Substituent effect study on the experimental 13C NMR chemical shifts of 3-(substituted phenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazoles

Article abstract of DOI:10.1016/j.molstruc.2019.04.121

Novel heterocyclic derivatives containing isoxazole ring were synthesized by the 1,3-dipolar cycloaddition reaction of substituted nitrile oxides with cis-4,7-dihydro-1,3-dioxepin in the present study. These 3-(substituted phenyl)-3a,4,8,8a-tetrahydro-1,3

Full text of DOI:10.1016/j.molstruc.2019.04.121

Accepted Manuscript
13
Substituent effect study on the experimental C NMR chemical shifts of 3-
(substituted phenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazoles
Yesim S. Kara, Sümeyye Yalduz
PII:
S0022-2860(19)30532-0
DOI:
https://doi.org/10.1016/j.molstruc.2019.04.121
MOLSTR 26493
Reference:
To appear in: Journal of Molecular Structure
Received Date: 21 February 2019
Revised Date: 15 April 2019
Accepted Date: 28 April 2019
13
Please cite this article as: Y.S. Kara, Sü. Yalduz, Substituent effect study on the experimental C NMR
chemical shifts of 3-(substituted phenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazoles,
Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2019.04.121.
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ACCEPTED MANUSCRIPT
Substituent effect study on the experimental 13C NMR chemical shifts of 3-
(substituted phenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2]
isoxazoles
Yesim S. Kara, Sümeyye Yalduz
Kocaeli University, Science and Art Faculty, Department of Chemistry, Umuttepe campus,
41380 Kocaeli, Turkey
Abstract
Novel heterocyclic derivatives containing isoxazole ring were synthesized by the 1,3-dipolar
cycloaddition reaction of substituted nitrile oxides with cis-4,7-dihydro-1,3-dioxepin in the
present study. These 3-(substituted phenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2]
1
isoxazole derivatives were characterized by their physical constants and IR, H NMR, 13C
NMR and HRMS data. 13C NMR spectra of studied molecules were measured in
Deuterochloroform (CDCl3). The correlation analysis for the substituent-induced
experimental 13C NMR chemical shifts (δ, ppm) (SSC) of C=N, C4, C5, C7, C9 and C10
carbons of these isoxazole derivatives have been correlated with various Hammett substituent
constants, and Swain-Lupton parameters using single (SSP) and multi-linear (DSP) regression
analysis. Negative ρ values were found for correlations of C=N, C4 and C5 carbons. The
other carbons were found to have positive ρ values for the electronic effect of substituent on
13C NMR chemical shifts.
Keyword: Isoxazole, Substituent effect, SSP analyses, DSP analyses, 13C NMR chemical
shifts.
1. Introduction
The substitution constants (σ), which continue to play an important role in the electron
affinity transfer studies of substituents in organic molecules, are the first quantitative
Corresponding author.
E-mail address: yesimkara@kocaeli.edu.tr
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measurements of the free energy of the electron distribution of substituents in the molecules
[1]. Since the substituent constant is related to the electron density of a substitution in the
studied region, the correlation with other properties that reflect the electron distribution of the
molecule is not surprising. Electron density around the nucleus of interest (1H, 11B, 13C, 15N,
17O, 19F, 31P, 33S) NMR is mostly affected by electron-donating and electron-withdrawing
ability of the substituent [2-8].
Many studies in the literature show how substitution constants correlate in a linear fashion
with reaction rates, equilibrium constants, corrosion inhibition efficiencies, entropy,
enthalpy, free energy, electrochemical and biochemical potential, UV absorption, infrared
spectral frequencies, and NMR chemical shifts of various conjugate compounds [9-15]. In our
previous work, 13C NMR chemical shift values were related to the transmission of substituent
effects both in the heterocyclic rings and on unsaturated side chains attached to substituted
organic molecules [16, 17].
Nitrile oxides, R-C≡N+-O-, are organic compounds which are well known as synthetic
intermediates, especially in the case of preparative heterocyclic compounds because of their
high reactivity with unsaturated C=C, C≡C, C=O, C=S, C=P, C≡P and C≡N bonds [18-21].
Generally, isoxazole skeletons are formed by the reaction of nitrile oxides with C-C
unsaturated bonds. Nitrile oxides can dimerize easily, to either 1,4,2,5-dioxadiazines or
furoxans in the absence of dipolarophiles [22]. Beginning with aldoximes, chlorination and
dehydrochlorination processes are carried out in a dry medium for preparation of nitrile oxide
[23]. Either N-Chlorosuccinimide or bubbling dry Cl2 gases into the oxime solution was used
as the usual chlorination method. With the addition of base, HCI is spontaneously eliminated
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from the molecule and simultaneously nitrile oxide forms. Then nitrile oxide is trapped by
using a dipolarophile.
Heterocyclic compounds which contain an isoxazole ring in their structure possess various
biological activities. These include anti-microbial [24], anti-inflammatory and analgesic [25],
anti-cancer [26], anti-ulcer [27], anti-viral [28], anti-oxidant [29], anti-fungal [30], anti-
malarial [31], anti-tubercular [32], anti-hyperglycemic [33], anti-bacterial [34], and cytotoxic
[35] effects. Consequently, it is interesting to investigate substituent effects on their
spectroscopic properties.
Therefore, the main purpose of this study was to obtain heterocyclic compounds containing an
isoxazole ring which may be biologically important. Our other goal was to investigate the
13
substitution effects on the C NMR spectroscopic properties of the carbon atoms of interest
(especially the CH2 carbon at ten sigma bond distance from the substituent) in these
synthesized compounds. We report the synthesis of eleven new 3-(substituted phenyl)-
3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole derivatives and subsequent
investigation of the transmission of substituent effects on the 13C NMR chemical shifts using
various Hammett substituent constants, and Swain-Lupton parameters and by applying single
substituent parameter (SSP) and dual substituent parameter (DSP) analyses.
2. Experimental procedure
All chemicals and analytical grade solvents were purchased from (Aldrich and Fluka)
chemical companies. The synthesis of 2(a-k) series was straightforward as illustrated in Fig.
13
1. C NMR substituent chemical shifts (SCS) of the investigated compounds were recorded
in Deuterochloroform (CDCl3) solutions employing Tetramethylsilane (TMS) as an internal
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standard. Melting points were determined on Stuart SMP30 apparatus and are uncorrected.
The FT-IR spectra of compound 2(a-k) were recorded on Bruker Alpha II spectrometer, in the
region of 4000-400 cm-1. 1H NMR and 13C NMR spectra were recorded on Bruker Avance III
(400 MHz) NMR spectrometer. The HRMS analyses were performed on Water SYNAPT G1
Mass Spectrometer.
3. Synthesis
1,3-Dipolar cycloaddition is the simplest mehod for preparation of dihydroisoxazole
derivatives [36-38]. The cycloaddition of nitrile oxides to cis-4,7-dihydro-1,3-dioxepin
proceed in CHCl3 to produce a single cycloadduct.
3.1. Synthetic procedures
3.1.1. 3-phenyl-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole (2a) (General
procedure)
N-hydroxy-benzenecarboximidoyl chloride (1.29 g, 8.3 mmol) (1a) without going forward
purification in chloroform (15mL) was added slowly into the mixture of triethylamine (0.5 g,
o
5 mmol) and cis-4,7-Dihydro-1,3-dioxepin (0.6 g, 6 mmol) in chloroform (15 mL) at 0 C
Then the mixture was warmed at room temperature. The reaction mixture was stirred for two
day at room temperature. The reaction mixture was then filtered through filter paper, and the
solution was evaporated at reduced pressure. After general work-up, the residue was purified
by column chromatography on silica gel using hexane-ethyl acetate (4:1) as eluent. The
product was crystallized in (ethyl acetate/petroleum ether, 1:3) to give (2a) 400 mg. Yield 30
%; mp 131-131.6 oC; IR (KBr), ν (cm-1): 3060 (C-H), 2967 (C-H), 2899 (C-H), 1601 (C=N);
1H NMR (400 MHz, CDCl3), δ (ppm) : 7.69-7.67 (m, aromatic, 2H), 7.44-7.43 (t, J=2.4,
J=3.2, aromatic, 3H), 4.94-4.90 (m, 7CH2, 10CH, 2H), 4.69-4.67 (d, J= 6.4, 7CH2, H), 4.42-
4.37 (dd, J= 3.6, J= 13.6, 9CH2, H), 4.17-4.12 (q, J= 7.2, J= 12.8, 5CH2, H), 4.05-4.00 (m,
4CH, 9CH, 2H), 3.97-3.93 (dd, J= 3.6, J= 12.6, 5CH2, H); 13C NMR (CDCl3), δ (ppm) :
157.42 (C=N), 130.19-126.95 (aromatic C), 98.43 (7CH2), 83.62 (10CH), 68.72 (9CH2),
66.45 (5CH2), 52.01 (4CH); HRMS m/z (ESI/TOF/MS, [M+H]+ )calcd for C12H14NO3:
220.0975, Found 220.0979.
3.1.2. 3-(4-methylphenyl)-3a,4,8,8a-tetrahydro-[1,3]dioxepino[5,6-d] [1,2] isoxazole (2b)
o
Yield 32 %; mp 161-162.6 C; IR (KBr), ν (cm-1): 2984 (C-H), 2958 (C-H), 2912 (C-H),
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1599 (C=N); H NMR (400 MHz, CDCl3), δ (ppm) : 7.58-7.56 (d, J=8, aromatic, 2H), 7.25-
7.23 (d, J=8, aromatic, 2H), 4.92-4.87 (m, 7CH2, 10CH, 2H), 4.70-4.68 (d, J= 6.0, 7CH2, H),
4.40-4.35 (dd, J= 4, J= 13.6, 9CH2, H), 4.14-4.09 (q, J= 6.8, J= 12.4, 5CH2, H), 4.03-3.97 (m,
4CH, 9CH, 2H), 3.96-3.92 (dd, J= 3.6, J= 12.2, 5CH2, H); 2.39 (s, CH3,3H); 13C NMR
(CDCl3), δ (ppm) : 157.36 (C=N), 140.43-125.90 (aromatic C), 98.37 (7CH2), 83.49 (10CH),
68.62 (9CH2), 66.43 (5CH2), 52.07 (4CH), 21.43 (CH3); HRMS m/z (ESI/TOF/MS, [M+H]+
)calcd for C13H16NO3: 234.1132, Found 234.1131.
3.1.3. 3-(4-ethylphenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole (2c) Yield
o
30 %; mp 114.6-115.2 C; IR (KBr), ν (cm-1): 2960 (C-H), 2911 (C-H), 2874 (C-H), 1599
(C=N); 1H NMR (400 MHz, CDCl3), δ (ppm) : 7.60-7.58 (d, J=8.0, aromatic, 2H), 7.27-7.25
(d, J=8.0, aromatic, 2H), 4.93-4.88 (m, 7CH2, 10CH, 2H), 4.70-4.68 (d, J= 6.0, 7CH2, H),
4.40-4.36 (dd, J= 3.6, J= 13.6, 9CH2, H), 4.15-4.10 (q, J= 6.8, J= 12.2, 5CH2, H), 4.03-3.98
(m, 4CH, 9CH2, 2H), 3.97-3.93 (dd, J= 3.6, J= 12, 5CH2, H), 2.72-2.66 (q, J= 7.6, J= 16.7,
CH2, 2H), 1.28-1.24 (t, J= 7.6, J= 8.4, CH3, 3H); 13C NMR (CDCl3), δ (ppm) : 157.38 (C=N),
146.69-126.11 (aromatic C), 98.37 (7CH2), 83.50 (10CH), 68.61 (9CH2), 66.46 (5CH2), 52.07
(4CH), 21.77 (CH2), 15.31 (CH3); HRMS m/z (ESI/TOF/MS, [M+H]+ )calcd for C14H18NO3:
248.1288, Found 248.1287.
3.1.4. 3-(4-fluorophenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole (2d)
o
Yield 30 %; mp 150-151.4 C; IR (KBr), ν (cm-1): 2956 (C-H), 2917 (C-H), 2870 (C-H),
1
1600 (C=N); H NMR (400 MHz, CDCl3), δ (ppm) : 7.68-7.64 (td, J=5.2, J=8.6, aromatic,
2H), 7.14-7.10 (t, J=8.8, J=9.4, aromatic, 2H), 4.94-4.89 (m, 7CH2, 10CH, 2H), 4.66-4.65 (d,
J= 6, 7CH2, H), 4.41-4.37(dd, J= 3.6, J= 13.8, 9CH2, H), 4.16-4.12 (q, J= 6.4, J= 12.4, 5CH2,
H), 4.01-3.96 (m, 4CH, 9CH, 2H), 3.94-3.90 (dd, J= 3.6, J= 12.6, 5CH2, H); 13C NMR
(CDCl3), δ (ppm) : 157.47 (C=N), 128.96-116.24 (aromatic C), 98.45 (7CH2), 83.66 (10CH),
68.85 (9CH2), 66.439 (5CH2), 52.08 (4CH); HRMS m/z (ESI/TOF/MS, [M+H]+ )calcd for
C12H13FNO3: 238.0881, Found 238.0883.
3.1.5. 3-(4-chlorophenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole (2e)
o
Yield 31 %; mp 165.5-165.8 C; IR (KBr), ν (cm-1): 2986 (C-H), 2963 (C-H), 2911 (C-H),
1
1595 (C=N); H NMR (400 MHz, CDCl3), δ (ppm) : 7.62-7.60 (d, J=8.0, aromatic, 2H),
7.42-7.40 (d, J=8.4, aromatic, 2H), 4.94-4.91 (m, 7CH2, 10CH, 2H), 4.66-4.64 (d, J= 6.0,
7CH2, H), 4.42-4.38 (dd, J= 2.8, J= 13.6, 9CH2, H), 4.16-4.11 (q, J= 6.8, J= 12.9, 5CH2, H),
4.01-3.98 (d, J= 12.4, 4CH, H), 4.00-3.95 (d, J= 16.8, 9CH2, H), 3.93-3.90 (d, J= 12.8, 5CH2,
13
H); C NMR (CDCl3), δ (ppm) : 156.48 (C=N), 136.16-127.32 (aromatic C), 98.46 (7CH2),
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83.81 (10CH), 68.86 (9CH2), 66.34 (5CH2), 51.89 (4CH); HRMS m/z (ESI/TOF/MS, [M+H]+
)calcd for C12H13ClNO3: 254.0586, Found 254.0583.
3.1.6. 3-(4-bromophenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole (2f)
o
Yield 29 %; mp 188.6-188.9 C; IR (KBr), ν (cm-1): 2986 (C-H), 2961 (C-H), 2910 (C-H),
1589 (C=N); 1H NMR (400 MHz, CDCl3), δ (ppm) : 7.58-7.56 (d, J=8.8, aromatic, 2H), 7.55-
7.53 (d, J=8.6, aromatic, 2H), 4.94-4.90 (m, 7CH2, 10CH, 2H), 4.66-4.64 (d, J= 6.4, 7CH2,
H), 4.42-4.38 (dd, J= 3.8, J= 13.8, 9CH2, H), 4.16-4.11 (q, J= 6.8, J= 12.8, 5CH2, H), 4.01-
3.95 (m, 4CH, 9CH, 2H), 3.93-3.89 (dd, J= 3.4, J= 12.6, 5CH2, H); 13C NMR (CDCl3), δ
(ppm) : 156.56 (C=N), 132.20-124.47 (aromatic C), 98.47 (7CH2), 83.84 (10CH), 68.86
(9CH2), 66.34 (5CH2), 51.83 (4CH); HRMS m/z (ESI/TOF/MS, [M+H]+ )calcd for
C12H13BrNO3: 298.0081, Found 298.0089.
3.1.7. 3-[4-( trifluoromethyl)phenyl]-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d]
[1,2]
o
isoxazole (2g) Yield 28 %; mp 143.8-145 C; IR (KBr), ν (cm-1): 2999 (C-H), 2936 (C-H),
1
2883 (C-H), 1605 (C=N); H NMR (400 MHz, CDCl3), δ (ppm) : 7.81-7.79 (d, J=8.0,
aromatic, 2H), 7.71-7.69 (d, J=8.4, aromatic, 2H), 4.99-4.95 (m, 7CH2, 10CH, 2H), 4.65-4.63
(d, J= 6.4, 7CH2, H), 4.45-4.41(dd, J= 3.3, J= 14, 9CH2, H), 4.21-4.16 (q, J= 6.4, J= 12.8,
13
5CH2, H), 4.06-3.98 (m, 4CH, 9CH, 2H), 3.95-3.91 (dd, J= 2.8, J= 12.7, 4CH, H); C NMR
(CDCl3), δ (ppm) : 156.33 (C=N), 132.37-125.91 (aromatic C), 98.56 (7CH2), 84.06 (10CH),
69.07 (9CH2), 66.32 (5CH2), 51.79 (4CH); HRMS m/z (ESI/TOF/MS, [M+H]+ )calcd for
C13H13F3NO3: 288.0849, Found 298.0850.
3.1.8. 3-(3-methylphenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole (2h)
o
Yield 30 %; mp 144.4-146 C; IR (KBr), ν (cm-1): 3002 (C-H), 2970 (C-H), 2895 (C-H),
1
1596 (C=N); H NMR (400 MHz, CDCl3), δ (ppm) : 7.53 (s, aromatic, H), 7.45-7.43 (d,
J=7.6, aromatic, H), 7.34-7.24 (m, aromatic, 2H), 4.94-4.89 (m, 7CH2, 10CH, 2H), 4.71-4.69
(d, J= 6.4, 7CH2, H), 4.41-4.37 (dd, J= 4.0, J= 13.6, 9CH2, H), 4.16-4.11 (q, J= 6.8, J= 12.4,
5CH2, H), 4.04-3.99 (m, 4CH, 9CH, 2H), 3.97-3.93 (dd, J= 3.6, J= 12.4, 5CH2, H), 2.40 (s,
CH3, 3H); 13C NMR (CDCl3), δ (ppm) : 157.52 (C=N), 138.74-124.04 (aromatic C), 98.42
(7CH2), 83.55 (10CH), 68.67 (9CH2), 66.45 (5CH2), 52.06 (4CH), 21.39 (CH3); HRMS m/z
(ESI/TOF/MS, [M+H]+ )calcd for C13H16NO3: 234.1132, Found 234.1130.
3.1.9. 3-(3-chlorophenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole (2i)
o
Yield 30 %; mp 139.2-141 C; IR (KBr), ν (cm-1): 2995 (C-H), 2956 (C-H), 2883 (C-H),
1
1596 (C=N); H NMR (400 MHz, CDCl3), δ (ppm) : 7.67 (s, aromatic, H), 7.55-7.53 (d,
J=7.2, aromatic, H), 7.42-7.35 (m, aromatic, 2H), 4.96-4.92 (m, 7CH2, 10CH, 2H), 4.65-4.63
(d, J= 6.4, 7CH2, H), 4.43-4.38 (dd, J= 3.6, J= 14.0, 9CH2, H), 4.19-4.14 (q, J= 6.4, J= 12.8,
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5CH2, H), 4.01-3.96 (d, J= 14, 4CH, 9CH, 2H), 3.94-3.90 (dd, J= 3.2, J= 12.6, 5CH, H); 13C
NMR (CDCl3), δ (ppm) : 156.35 (C=N), 134.96-125.04 (aromatic C), 98.52 (7CH2), 83.88
(10CH), 68.94 (9CH2), 66.40 (5CH2), 51.83 (4CH) HRMS m/z (ESI/TOF/MS, [M+H]+ )calcd
for C12H13ClNO3: 254.0586, Found 254.0602.
3.1.10. 3-(3-bromophenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole (2j)
o
Yield 29 %; mp 175-175.8 C; IR (KBr), ν (cm-1): 2991 (C-H), 2954 (C-H), 2882 (C-H),
1
1595 (C=N); H NMR (400 MHz, CDCl3), δ (ppm) : 7.83 (s, aromatic, H), 7.60-7.55 (td,
J=8.4, J=13, aromatic, H), 7.33-7.29 (t, J=8.0, J=8.6, aromatic,2H), 4.96-4.92 (m, 7CH2,
10CH, 2H), 4.66-4.64 (d, J= 6.4, 7CH2, H), 4.42-4.38 (dd, J= 3.6, J= 13.8, 9CH2, H), 4.18-
4.14 (q, J= 6.2, J= 12.6, 5CH2, H), 4.00-3.95 (m, 4CH, 9CH2, 2H), 3.94-3.90 (dd, J= 3.2, J=
13
12.8, 5CH2, H); C NMR (CDCl3), δ (ppm) : 156.23 (C=N), 133.09-123.04 (aromatic C),
98.51 (7CH2), 83.88 (10CH), 68.93 (9CH2), 66.37 (5CH2), 51.81 (4CH) HRMS m/z
(ESI/TOF/MS, [M+H]+ )calcd for C12H13BrNO3: 298.0081, Found 298.0090.
3.1.11. 3-(3-nitrophenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole (2k)
o
Yield 25 %; mp 138-138.7 C; IR (KBr), ν (cm-1): 2991 (C-H), 2968 (C-H), 2885 (C-H),
1596 (C=N); 1H NMR (400 MHz, CDCl3), δ (ppm) : 8.45 (s, aromatic, H), 8.29-8.27 (d, J=8,
aromatic, H), 8.07-8.05 (d, J=7.6, aromatic, H), 7.66-7.62 (t, J=8.0, J=8.6, aromatic, H), 5.02-
4.97 (m, 7CH2, 10CH, 2H), 4.60-4.59 (d, J= 6.4, 7CH2, H), 4.47-4.43 (dd, J= 3.2, J= 14.0,
9CH2, H), 4.27-4.22 (q, J= 5.6 J= 13.2, 5CH2, H), 4.11-4.07 (m, 4CH, H), 4.00-3.92 (td, J=
13
3.2, J= 16, 9CH2, 5CH2, 2H); C NMR (CDCl3), δ (ppm) : 155.66 (C=N), 148.53-121.62
(aromatic C), 98.68 (7CH2), 84.23 (10CH), 69.45 (9CH2), 66.4 (5CH2), 51.71 (4CH); HRMS
m/z (ESI/TOF/MS, [M+H]+ )calcd for C12H13BrN2O5: 265.0826, Found 298.0823.
4. Result and Discussion
In this work a series of eleven 3-(substituted phenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-
d] [1,2] isoxazoles were synthesized and characterized. The sites of interest in the 2(a-k)
series are at C=N, C4, C5, C7, C9 and C10 carbons (Fig.1.). The 13C NMR chemical shifts of
the corresponding carbon atoms of compound 2(a-k) are shown in Table 1. The
measurements were performed with a low and constant sample concentration (0.1 M) to
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13
diminish intermolecular associations. The C NMR chemical shift values refer to the central
peak of CDCl3 which has a value of 77.050 ppm.
An examination of the data in Table 1 shows that the chemical shifts of the investigated
carbon atoms depended on the electronic properties of the substituent on the phenyl ring. The
electron-withdrawing and electron-donating substituents caused a change in the chemical
shifts. The range of chemical shifts for C=N for the studied compounds was 1.885 ppm (from
157.513 to 155.628 ppm), whereas that for C4 was only 0.371 ppm (from 52.047 to 51.676
ppm), for C5 was only 0.126 ppm (from 66.443 to 66.317 ppm), for C7 was only 0.320 ppm
(from 98.644 to 98.324 ppm), for C9 was only 0.858 ppm (from 69.421 to 68.563 ppm) and
for C10 was only 0.737 ppm (from 84.196 to 83.459 ppm) and shows that changes in
electron density for C=N carbon under the influence of substituents in the aryl ring was much
13
larger than for other carbons. The range of the C NMR chemical shift values of the C=N
carbon (1.885 ppm) value was larger than the value observed for the C=N carbon of the five
membered rings in the previous studies (1.342 ppm for diacetate derivatives, 0.438 ppm for
1,2,4-oxadiazole-5-one derivatives, 0.376 ppm for 1,2,4-oxadiazole-5-thione derivatives ) [16,
17].
The values in Table 1 reveal that all electron withdrawing substituents caused an upfield shift
of C=N carbon, C4 (except p-F) and C5 signals. This behavior was contrary to the general
tendency for SCS that suggests that the NMR chemical shifts of substituents with either an
electron-withdrawing or electron-donating property would be downfield and upfield
respectively. The opposite is true for C7, C9 (except m-NO2) and C10 carbons. That is, the
electron withdrawing substituents caused a shift downfield.
8

ACCEPTED MANUSCRIPT
Among the CH2 carbons, C5 appeared in mostly upfield while C7 appeared in mostly
downfield. Similarly, the chemical shifts of the C9 (CH2) carbon atom were seen in the
upfield when compared to C7 (CH2) carbon atom (Table1). This was because the C9 (CH2)
carbon atom of the isoxazole derivative is adjacent to a single oxygen atom while the C7
(CH2) carbon atom is adjacent to two oxygen atoms. Thus, the C7 carbon has the highest
chemical shift value among the sp3 hybridized methylene carbons (CH2).
The C=N chemical shifts is very characteristic (ca 157 ppm), typical for sp2 hybridized
carbon, bonded to one oxygen or one nitrogen atom [16, 17]. Although the C4 (ca 52 ppm)
and C10 (ca 83 ppm) carbons are both sp3 hybridized methine carbons (CH), the chemical
shift values are quite different from each other. When examining the structure of the
molecule, it is evident that this difference is due to the electronegative oxygen atom that is
near the C10 carbon. Such results were encountered because the estimation of the magnitude
of the sign and the substitution chemical shifts was determined by various factors affecting
the chemical shift.
The substituent effects on the chemical shifts are typically analyzed by single substituent
parameter (SSP) and dual substituent parameter (DSP) approaches, which are represented by
Equation 1, 2 and 3 respectively [39]
SCS = ρ σ + h
(1)
(2)
(3)
SCS = ρ σI + ρ σR + h
SCS = ρ F + ρ R + h
13
Where SCS is the C NMR chemical shift of investigated carbons, ρ is the proportionality
constant reflecting the sensitivity of the 13C NMR chemical shifts to substituent effects which
9

ACCEPTED MANUSCRIPT
is dependent upon the nature of the reaction. σ (σI, σR), F and R are the corresponding
substituent constants and h is the intercept.
Equation (1) (the simple Hammett Equation-SSP) uses σ values which express the blending of
polar and π-delocalization effects. DSP analysis may be more meaningful than SSP analysis
because the SCS are correlated by a linear combination of the inductive (σI) or field (F) and
o
+
-
various resonance scales (σR, σR , σR , σR , R), depending on the electronic demand of the
atom under examination [40, 41]. The following substituent constant data were taken from the
literature: σ, σI, σR, F, R [42].
The 13C NMR chemical shifts data were analyzed using Equation (1). The result of SSP
analysis is shown in Table 2. The optimal Hammett substituent constants chosen were σ
values for C4, C9 and C10, σI values for the carbon of the C=N group and C5 and σ+ values
for C7 in the molecules under analysis. The high correlation coefficient (ρ) of the C=N
carbon indicated that the chemical shift values of this carbon are most affected by the
substituents (Table 2). Figure 2 shows a negative correlations (r: -0.9468) between the
chemical shift values of the C4 carbon atom with Hammett σ values. In contrast there was a
positive correlation (r: 0.9944) between the 13C NMR chemical shift values of C10 carbon
atom with the Hammett substituent constant σ values in Figure 3.
Multi-linear regression analysis yielded slightly better correlation than the single regression
analysis and the results of multi-linear regression analysis are shown in Table 3. The
variation in the ρ values obtained with different inductive (σI, F) and resonance (σR, R)
parameter combinations were usually small, for example correlation coefficient 0.9838 using
F, R and 0.9856 using σI, σR at the C=N carbon. However, as a result of the correlation
10

ACCEPTED MANUSCRIPT
analysis shown in Table 3, the SCS values of the C=N and C4 carbons appear to correlate
better with the σI, σR substituent constants and the other carbon atoms with the F and R
values. The results of dual parameter statistical analysis of 13C NMR chemical shifts of C=N,
C5, C7 and C9 carbon atoms of 3-(substituted phenyl)-3a,4,8,8a-tetrahydro-1,3-
dioxepino[5,6-d] [1,2] isoxazole derivatives with Hammett substituent constants (σI, σR) and
Swain-Lupton F and R values have shown satisfactory correlation (r ≥ 0.9).
The DSP equation provided a slight improvement in fit when compared to the single
parameter analysis, except in case of the C4 carbon. The chemical shift of C4 carbon has
shown a fair correlation (r < 0.9) with multi-linear regression analysis. This can be attributed
to weak inductive, resonance and field effects of the substituents on the chemical shifts of the
C4 carbon. It was important to notice that a highest correlation coefficient value (r= 0.997) of
C10 carbon atom to substituents effects of investigated serie with Swain-Lupton F and R
values using dual substituent parameter approaches, which could be called the excellent
correlation.
The DSP equation showed, through negative values for each ρ, that reverse substituent effect
operates through both the polar and the resonance component of electronic effect for C=N, C4
and C5. The positive ρI and ρR values show that a normal substituent effect is transmitted
through both polar and resonance pathways for C7, C9, C10 carbons. This implies that the
normal and reverse substituent effects operate at different carbon atoms of compound 2(a-k)
as illustrated in Fig. 4. The aromatic ring electron-donating substituent increased the electron
density at the C7, C9 and C10 carbon atoms (upfield shifts), indicating that normal substituent
effect operates at the C7, C9 and C10 carbon atoms, while electron-withdrawing substituents
have a reverse effect. An electron-donating substituent caused a decrease in the electron
11

ACCEPTED MANUSCRIPT
density at the C=N, C4 and C5 carbons (down field shifts), which was considered to be π-
polarization, indicating a reverse substituent effect (RSE) [43, 44].
A similar effect has been observed in other system, examples being in 1,2,4-oxadiazole and
1,2,4-thiadiazole derivatives [10], in (3-(substituted phenyl)-cis-4,5-dihydroisoxazole-4,5-
diyl)bis(methylene)diacetate derivatives [16], in N(1)-(4-substituted phenyl)-3-cyano-4,6-
dimethyl-2-pyridones [43], in 3-aryl-2-cyanoacrylamides [45], 4-substituted p-terphenls [46],
4-substituted
phenyl-4,5-dihydrobenzo[f][1,4]oxazepin-3(2H)-ones(thiones)
[47],
5-
arylidene-2,4-thiazolidinediones[48]
uracils [49].
and
N-1-p-substitutedphenyl-5-methyl-4-carboxy
RSE can be termed a π-polarization mechanism [50]. Each π-unit is thought to be polarized
separately, the polarization being induced by the substituent dipole in another part of the
molecule, not be transmitted via an interventing π-system [44]. This has also been called
‘‘localized polarization” (direct π -polarization) [51]. This interaction can be transmitted
through the molecular framework or solvent continuum [50-53]. On the other hand, the
terminal atoms of a conjugated π-system show some additional polarization of the whole π-
network, which is known as ‘‘extended polarization”. This second type of polarization has
been called a field-transmitted resonance-polar effect [16, 17, 54]. Transmission of substituent
electronic effects could be presented by mesomeric structures of the investigated isoxazole
derivatives of π-polarization in Fig.5.
In the structure of (1) in Fig.5, if X is an electron-donating substituent, a dipole is formed on
C-X bond (structure (2)) and this dipole interaction, through the space of the molecule, result
in polarization of each individual π-unit (localized polarization). The reverse is true for
12

ACCEPTED MANUSCRIPT
electron-withdrawing substituted compounds (structure (4)). The polarization mechanism of
each localized π-units, represented by structure (2) and (4), is very important as well as
polarization of the entire conjugated of the investigated compound (extended polarization).
In the case of electron-donating substituents, resonance interaction in the extended conjugate
system can be represented by the structure (3) and with an electron-withdrawing substituent
(structure (5)) has an effect against the polarization cause. The net result is that the electron-
withdrawing substituents increase the electron density at the C=N, C4 and C5 carbons, hence
increased shielding, caused an upfield shift. Conversely, the electron-donating substituents
reduces the electron density at C=N, C4, and C5 carbons in the molecules under study,
thereby causing increased deshielding leading to downfield shifts.
The regression coefficient (ρI, ρR) values of the investigated molecules were the lowest for the
C5 atom. This indicated that the electron density around the C5 carbon atom exhibited a low
sensitivity to the effects of phenyl substituents. This value (ρ) was also the highest at the C=N
carbon atom. This result is consistent with the expected effects because C=N is the closest
carbon to the substituent. According to Table 3, this high substituent effect is effectively a
result of inductive effects (ρI(F)> ρR).
The magnitude and sign of ρ should have enable an understanding of the transfer mechanism
of the substitution effect. The ρI values in Table 3 show the dependence of the inductive
effects as a distance-dependent phenomenon from the substituent. It can be seen from Table 3
that DSP analysis of C=N shows the largest ρI value among the investigated carbon atoms of
compound 2(a-k). This carbon is directly bonded to the substituted-phenyl ring meaning that
resonance effects were minimal but the inductive effect was greatly dominant (ρR=
-
0.426±0.258, ρI= - 2.221±0.203 with Swain-Lupton F and R values). According to this
13

ACCEPTED MANUSCRIPT
generally accepted view, the inductive effect appears to be increased due to the shorter
distance between the substituent in the phenyl side and the C=N carbon atom isoxazole
derivatives.
The correlation coefficient of C7 carbon was r: 0.9882 (using F, R values) (ρF: 0.318, ρR:
0.323) with a normal substituent effect and was believed to be connected through a space-type
of transmission which becomes significant at this carbon. As the C7 carbon is far from the
substituent (ten bond away), essentially the electronic effect transmitted by bond should be
weaker as it moves away from the substituent. This means that the systematic electronic
effects on the entire molecule are transmitted. In addition, although the C7 atom of the
dioxepane ring was not directly conjugated with the substituted-phenyl ring, it was
approximately equal to the polar and resonance effects as indicated by λ = ρR / ρF = 0.97 with
F and R parameters.
The DSP analysis also showed that the ratio of resonance to inductive effects (λ= ρR / ρI(F))
changed considerably from one series to another, indicating that a single parameter equation
would be inadequate for data analysis [44]. The field effects varied with changing position of
each investigated atom in the molecular structure of the studied compounds [55]. λ values
were less than 1, indicating that the inductive effect was more important than resonance effect
in the C=N and C5 carbons in the studied molecules. The observed ρI and ρR values for other
carbons indicated a similar contribution from the field and resonance effects, considering the
λ values are approximately equal to 1.
In addition, it is well known that the difference between SSP analyses and DSP analyses is
meaningless, exactly within the λ range, (about 0.5 to 1.5). Most of our results were in this
14

ACCEPTED MANUSCRIPT
range. However, DSP analyses provided slightly better fits in this study, except for the C4
atom. Moreover, even in those cases where the correlation coefficients (r) using the two types
of analysis was similar, DSP analyses provided important additional information, not
obtainable from SSP analyses, for example, the relative size of the ρI and ρR values [56].
5. Conclusion
A number of 3-(substituted phenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole
derivatives were synthesized by a 1,3-dipolar cycloaddition reaction of substituted nitrile
oxides with cis-4,7-dihydro-1,3-dioxepin in the presence Et3N and chloroform. A linear
relationship was shown to exist between the 13C NMR chemical shift values of these
compounds and Hammett sigma constants and F&R parameters using both single and multi-
linear regression analysis. However using the multiple regression analysis, slightly larger
correlation coefficients were obtained. The results of DSP analysis of 13C NMR chemical
shifts of C=N, C5, C7 and C9 carbon atoms with Hammett substituent constants (σI, σR) and
Swain-Lupton F and R values showed satisfactory correlation. Although poor correlation
between the substitution parameters of the C4 carbon were observed, excellent correlation
was found at the C10 (CH) carbon in this study. In addition, a normal substitution effect
operates on carbon atoms C7, C9 and C10, while the reverse substitution effect on C=N, C4
and C5 carbons was seen.
Acknowledgements
We would like to thank the Research Fund of Kocaeli University (2018/133) for financial
support of this research.
Supplementary materials
IR, 1H NMR, 13C NMR and HRMS spectral data of the all newly synthesized compounds and
COSY and HMQC spectral data of 2a are added part of Supplementary materials.
15

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Figure Capture
Fig.1. Synthesis of 3-(substituted phenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2]
isoxazoles 2(a-k).
Fig.2. Plot of 13C NMR chemical shifts of C4 carbon atom against Hammett
substituent constants σ values.
13
Fig.3. Plot of C NMR chemical shifts of C10 carbon atom against Hammett substituent
constants σ values.
Fig.4. The patterns of the substituent effect of compounds 2(a-k) in term 13C NMR shifts.
Fig.5. Mesomeric structures with the contribution of π-polarization in 3-(substituted phenyl)-
3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole derivatives 2(a-k).

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Table 1
13C NMR chemical shifts (ppm) of 3-(substituted phenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d][1,2] isoxazoles 2(a-k).
δ C=N a
δ C4 a
δ C5 a
δ C7 a
δ C9 a
δ C10 a
Substituent(x)
a (H)
157.388
157.330
157.335
156.445
156.458
156.544
156.336
157.513
156.321
156.215
155.628
51.978
52.036
52.031
52.047
51.870
51.814
51.797
52.047
51.807
51.789
51.676
66.426
66.400
66.412
66.358
66.317
66.318
66.326
66.443
66.375
66.349
66.411
98.403
98.335
98.324
98.423
98.444
98.451
98.564
98.410
98.491
98.494
98.644
68.684
68.588
68.563
68.824
68.835
68.843
69.070
68.662
68.919
68.913
69.421
83.591
83.459
83.460
83.630
83.790
83.817
84.063
83.536
83.853
83.868
84.196
b (p-CH3)
c (p-C2H5)
d (p-F)
e (p-Cl)
f (p-Br)
g (p-CF3)
h (m-CH3)
i (m-Cl)
j (m-Br)
k (m-NO2)
a Chemical shifts of the synthesized compounds relative to the residual solvent signal at 77.050 ppm.

ACCEPTED MANUSCRIPT
Table 2
Result of the SSP analyses of the 13C NMR chemical shifts (ppm) for 2(a-k).
Atom
3C=N
3C=N
3C=N
3C=N
3C=N
4C
sigma
ra
ρb
hc
nd
11
σ
-0.9154
-0.7232
-0.7392
-0.9787
0.1549
-0.9468
-0.8651
-0.9037
-0.5967
-0.4816
-0.4209
-0.6846
-0.7385
-0.9120
0.0954
0.9743
0.9864
0.9725
0.7422
0.4226
0.9542
0.9505
0.9439
0.8269
0.2827
0.9944
0.9807
0.9901
0.7463
0.4296
-1.938±0.284
-1.123±0.480
-1.229±0.501
-1.800±0.169
-0.569±1.622
-0.434±0.049
-0.301±0.078
-0.336±0.071
-0.246±0.148
-0.396±0.322
-0.066±0.047
-0.102±0.049
-0.118±0.048
-0.161±0.032
0.034±0.157
0.316±0.024
0.253±0.019
0.267±0.029
0.226±0.091
0.256±0.246
0.808±0.084
0.532±0.078
0.566±0.089
0.548±0.167
0.374±0.568
0.830±0.030
0.680±0.061
0.735±0.046
0.613±0.245
0.704±0.662
157.060±0.096
156.864±0.140
156.957±0.145
157.281±0.059
156.900±0.276
51.984±0.017
51.947±0.023
51.973±0.021
52.000±0.052
51.893±0.055
66.389±0.016
66.368±0.014
66.377±0.014
66.405±0.011
66.369±0.027
98.391±0.008
98.414±0.006
98.394±0.008
98.364±0.032
98.451±0.042
68.690±0.028
68.758±0.023
68.716±0.026
68.636±0.058
68.816±0.096
83.590±0.010
83.669±0.018
83.614±0.013
83.535±0.085
83.770±0.112
σ+
σ-
7
7
σI
7
σR
7
σ
11
7
4C
σ+
σ-
4C
7
4C
σI
7
4C
σR
σ
7
5C
11
7
5C
σ+
σ-
5C
7
5C
σI
7
5C
σR
7
7C
σ
11
7
7C
σ+
σ-
7C
7
7C
σI
7
7C
σR
σ
7
9C
11
7
9C
σ+
σ-
σI
9C
7
9C
7
9C
σR
7
10C
10C
10C
10C
10C
σ
11
7
σ+
σ-
σI
7
7
σR
7
a Correlation coefficient, bWeighting coefficient ratio, cIntercept, d Number of compound
in correlation.

ACCEPTED MANUSCRIPT
Table 3 Result of the DSP analyses of 13C NMR chemical shifts (ppm) for 2(a-k).
b
Scale
(F,R)
(σI,σR)
(F,R)
(σI,σR)
(F,R)
(σI,σR)
(F,R)
(σI,σR)
(F,R)
(σI,σR)
(F,R)
(σI,σR)
Atom
C=N
C=N
C-4
C-4
C-5
C-5
C-7
C-7
C-9
ra
ρR
ρF /ρIb
hc
λd
0.9838
0.9856
0.8876
0.8967
0.9369
0.9257
0.9882
0.9861
0.9841
0.9809
0.9970
0.9947
-0.426±0.258
-0.442±0.323
-0.416±0.149
-0.572±0.189
-0.045±0.048
-0.058±0.069
0.318±0.036
0.401±0.053
0.577±0.092
0.726±0.134
0.861±0.050
1.121±0.088
-2.221±0.203
-1.861±0.162
-0.377±0.117
-0.324±0.095
-0.204±0.038
-0.169±0.035
0.323±0.029
0.281±0.026
0.751±0.073
0.647±0.067
0.884±0.039
157.327±0.068
157.244±0.061
51.957±0.039
51.953±0.036
66.410±0.013
66.401±0.013
98.385±0.010
98.399±0.010
68.666±0.024
68.697±0.134
83.587±0.013
83.628±0.017
0.19
0.24
1.10
1.76
0.22
0.34
0.98
1.43
0.77
1.12
0.97
1.46
C-9
C-10
C-10
0.766±0.044
c
a Correlation coefficient, b Weighting coefficient ratio, Intercept, d λ- the ratio of resonance to
inductive effects, ρR / ρI .

ACCEPTED MANUSCRIPT
X
X
X
Na2CO3
Cl2
O
N
N
NH2OH.HCl
OH
OH
H
H
Cl
(1)
X
CH3Cl
Et3N
a (H)
b (p-CH3)
c (p-C2H5)
d (p-F)
X
O
O
N
e (p-Cl)
O
f (p-Br)
4
10
g (p-CF3)
h (m-CH3)
i (m-Cl)
j (m-Br)
k (m-NO2)
5
9
O
O
7
(2)
Fig.1. Synthesis of 3-(substituted phenyl)-3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazoles
2(a-k).

ACCEPTED MANUSCRIPT
Fig.2. Plot of 13C NMR chemical shifts of C4 carbon atom against Hammett
substituent constants σ values.

ACCEPTED MANUSCRIPT
Fig.3. Plot of 13C NMR chemical shifts of C10 carbon atom against Hammett substituent
constants σ values.

ACCEPTED MANUSCRIPT
X
N
O
= reverse effect
= normal effect
O
O
Fig.4. The patterns of the substituent effect of compounds 2(a-k) in term 13C NMR shifts.

ACCEPTED MANUSCRIPT
δ+
δ-
X
X
X
δ-
δ+
N
N
δ+
δ+
δ-
δ-
N
O
O
O
δ+
δ-
δ-
δ+
δ+
δ-
O
O
O
O
O
O
δ+
δ-
(1)
(2)
(4)
+
-
X
X
-
δ+
+
N
N
δ-
δ-
O
O
δ+
δ-
δ-
δ+
δ-
δ+
δ+
O
O
O
O
δ-
δ+
electron-donating
electron-withdrawing
(3)
(5)
Fig.5. Mesomeric structures with the contribution of π-polarization in 3-(substituted phenyl)-
3a,4,8,8a-tetrahydro-1,3-dioxepino[5,6-d] [1,2] isoxazole derivatives 2(a-k).

ACCEPTED MANUSCRIPT
* Negative ρ values were found for at C=N, C4, C5 carbons for SSP (Single substituent
parameter) and DSP (Dual substituent parameter) analysis.
* Positive ρ values were found for at C7, C9 and C10 carbons with same analyses methods.
* It has been observed that substituent effects from phenyl ring are efficiently transmitted to
isoxazole ring and 1,3-dioxepane ring.