 ppm is assigned to the C4 and C8 respectively on account of the strong electronegative property of the N hetero atom. data for all 13 aromatic carbons for which experimental data are available. It can be seen that the calculated results are comparable. There is excellent agreement with the experimental data. Even though all of the carbons are aromatic, the range of nearly 100 ppm is about half of the total 13C NMR chemical shift range. The prediction of chemical shifts to this accuracy is remarkable, considering that solvent effects were not considered. There are also clear trends in the calculated 13C NMR chemical shifts. All of the 13C NMR chemical shifts in TABLE 1 for Theoretical shift are lesser than those experimental data. calculations underestimate the 13C NMR chemical shifts at ortho and para carbons of N hetero atom. In general, the terminal =CH2 group absorbs (C25=114.4) to the right relative to an internal =CH- group (C24=141.7), Also it can be seen that the aliphatic carbons at highest frequency are those in the range of 43-72 ppm for the attached carbons of the N(C21, C22, and C23) and O (C12) atoms.

In TABLE 18 it can be seen that the aliphatic Hydrogen at high frequency for the Hydrogen attached on carbons include double bond (C24 and C25). Also, Hydrogen attached to carbon connected to Oxygen atom (C12) showed a chemical shift at 3.89. Normally, the protons on phenyl ring are expected to yield NMR signals in the δHrange of 6–8 ppm. The electronegative property of the N heteroatom causes a decrease in shielding constants around the ortho protons connected to C8 (FIG. 9). The calculated chemical shifts of 8.5036 ppm are attributed to this hydrogen atom. Unlike the frequency calculations, the basis set effect is rather significant for chemical shifts. The correlation analysis of the calculation and experimental data was performed in order to quantify the disagreement, and the result is listed in TABLE 17 and 18. 1H and 13C chemical shift values have been calculated for the optimized structures of the Quinine compound and compared to the experimental chemical shift values. The last drug we studied is Tacrine. Chemical shifts of it are given in TABLE 19 and 20.

These rings include nitrogen atom which shows the electronegative property. On the other side, NH2 substitute shows the more electronegative property. In TABLE 19 it can be seen that the aromatic carbons at highest frequency are those in the range of 138-157 ppm for the Ipso and Meta (C4, C9, and C12) carbons of the aminopyrimidines and C16 in imidazole ring. Also, it can be seen that the aliphatic carbons at highest frequency are those in the 60.52 ppm for the Attached (C18) carbons to Nitrogen atom. data for all 13 aromatic carbons for which experimental data are available. It can be seen that the calculated results are comparable [23]. There is excellent agreement with the experimental data. Even though all of the carbons are aromatic, the range of nearly 100 ppm is about half of the total 13C NMR chemical shift range. The prediction of chemical shifts to this accuracy is remarkable, considering that solvent effects were not considered. It can be seen that the aromatic carbons at highest frequency are those in the range of 130-150 ppm for the ortho and para of the N hetero atom (C4, C7, and C8). Calculated results for all carbons are greater by averages of 20 ppm if polarization functions are included. There are also clear trends in the calculated 13C NMR chemical shifts. All of the 13C NMR chemical shifts in TABLE 19 for the Theoretical shift are lesser than those experimental data. calculations underestimate the 13C NMR chemical shifts at ortho and para carbons of N hetero atom.

The methylene protons of Ar–(CH2)4-Ar group in Tacrine showed at 2.3 ppm, 1.9 ppm and 1.7 ppm (H17, H25, H16, H22 and H15, H18, H23, H24 Respectively) integrating for two, two and three protons respectively in its 1H NMR spectra. The electronegative property of the N heteroatoms causes a decrease in shielding constants around the protons connected to C2 in the aliphatic ring (FIG. 10).

References