Is there substituent cross-interaction effect in all the conjugated systems containing CN polar bond? The substituent effects on the NMR chemical shifts of 2,5-disubstituted pyrimidines

Journal of Molecular Structure 1155 (2018) 143e151

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Is there substituent cross-interaction effect in all the conjugated systems containing C]N polar bond? The substituent effects on the NMR chemical shifts of 2,5-disubstituted pyrimidines Hua Yuan*, Yan Zhang, Chun-Ni Chen, Meng-Yang Li Key Laboratory of Theoretical Organic Chemistry and Function Molecule, Ministry of Education, Hunan Provincial University Key Laboratory of QSAR/QSPR, National Demonstration Center for Experimental Chemical Engineering and Materials, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, 411201, Hunan Province, PR China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 27 August 2017 Received in revised form 28 October 2017 Accepted 30 October 2017 Available online 31 October 2017

The substituent cross-interaction effect in the substituted benzylidene anilines (p-XeC6H4eCH]Ne C6H4eY-p) has been observed and widely investigated. In order to investigate whether the substituent cross-interaction effect exist in all the conjugated systems containing C]N polar bond, this paper employed 2-X-5-Y pyrimidines as the model compounds for study. The influences of substituents X and Y on the 1H NMR and 13C NMR chemical shifts of 2, 5-disubsitituted pyrimidines have been systematically investigated. Quantitative structure-chemical shifts relationship models have been built for d(H4,6), d(C2), d(C4,6) and d(C5) with four to six molecular descriptors. These models were confirmed of good stability and predictive performances by leave-one-out cross validation. This study indicates that the substituent effects of 2,5-disubstituted pyrimidines are much more complex than that of the substituted benzylidene anilines. More structural factors besides of Hammett parameter should be taken into consideration. Different from the substituted benzylidene anilines, the cross-interaction effect (Ds2) of substituents X and Y has little contribution to d(H4,6), d(C2), d(C5) and d(C4,6) of 2,5-disubstituted pyrimidines. © 2017 Elsevier B.V. All rights reserved.

Keywords: 2,5-Disubstituted pyrimidine Substituent effect NMR chemical shifts The cross-interaction effect (Ds2) Quantitative structure-property relationship

1. Introduction Extensive investigations have been reported about the substituent effects on the electronic character of the C]N bridging group in Schiff bases due to the promising liquid-crystal and nonlinear optical properties of Schiff bases [1e3]. The substituted benzylidene anilines (p-XeC6H4eCH]NeC6H4eY-p) are the most interested model compounds. Both Neuvonen [3,4] and Cao [5,6] have observed that the benzylidene substituent X and the aniline substituent Y exert different effects on dC(C]N) and dN(C]N): for substituent X, the electron-withdrawing substituent causes shielding and the electron-donating one results in deshielding; while for substituent Y, the electron-withdrawing substituent leads to deshielding and the electron-donating one behaves oppositely. In the early year, Kawasaki [7] and Akaba [8] qualitatively demonstrated that the substituent on the benzylidene ring can influence the sensitivity of the azomethine carbon to the aniline

* Corresponding author. E-mail address: [email protected] (H. Yuan). https://doi.org/10.1016/j.molstruc.2017.10.111 0022-2860/© 2017 Elsevier B.V. All rights reserved.

substituent. Neuvonen [3] also found that the neighboring aniline substituent Y can modify the sensitivity of the electronic character of C]N group to the benzylidene substituent X. The crossinteraction effect between substituents X and Y has been demonstrated and investigated systematically. Guo [9e12] developed the parameter sXY (sXY ¼ sXsY) to describe the cross-interaction effect of substituents X and Y in the investigation of the bond dissociation. Cao [5] proposed another parameter Ds2 ¼ (sX - sY)2 to scale the substituent specific cross-interaction effect in the correlation of 13C NMR chemical shifts of the C]N bridging group in the substituted benzylidene anilines. In the investigation of the substituent effects of X and Y on the dC of 4, 40 -disubstituted cinnamyl anilines (pXeC6H4eCH]CHeCH]NeC6H4eY-p), Chen [13] modified the substituent cross-interaction item (Ds2 ) by the bond number (m). All the above studies focused on the substituent effects on the electronic character of the polar C]N bond in Schiff bases, which are very valuable for tailoring the specific properties of the mesogenic molecules or design of new materials for nonlinear optical purposes. The substituent cross-interaction effect has been observed in all the above investigations. However, the C]N groups in the above interested model compounds all situate in the open

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chain of the molecule. If the polar C]N group locates in a ring, what is the substituent effect on the electronic feature of the C]N bond? Does the substituent cross-interaction effect still influence the properties of compounds? Pyrimidine, a symmetrical molecule with C]N bond in the ring, is taken as the ideal parent structure for this purpose. There are two reasons for this selection. One is that pyrimidines are a class of important organic compounds with various biological activities [14e16]. Not only they serve as the nucleic acid core performing vital physiological functions, but also they exhibit a broad range of biological activities including antitumor, antihypertensive, antiinflammatory, antibacterial and insecticidal activities. The study on the substituent effect will contribute to the design of biologically active molecules with pyrimidine unit. The other reason is that pyrimidine is a symmetrical six-membered heterocyclic compound containing C]N bond, where the line through carbons 2 and 5 (expressed by C2 and C5) serves as the symmetry axis of the molecule (Fig. 1a). By reference to the symmetry axis, N1 and N3 are equivalent to each other, and the same to C4 and C6. The two nitrogen atoms on the pyrimidine ring result in a high electronegativity and electron-scare ring. The dipole moment of pyrimidine is 2.3D [17,18], while C2 and C5 lie at each ends of the dipole. We abstract the structure of 2, 5-disubstituted pyrimidine to X/C ¼ N/Y (where / represents some conjugated groups), which is similar to the substituted benzylidene anilines (p-Xe C6H4eCH]NeC6H4eY-p) in structure. How do the substituents X and Y on the two ends of the dipole ring (i.e., C2 and C5) affect the electron distribution and the properties of 2-X-5-Y pyrimidine (Fig. 1b)? Several reports [19,20] have investigated the substituent effects on the electron distribution and properties of the substituted pyrimidines. For example, Bolognesi [19] investigated the inner shell ionization of pyrimidine and some halogenated pyrimidines by Xray photoemission spectroscopy (XPS). It was indicated that the C(1s) binding energy is influenced by the nature of the substituent and the substituted site. All the C(1s) binding energies shift toward higher values due to halogenation, but the range of the shift varies for different halogenated pyrimidines. Taking 2-Br pyrimidine and 5-Br pyrimidine for comparison, the increment of C(1s) binding energy of C2 in 2-Br pyrimidine is larger than that in 5-Br pyrimidine, but the increment of C(1s) binding energy of C5 in the former is smaller than that in the latter. By comparison of 2-Cl pyrimidine with 2-Br pyrimidine, the C(1s) binding energy of C2 in 2-Cl pyrimidine is larger than that of 2-Br pyrimidine, due to the higher electronegativity of Cl than that of Br. In addition, Gompper [20] found that the donor-acceptor substituted 2,5-diarylpyrimidines have interesting nonlinear optical properties. The relative positions of nitrogen atoms as to the acceptor and donor substituents influence the dipole moments of the molecules. Therefore, the fluorescence of these compounds can be tuned over a wide spectral range by varying the number and position of N atoms. The above reports observed the influence of the substituents on the electron distribution and the properties of 2, 5-disubstituted pyrimidines, but the quantitative structure-property relationship has not been systematically investigated. Nuclear magnetic

resonance (NMR) spectrum is a special fingerprint characterizing the molecular structure. The chemical shifts of each atom provide a local probe of the chemical environment of atoms. In this paper, we try to investigate the effect of substituents X and Y on the NMR chemical shifts of 2-X-5-Y pyrimidines. 2. Experimental sections Thirty-one 2,5-disubstituted pyrimidines (X-Pym-Y, Pym denoting 2,5-pyrimidinylene) were synthesized according to the methods reported by literature [21e24]. The substituents X and Y on the pyrimidine ring include NMe2, OCH3, CH3, H, Cl, Br, I, CN and NO2. The structures of all compounds were characterized by 1H NMR and 13C NMR spectra, which were recorded in CDCl3 at 293 K. The measurements were performed with a low and constant sample concentration in order to diminish the molecular interactions. The 1H NMR chemical shifts were expressed in ppm relative to TMS (0.00 ppm) at 500 MHz, and the 13C NMR chemical shifts were expressed in ppm relative to CDCl3 (77.00 ppm) at 126 MHz. All the 1H NMR and 13C NMR information for the characterization of compounds were shown in Table 1. The chemical shifts of C2, C4 (same to C6) and C5 on the pyrimidine were represented as d(C2), d(C4,6) and d(C5), respectively. The chemical shifts of the hydrogens on C4 and C6 were represented as d(H4,6). All the experimental values d(C2)exp, d(C4,6)exp, d(C5)exp and d(H4,6)exp were shown in Table 2. The ranges of d(C2), d(C4,6) and d(C5) are 125.87e167.37 ppm, 145.39e164.81 ppm and 74.58e152.67 ppm, respectively. The d(H4,6) ranges from 8.12 to 9.38 ppm. 3. Results and discussion In order to systematically investigate the substituent effects on the NMR chemical shifts of 2, 5-disubstituted pyrimidines, we try to build quantitative structure-property relationship models for d(H4,6), d(C2), d(C4,6) and d(C5), respectively. Since the chemical environments of H4,6, C2, C4,6 and C5 are different from each other, the models for d(H4,6), d(C2), d(C4,6) and d(C5) will also be distinctive. The establishment and discussion of models for the chemical shift of each atom will be presented separately. 3.1. Effect of substituents X and Y on d(H4,6) As known from Refs. [3e8], the chemical shifts are closely related to Hammett parameter s [25] and the substituent crossinteraction parameter (Ds2). Hammett parameters of substituents X and Y are expressed by s(X) and s(Y), respectively. Because substituents X and Y are in the para-situation relative to each other in the 2,5-disubstituted pyrimidine, Hammett parameter sp for the para-substituent is employed for s(X) and s(Y). According to Ref. [5], the substituent cross-interaction parameter Ds2 is calculated by Eq. (1).

Ds2 ¼ [s(X)s(Y)]2

(1)

We regressed d(H4,6) against s(X), s(Y) and Ds2. The obtained model was shown in Eq. (2).

d(H4,6) ¼ 8.4252 þ 0.4129s(X) þ 0.8261s(Y) þ 0.1295Ds2

(2)

R ¼ 0.9160 s ¼ 0.129 F ¼ 45.19 n ¼ 30 Fig. 1. (a) The structure of pyrimidine, (b) The structure of 2-X-5-Y pyrimidine.

The low correlation coefficient (R) and large standard deviation

H. Yuan et al. / Journal of Molecular Structure 1155 (2018) 143e151

145

Table 1 The 1H NMR and13C NMR information of thirty-one 2, 5-disubstituted pyrimidines. no.

Molecular structure

1

1

13

d: 3.90 (s, 3H), 6.84 (t, J ¼ 9.5 Hz, 1H), 8.42 (d, J ¼ 5.0 Hz, 2H)

d: 54.53, 114.68, 159.00, 165.33

d: 3.98 (s, 3H), 8.43 (s, 2H)

d: 55.37, 123.95, 157.36, 163.84

d:3.99 (s, 3H), 8.52 (s, 2H)

d: 55.37, 111.77, 159.53, 164.16

d: 3.98 (s, 3H), 8.63 (s, 2H)

d: 55.26, 82.40, 164.27, 164.49

d: 2.19 (s, 3H), 3.94 (s, 3H), 8.29 (s, 2H)

d: 14.47, 54.61, 123.52, 159.03, 164.14

d: 4.15 (s, 3H), 9.30 (s, 2H)

d: 56.67, 138.21, 155.93, 167.37

d: 3.84 (s, 3H), 3.94 (s, 3H), 8.18 (s, 2H)

d: 54.94, 56.52, 145.39, 149.37, 160.40

d: 7.28 (t, J ¼ 9.6 Hz, 1H), 8.63 (d, J ¼ 4.8 Hz, 2H)

d: 119.72, 159.56, 161.63

d: 8.59 (s, 2H)

d: 130.36, 157.86, 159.02

d: 8.68 (s, 2H)

d: 118.82, 159.69, 160.06

d: 8.80 (s, 2H)

d: 90.67, 160.43, 164.81

d: 9.38 (s, 2H)

d: 141.30, 154.93, 165.66

d: 2.31 (s, 3H), 8.45 (s, 2H)

d: 14.84, 129.42, 158.80, 159.58

d: 3.91 (s, 3H), 8.28 (s, 2H)

d: 56.33, 145.69, 152.33, 152.67

d: 7.32 (t, J ¼ 9.3 Hz, 1H), 8.57 (d, J ¼ 4.5 Hz, 2H)

d: 120.13, 153.30, 159.36

d: 8.54 (s, 2H)

d: 131.12, 150.07, 157.72

d: 8.62 (s, 2H)

d: 119.71, 150.79, 159.91

d: 8.74 (s, 2H)

d: 91.68, 151.73, 164.61

d: 7.32 (t, J ¼ 9.3 Hz, 1H), 8.46 (d, J ¼ 4.5 Hz, 2H)

d: 120.53, 129.51, 158.48

H NMR (500 MHz, CDCl3)

C NMR (125 MHz, CDCl3)

C5H6N2O 2

C5H6ClN2O 3

C5H5BrN2O 4

C5H5IN2O 5

C6H8N2O 6

C5H5N3O3 7

C6H8N2O2 8

C4H3ClN2 9

C4H2Cl2N2 10

C4H2BrClN2 11

C4H2ClIN2 12

C4H2ClN3O2 13

C5H5ClN2 14

C5H5ClN2O 15

C4H3BrN2 16

C4H2BrClN2 17

C4H2Br2N2 18

C4H2BrIN2 19

C4H3IN2 (continued on next page)

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H. Yuan et al. / Journal of Molecular Structure 1155 (2018) 143e151

Table 1 (continued ) no.

Molecular structure

20

1

13

H NMR (500 MHz, CDCl3)

C NMR (125 MHz, CDCl3)

d: 8.44 (s, 2H)

d: 125.08, 132.16, 157.06

d: 8.53 (s, 2H)

d: 120.99, 125.87, 159.19

d: 2.26 (s, 3H), 8.29 (s, 2H)

d: 15.07, 125.64, 130.36, 158.91

d: 8.29 (s, 2H)

d: 93.20, 126.85, 163.82

d: 3.14 (s, 6H), 6.40 (t, J ¼ 9.0 Hz, 1H), 8.27 (d, J ¼ 5.0 Hz, 2H)

d: 36.97, 108.77, 157.47, 162.09

d: 3.14 (s, 6H), 8.20 (s, 2H)

d: 37.29, 117.42, 155.61, 160.36

d: 3.13 (s, 6H), 8.25 (s, 2H)

d: 37.25, 105.02, 157.62, 160.36

d: 3.14 (s, 6H), 8.37 (s, 2H)

d: 37.12, 74.58, 160.15, 162.16

d: 3.32 (s, 6H), 9.06 (s, 2H)

d: 37.80, 133.00, 154.61, 162.23

d: 2.08 (s, 3H), 3.13 (s, 6H), 8.12 (s, 2H)

d: 14.46, 37.16, 116.93, 157.57, 161.04

d: 7.57 (t, J ¼ 9.6 Hz, 1H), 8.87 (d, J ¼ 4.9 Hz, 2H)

d: 115.52, 123.63, 145.13, 158.03

d: 8.80 (s, 2H), 9.11 (s, 1H)

d: 120.78, 156.51, 157.68

C4H2ClIN2 21

C4H2BrIN2 22

C4H2BrIN2 23

C4H2I2N2 24

C6H9N3 25

C6H8ClN3 26

C6H8BrN3 27

C6H8IN3 28

C6H8N4O2 29

C7H11N3 30

C5H3N3 31

C4H3BrN2

(s) of Eq. (2) indicate that the chemical shift of H4,6 cannot be accurately modeled by s(X), s(Y) and Ds2. As we know, Hammett parameter s consists of the inductive effect (sF) and the resonance effect (sR), i.e., s ¼ sF þ sR, we try to replace s with sF and sR for the modeling of d(H4,6) as shown in Eq. (3).

d(H4,6) ¼ 9.9667e2.5872sF(X) þ 1.4165sR(X) þ 0.7812sF(Y) þ 1.1010sR(Y) þ 0.0713Ds2

(3)

R ¼ 0.9396 s ¼ 0.114 F ¼ 36.18 n ¼ 30 Compared Eq. (3) to Eq. (2), although the performance of the model is slightly improved, Hammett parameter and substituent cross-interaction parameter are not enough to characterize the influences of substituents on d(H4,6). Different from the 13C NMR chemical shifts dC(C]N) of C]N bridging group in the substituted benzylidene anilines, there may be some other structural factors closely related to the chemical shifts of hydrogens and carbons in the substituted pyrimidines. We think over the additional influencing factors from three

perspectives: 1) The electronegativity effect of substituents or the electric charge of the interested atom. As we know, the chemical shift of an atom depends on the electron density around it, which is affected by the electronegativity of the substituents directly or indirectly attached to the atom. In this paper, Pauling electronegativity (c) [26,27] of the atom in the substituent directly connected to C2 or C5 of the pyrimidine ring is used to characterize the substituents X and Y. The electric charge (Q) of the atom can be computed with two steps. Firstly, the molecular electronegativity (cM) was calculated according to the principle of electronegativity equalization [28], as shown in Eq. (4).

cM ¼

n   P ni

(4)

c0i

n in Eq. (4) is the sum of atoms in the molecule, ni is the number of P atom i, where n ¼ ni . c0i is the Pauling electronegativity of atom i. Then, based on cM, the electric charge (Qi) of atom i is calculated by Eq. (5).

H. Yuan et al. / Journal of Molecular Structure 1155 (2018) 143e151 Table 2 The values of d(H4,6)exp, d(C2)exp, d(C5)exp and d(C4,6)exp of 2,5-disubstituted pyrimidines.

147

Table 3 The polarizabilities(a), electronegativities(c) and indicator variables(D) of Cl, Br and I.

no.

X

Y

d(H4,6)exp

d(C2)exp

d(C5)exp

d(C4,6)exp

Atom

aa

c

D

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

OMe OMe OMe OMe OMe OMe OMe Cl Cl Cl Cl Cl Cl Cl Br Br Br Br I I I I I NMe2 NMe2 NMe2 NMe2 NMe2 NMe2 CN H

H Cl Br I Me NO2 OMe H Cl Br I NO2 Me OMe H Cl Br I H Cl Br Me I H Cl Br I NO2 Me H Br

8.42 8.43 8.52 8.63 8.29 9.30 8.18 8.61 8.59 8.68 8.80 9.38 8.45 8.28 8.57 8.54 8.62 8.74 8.46 8.44 8.53 8.29 8.63 8.26 8.20 8.25 8.37 9.06 8.12 8.87 8.80

165.33 163.84 164.16 164.49 164.14 167.37 160.40 161.63 159.02 159.69 160.43 165.66 158.80 152.33 153.30 150.07 150.79 151.73 129.51 132.16 125.87 130.36 126.85 162.09 160.36 160.36 160.15 162.23 161.04 145.13 156.51

114.68 123.95 111.77 82.40 123.52 138.21 149.37 119.72 130.36 118.82 90.67 141.30 129.42 152.67 120.13 131.12 119.71 91.68 120.53 125.08 120.99 125.64 93.20 108.77 117.42 105.02 74.58 133.00 116.93 123.63 120.78

159.00 157.36 159.53 164.27 159.03 155.93 145.39 159.56 157.86 160.06 164.81 154.93 159.58 145.69 159.36 157.72 159.91 164.61 158.48 157.06 159.19 158.91 163.82 157.47 155.61 157.62 162.16 154.61 157.57 158.03 157.68

Cl Br I

2.18 3.05 4.70

3.16 2.96 2.66

0.48 1.06 3.12

Qi ¼

cM  c0i c ¼ M 1 c0i c0i

a

calculated. All the values of these descriptors were listed in Tables 4 and 5. The d(H4,6) was correlated to the above descriptors by stepwise regression. Finally, a six-descriptor regression model was built as Eq. (7). To test the stability and predictability of Eq. (7), leave-one-out cross validation was conducted and the results were also listed below.



(7)

R ¼ 0.9966 R2 ¼ 0.9933 S ¼ 0.028 ARD ¼ 0.23% F ¼ 589.00 n ¼ 31 Rcv ¼ 0.9934 R2cv ¼ 0.9868 Scv ¼ 0.039 ARDcv ¼ 0.32% Known from Eq. (7), d(H4,6) is accurately modeled with high correlation coefficient, low standard deviation and average relative deviation (ARD). The cross validation results (Rcv, Scv and ARDcv) indicate that Eq. (7) is of good stability and predictability. In the investigation of the influence of substituents on the NMR chemical shifts dC(C]N) of disubstituted benzylidene anilines (p-X-

(5)

 2

a c



d H4;6 ¼ 8:6592  0:0518 DðXÞ þ 0:4897sR ðXÞ þ 0:5302sF ðYÞ þ 0:8377sR ðYÞ  0:4462sex CC ðYÞ þ 0:5394Q ðYÞ

2) The excited-state substituent constant sex CC . The excited-state substituent constant sex [29] is a molecular descriptor CC describing the stability of the excited state, which has been widely applied to the quantitative structure-property relationship study of the ultraviolet maximum absorption [30,31], the reduction potentials [32,33] and the NMR chemical shifts [34]. Therefore, we also employed the excited-state substituent constants sex cc to correlate the NMR chemical shift in this paper. 3) The heavy atom effect of halogens. The heavy atom effect of halogen atoms (Cl, Br, I) on the NMR chemical shifts has been known for a long time [35,36]. In order to characterize such effect, we define an indicator variable (D) for substituents Cl, Br and I as Eq. (6).

D¼

Taken from Ref. [38].

(6)

In Eq. (6), a is the atomic polarizability [37,38], and c is the electronegativity of halogen atom. According to Eq. (6), the indicator variables (D) for Cl, Br and I are calculated, as listed in Table 3. The values of D for substituents other than Cl, Br and I in this paper equal zero. D(X) and D(Y) are employed to represent the indicator variables of substituents X and Y, respectively. Based on the above analysis, a series of molecular structural descriptors such as sF(X), sR(X), sF(Y), sR(Y), Ds2, c(X), c(Y), Q(X), ex Q(Y), sex CC ðXÞ sCC ðYÞ, D(X) and D(Y) have been considered and

Table 4 The structural descriptors sF, sR, Ds2 and c of 2-X-5-Y pyrimidines. no.

X

Y

sF(X) a sF(Y) a sR(X) a sR(Y) a Ds2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

OMe OMe OMe OMe OMe OMe OMe Cl Cl Cl Cl Cl Cl Cl Br Br Br Br I I I I I NMe2 NMe2 NMe2 NMe2 NMe2 NMe2 CN H

H Cl Br I Me NO2 OMe H Cl Br I NO2 Me OMe H Cl Br I H Cl Br Me I H Cl Br I NO2 Me H Br

0.29 0.29 0.29 0.29 0.29 0.29 0.29 0.42 0.42 0.42 0.42 0.42 0.42 0.42 0.45 0.45 0.45 0.45 0.42 0.42 0.42 0.42 0.42 0.15 0.15 0.15 0.15 0.15 0.15 0.51 0

a b

Taken from Ref. [25]. Taken from Ref. [26].

0 0.42 0.45 0.42 0.01 0.65 0.29 0 0.42 0.45 0.42 0.65 0.01 0.29 0 0.42 0.45 0.42 0 0.42 0.45 0.01 0.42 0 0.42 0.45 0.42 0.65 0.01 0 0.45

0.56 0.56 0.56 0.56 0.56 0.56 0.56 0.19 0.19 0.19 0.19 0.19 0.19 0.19 0.22 0.22 0.22 0.22 0.24 0.24 0.24 0.24 0.24 0.98 0.98 0.98 0.98 0.98 0.98 0.15 0

0 0.19 0.22 0.24 0.18 0.13 0.56 0 0.19 0.22 0.24 0.13 0.18 0.56 0 0.19 0.22 0.24 0 0.19 0.22 0.18 0.24 0 0.19 0.22 0.24 0.13 0.18 0 0.22

0.0729 0.2500 0.2500 0.2025 0.0100 1.1025 0 0.0529 0 0 0.0025 0.3025 0.1600 0.2500 0.0529 0 0 0.0025 0.0324 0.0025 0.0025 0.1225 0 0.6889 1.1236 1.1236 1.0201 2.5921 0.4356 0.4356 0.0529

c(X) b c(Y) b 3.44 3.44 3.44 3.44 3.44 3.44 3.44 3.16 3.16 3.16 3.16 3.16 3.16 3.16 2.96 2.96 2.96 2.96 2.66 2.66 2.66 2.66 2.66 3.04 3.04 3.04 3.04 3.04 3.04 2.55 2.20

2.20 3.16 2.96 2.66 2.55 3.04 3.44 2.20 3.16 2.96 2.66 3.04 2.55 3.44 2.20 3.16 2.96 2.66 2.20 3.16 2.96 2.55 2.66 2.20 3.16 2.96 2.66 3.04 2.55 2.20 2.96

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H. Yuan et al. / Journal of Molecular Structure 1155 (2018) 143e151

Table 5 The structural descriptors Q, sex cc and D of 2-X-5-Y pyrimidines. a

no.

X

Y

Q(X)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

OMe OMe OMe OMe OMe OMe OMe Cl Cl Cl Cl Cl Cl Cl Br Br Br Br I I I I I NMe2 NMe2 NMe2 NMe2 NMe2 NMe2 CN H

H Cl Br I Me NO2 OMe H Cl Br I NO2 Me OMe H Cl Br I H Cl Br Me I H Cl Br I NO2 Me H Br

0.28 0.28 0.28 0.28 0.28 0.28 0.28 0.19 0.19 0.19 0.19 0.19 0.19 0.19 0.14 0.14 0.14 0.14 0.05 0.05 0.05 0.05 0.05 0.20 0.20 0.20 0.20 0.20 0.20 0 0.16

a b c

Q(Y)

a

0.13 0.21 0.16 0.07 0.03 0.18 0.28 0.16 0.19 0.14 0.04 0.16 0 0.26 0.16 0.19 0.14 0.04 0.15 0.20 0.15 0.01 0.05 0.10 0.23 0.18 0.09 0.20 0.05 0.16 0.14

b sex CC ðXÞ

b sex CC ðYÞ

D(X)

0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.22 0.22 0.22 0.22 0.22 0.22 0.22 0.33 0.33 0.33 0.33 0.56 0.56 0.56 0.56 0.56 1.81 1.81 1.81 1.81 1.81 1.81 0.7 0

0 0.22 0.33 0.56 0.17 1.17 0.5 0 0.22 0.33 0.56 1.17 0.17 0.5 0 0.22 0.33 0.56 0 0.22 0.33 0.17 0.56 0 0.22 0.33 0.56 1.17 0.17 0 0.33

0 0 0 0 0 0 0 0.48 0.48 0.48 0.48 0.48 0.48 0.48 1.06 1.06 1.06 1.06 3.12 3.12 3.12 3.12 3.12 0 0 0 0 0 0 0 0

c

D(Y)

c

0 0.48 1.06 3.12 0 0 0 0 0.48 1.06 3.12 0 0 0 0 0.48 1.06 3.12 0 0.48 1.06 0 3.12 0 0.48 1.06 3.12 0 0 0 1.06

Calculated by Eqs. (4) and (5). Taken from Ref. [29]. Calculated by Eq. (6).

C6H4eCH]NeC6H4eY-p), Cao found that the cross-interaction parameter Ds2 is very important to the model. However, in this paper we found that Ds2 has little contribution to the model and could be ignored. In Eq. (7), four of the six descriptors characterize substituent Y, and the other two descriptors describe substituent X, which indicates that d(H4,6) is mainly influenced by the substituent Y close to H4,6. Known from the regression coefficients before each descriptors, the electron-withdrawing resonance effect of both substituents X and Y increase d(H4,6), and the same to the electronwithdrawing inductive effect of substituent Y. The more positive charge on substituent Y enhances its electron-withdrawing ability and decreases the electron density around H4,6, which results in the larger chemical shifts. The indicator variable D(X) for the heavy atom effect of substituent X has contribution to d(H4,6), but D(Y) can be ignored. In addition, the excited-state substituent constant sex CC ðYÞ of substituent Y also has effect on d(H4,6). The calculated chemical shifts of H4,6 by Eq. (7) and cross validation were represented as d(H4,6)cal and d(H4,6)cv, respectively. All the experimental and calculated values of d(H4,6) were listed in Table S1 in the Supporting Information. In order to exhibit the relationship between d(H4,6)exp and d(H4,6)cal intuitively, the plot of d(H4,6)cal versus d(H4,6)exp was shown in Fig. 2, which indicated that d(H4,6)cal was very close to d(H4,6)exp. To evaluate the importance of each structural factor to d(H4,6), the relative contribution (Jr) and fraction contribution (Jf) were calculated as Eqs. (8) and (9) [39,40], respectively.

Jr ðiÞ ¼ mi Xi

(8)

Fig. 2. Plot of the calculated d(H4,6) vs. the experimental ones of 2,5-disubstituted pyrimidines.

R2 jJr ðiÞj  100% jJr ðiÞj

Jf ðiÞ ¼ P

(9)

i

In Eqs. (8) and (9), mi and Xi are the regression coefficient and the average value of each descriptor in the quantitative structureproperty relationship model. R is the correlation coefficient. The relative contribution (Jr) and fraction contribution (Jf) of each descriptors in Eq. (7) were shown in Table 6. Known from Table 6, the resonance effect of substituent X is the most important structural factor for d(H4,6). The resonance effect of substituent Y also has large effect on d(H4,6), but its contribution is smaller than that of substituent X. In addition, both the inductive effect and the excited-state substituent constant of substituent Y have notable influences on d(H4,6). Compared to the above structural factors, the electric charge and the heavy atom effect indicator variable of substituent Y has less contribution to d(H4,6), but they cannot be neglected.

3.2. Effect of substituents X and Y on d(C2) By reference to Section 3.1, we also investigated the substituent effects on the chemical shift d(C2) of C2 on the pyrimidine ring, but the performance of the model was not satisfactory. Analyzing the interested 31 compounds carefully, only 5-bromopyrimidine has no substituent (i.e., X ¼ H) on C2. The d(C2) of 5-bromopyrimidine is just influenced by substituent Y, which is different from the other compounds. We attempted to build quantitative structure-property relationship model for 30 compounds with the deletion of 5bromopyrimidine, and the performance of the model was greatly improved. The obtained regression model with six descriptors was shown in Eq. (10).

Table 6 The relative and fraction contributions of each descriptor in Eq. (7). descriptor

sF(Y)

sR(X)

sR(Y)

sex CC ðYÞ

Q(Y)

D(X)

Jr(i) Jf(i)(%)

0.1644 21.86

0.2057 27.36

0.1340 17.83

0.1606 21.37

0.0432 5.74

0.0389 5.17

H. Yuan et al. / Journal of Molecular Structure 1155 (2018) 143e151

dðC2 Þ ¼ 1646:50 þ 980:3973sF ðXÞ þ 122:6500sR ðXÞ  270:8270sex CC ðXÞ þ 424:9631cðXÞ þ 36:2360 DðXÞ þ 12:0320sR ðYÞ (10)

R ¼ 0.9945 R2 ¼ 0.9891 S ¼ 1.49 ARD ¼ 0.67% F ¼ 346.78 n ¼ 30 Rcv ¼ 0.9509 R2cv ¼ 0.9042 Scv ¼ 4.51 ARDcv ¼ 1.31% Eq. (10) indicated that d(C2) is mainly affected by the nearer substituent X, where five of the six descriptors characterize substituent X. The electron-withdrawing inductive effect of substituent X and the electron-withdrawing resonance effects of both substituents X and Y make d(C2) migrate to the low field, but the contributions of X and Y are not equivalent. The positive coefficient before c(X) can be understood that the substituent with large electronegativity will reduce the electron density of C2, and then the chemical shift of C2 will be increased. In addition, both the heavy atom effect indicator variable D(X) and the excited-state substituent constant sex CC ðXÞ of substituent X have contribution to d(H4,6). The experimental and calculated d(C2) were all listed in Table S2. The d(C2)cal was plotted against d(C2)exp, as shown in Fig. 3. The relative and fraction contributions (Jr, Jf) of each descriptors in Eq. (10) were calculated and listed in Table 7. Table 7 indicates that the electronegativity of substituent X has the largest effect on d(C2). The inductive effect and the excited-state substituent constant of substituent X also have notable influences on d(C2). By comparison, sR(X), D(X) and sR(Y) contribute less to d(C2). However, these three descriptors cannot be ignored, otherwise the standard deviation of the model will increase a lot.

3.3. Effect of substituents X and Y on d(C5) C5 situates on the other end of the dipolar pyrimidine ring relative to C2. The chemical shift d(C5) of C5 on the pyrimidine ring was also correlated to the above mentioned descriptors by stepwise regression and obtained Eq. (11).

149

Table 7 The relative and fraction contributions of each descriptor in Eq. (10). descriptor

sF(X)

sR(X)

sR(Y)

sex CC ðXÞ

c(X)

D(X)

Jr(i) Jf(i)(%)

333.3351 17.27

53.9660 2.80

1.9251 0.10

186.8704 9.68

1304.6366 67.71

27.9017 1.45

dðC5 Þ ¼ 103:6325 þ 15:7683sR ðXÞ  24:7290sR ðYÞ þ 8:5833cðYÞ  17:1225sex cc ðYÞ  15:7246DðYÞ

(11)

R ¼ 0.9936 R2 ¼ 0.9872 S ¼ 2.21 ARD ¼ 1.50% F ¼ 387.10 n ¼ 31 Rcv ¼ 0.9896 R2cv ¼ 0.9794 Scv ¼ 2.81 ARDcv ¼ 1.89% The leave-one-out cross validation results show that Eq. (11) has good stability and predictive performance. Similar to d(H4, 6) and d(C2), d(C5) is mainly affected by the nearer substituent. The signs of the regression coefficients before sR(X) and sR(Y) are contrary, which indicates that the effects of substituents X and Y to d(C5) are opposite. The electron-withdrawing resonance effect of substituent X results in the larger d(C5), but the electron-withdrawing resonance effect of substituent Y decreases the d(C5). The positive coefficient before c(Y) can be illustrated that the large electronegativity of the atom bonded to C5 will decrease the electron cloud density around C5 and then increase the d(C5). The negative coefficient before D(Y) can be understood that the heavy atom effect of substituent Y will migrate the chemical shift of C5 to the high field, which is consistent with the physical meaning of the heavy atom effect. The experimental and calculated chemical shifts of C5 in 2,5disubstituted pyrimidines were listed in Table S3. The plot of d(C5)cal versus d(C5)exp was shown in Fig. 4. The contributions of each descriptors in Eq. (11) were calculated and listed in Table 8. As indicated in Table 8, the electronegativity c(Y) is the most important structural factor influencing d(C5). The heavy atom effect indicator variable D(Y) takes the second place. The resonance effects of both substituents X and Y also contribute to d(C5), but the contribution of sR(X) is larger than that of sR(Y). In addition, the excited-state substituent constant sex CC ðYÞ of substituent Y also is responsible for the modeling of d(C5). 3.4. Effect of substituents X and Y on d(C4,6) Based on the above descriptors characterizing substituents X and Y, a four-parameter regression model was built as Eq. (12).





d C4;6 ¼ 160:7287þ17:2435 sR ðYÞþ3:7018DðYÞþ0:9136sex CC ðXÞ ðYÞ þ5:9824sex CC (12)

R ¼ 0.9372 R2 ¼ 0.8782 S ¼ 1.60 ARD ¼ 0.73% F ¼ 46.93 n ¼ 31 Rcv ¼ 0.9058 R2cv ¼ 0.8204 Scv ¼ 1.94 ARDcv ¼ 0.89%

Fig. 3. Plot of the calculated d(C2) vs. the experimental ones of 2,5-disubstituted pyrimidines.

Eq. (12) only employed four descriptors and the standard deviation was within the experimental uncertainty. The cross validation result shows good stability of the model. Because C4 and C6 are nearer to the substituent Y than to the substituent X, d(C4,6) is mainly affected by substituent Y. The resonance effect sR(Y), heavy atom effect indicator variable D(Y) and the excited-state substituent constant sex CC ðYÞ of substituent Y are responsible for the d(C4,6).

150

H. Yuan et al. / Journal of Molecular Structure 1155 (2018) 143e151 Table 9 The relative and fraction contributions of each descriptor in Eq. (12). descriptor

sR(Y)

sex CC ðXÞ

sex CC ðYÞ

D(Y)

Jr(i) Jf(i)(%)

2.7590 28.68

0.6121 6.36

2.1537 22.39

2.9244 30.40

4. Conclusion Based on the investigation of the quantitative structureproperty relationship of the 1H NMR and 13C NMR chemical shifts of 2-X-5-Y pyrimidines, this paper studied the substituent effects of X and Y at two ends of the dipole on the NMR chemical shifts of the carbon and hydrogen atoms on the pyrimidine ring. Several conclusions have been obtained as follows.

Fig. 4. Plot of the calculated d(C5) vs. the experimental ones of 2,5-disubstituted pyrimidines.

Table 8 The relative and fraction contributions of each descriptor in Eq. (11). descriptor

sR(X)

sR(Y)

sex CC ðYÞ

c(Y)

D(Y)

Jr(i) Jf(i)(%)

6.6227 12.33

3.9566 7.37

6.1641 11.48

23.8617 44.42

12.4224 23.13

While for substituent X, only the excited-state substituent constant sex CC ðXÞ is taken into consideration. The experimental and calculated chemical shifts of C4,6 in 2,5disubstituted pyrimidines were listed in Table S4. The d(C5)cal was plotted against d(C5)exp as shown in Fig. 5. ex The contributions of sR(Y), sex CC ðXÞ, sCC ðYÞ and D(Y) to d(C4,6) were all listed in Table 9. Known from Table 9, the heavy atom effect indicator variable D(Y) and the resonance effect sR(Y) of substituent Y exert the most important effect on d(C4,6). Both the excitedstate substituent effects of substituents X and Y influence the d(C4,6) in the same direction, but the influence of sex CC ðYÞ is much larger than that of sex ðXÞ. CC

(1) Compared to the substituted benzylidene anilines, the substituent effects of the 2,5-disubstituted pyrimidine derivatives are much complex. Hammett parameter is not enough for the characterization of the influence of substituents X and Y on the 1 H NMR and 13C NMR chemical shifts of pyrimidines. More structural factors, such as the excited-state substituent effect parameter (sex CC ), the heavy atom effect (D) of halogens (Cl, Br, I), the electronegativity (c) and the electric charge (Q) of the atom connecting to the pyrimidine ring, should also be taken into consideration. It is confirmed that the performances of the model can be improved largely if the above molecular descriptors are considered. However, the cross interactions (Ds2) of substituents X and Y has little contribution to d(H4,6), d(C2), d(C5) and d(C4,6), which is different from what had been observed previously with the substituted benzylidene anilines. (2) For various carbon atoms on the pyrimidine ring, the influences of substituents X and Y on their 13C NMR chemical shifts are different. For example, d(C2) is mainly affected by sF(X), sR(X), sR(Y), c(X), sex CC ðXÞ and D(X), while d(C4,6) is closely ex related to sR(Y), sex CC ðXÞ, sCC ðYÞ and D(Y). However, not only d(H4,6) but also d(C2), d(C5) and d(C4,6) are influenced mostly by the nearer substituent. For instance, d(C2) is affected mainly by substituent X, while d(H4,6), d(C5) and d(C4,6) are influenced majorly by substituent Y. (3) In the investigation of the substituent effects on the NMR chemical shifts dC(C]N) of the disubstituted benzylidene anilines, Nevonen and Cao have found that substituents X and Y show the opposite effect. That is, for substituent X, the electrondonating group increases the dC(C]N), and the electronwithdrawing one decreases the dC(C]N). While for substituent Y, the observed rule is contrary to that of substituent X. However, for the 2-X-5-Y pyrimidines studied in this paper, except for the modeling of d(C5), no opposite electronic effects are observed for substituents X and Y. Therefore, we can conclude that the substituent effect does not follow a simple fixed mode, but it varies depending on the parent skeleton. Acknowledgements The work was supported by the National Natural Science Foundation of China (Nos. 21402047, 21672058), and aid program for Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province. Appendix A. Supplementary data

Fig. 5. Plot of the calculated d(C4,6) vs. the experimental ones of 2,5-disubstituted pyrimidines.

Supplementary data related to this article can be found at https://doi.org/10.1016/j.molstruc.2017.10.111.

H. Yuan et al. / Journal of Molecular Structure 1155 (2018) 143e151

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