NMR Spectral correlations in some Tröger’s bases

Some Tröger’s bases have been synthesised from substituted anilines and paraformaldehyde in presence of Lewis acid catalyst such as anhydrous AlCl 3 , through electrophilic substitution reaction. The purities of these Tröger’s bases have been checked by their physical constants and spectroscopic data published earlier in the literature. The NMR chemical shift (δ, ppm) of methylene protons and carbon were assigned. The assigned methylene protons and carbon chemical shifts (δ, ppm) of synthesised Tröger’s bases have been correlated with Hammett substituent constants, F and R parameters using single and multi-regression analyses. From the results of statistical analyses, the effects of substituent on methylene protons and carbon were discussed.


1. Materials and methods
All chemicals used were purchased from Sigma-Aldrich and E-Merck chemical companies. Melting points of all Tröger's bases were determined in open glass capillaries on Mettler FP51 melting point apparatus and are uncorrected. Infrared spectra (KBr, 4000-400 cm −1 ) were recorded on AVATAR-300 Fourier transform spectrophotometer. The NMR spectra are recorded in INSTRUM AV500 NMR spectrometer, operating at 500 MHz for 1 H spectra and 125.46 MHz for 13 C spectra in CDCl 3 solvent using TMS as internal standard. Electron impact (EI) (70 eV) and FAB + mass spectra were recorded using VARIAN 500 mass spectrometer.

General procedure for the synthesis of substituted Tröger's bases [33]
To an appropriate molar mass of substituted anilines (10 mmol) and paraformaldehyde (20 mmol) in CH 2 Cl 2 (30 mL), anhydrous AlCl 3 (1.36 g, 10 mmol) was added under N 2 atmosphere. The reaction mixture was stirred for 12 h at 25 °C (Scheme 1) and quenched with cold water (10 mL). The reaction mixture was extracted with CH 2 Cl 2 (20 mL) and the combined organic extracts were successively washed with water, brine and dried over anhydrous Na 2 SO 4 . After removal of the solvent, the residue was subjected to chromatography on alumina (basic) column using 10 % ethyl acetate in hexane to elute the desired Tröger's base analogs [14,15,33]. The analytical and Mass and NMR spectroscopic data are presented in Table 1.

1. 1 H NMR spectral study
In the present study, the compounds chosen for evaluating the effects of substituents on methylene unit in Tröger's bases is shown in Scheme 1. The NMR spectra of synthesised Tröger's bases were recorded in CDCl 3 solvent using TMS as internal standard. The Chemical shifts (δ, ppm) of methylene protons and carbons of synthesised Tröger's bases were presented in Table 1. These chemical shifts(δ, ppm) have been correlated with Hammett substituent constants, F and R parameters using single and multi-linear regression analysis [32,[34][35][36][37][38][39][40][41][42][43][44]. In this correlation the Hammett equation was taken in the form as where δ o is the frequency for the parent member of the series.
The results of statistical analyses of correlation of δHa and Hb chemical shifts (ppm) of Tröger's bases with Hammett substituent constants, F and R parameters were presented in Table 2. From Table 2, the correlation of δHa chemical shifts (ppm) values correlated satisfactorily with Hammett substituent constants and F parameters individually except NH 2 , 4-OCH 3 , 4-COOC 2 H 5 , 4-NO 2 , 4-CN, 4-OC 2 H 5 and 4-F substituents. The resonance parameter was failed in correlation with these frequencies. This is due to the lone pair of nitrogen atom opposes the of effect of substituents on the methylene moiety and is associated with the resonance conjugative structure shown in Fig. 2. All correlations gave positive ρ values except σ R constants and Resonance parameters.   This is implies that there is a normal-substituent effects operates in all correlation. The correlation of δHb chemical shifts (ppm) values correlated satisfactorily with Hammett σ, σ + substituent constants and F parameters individually except NH 2 , 4-COOC 2 H 5 , 4-NO 2 , 4-CN and 4-OC 2 H 5 substituents. If these substituents were included in the analysis, the result will be poor correlation. The remaining Hammett substituent constants and resonance parameters were fails in correlation. This is due to the inability of inductive and resonance effects of substituents on the methylene of all bases by opposing the lone pair of nitrogen atom and associated with the resonance conjugative structure shown in Fig. 2. The ratio of ρHa and ρHb is greater than 1 for σ and σ + . This implies that the transmittance of substituents effects on the methylene protons is higher extent for Ha chemical shifts(ppm) than Hb.
In single parameter regression analysis, some of the correlations of δHa and Hb chemical shifts (ppm) of Tröger's bases were fails with some Hammett substituent constants, F and R values. While seeking the multi linear correlation, these frequencies correlated satisfactorily with Inductive, Resonance and Swain-Lupton's [44] constants collectively and the correlated equations are given in 2-5.

2. 13 C NMR Spectral study
The Chemical shifts (δ, ppm) of methylene carbons of synthesised Tröger's bases were presented in Table 1. These chemical shifts (δ, ppm) have been correlated with Hammett substituent constants, F and R parameters using single and multi-linear regression analysis [32,[34][35][36][37][38][39][40][41][42][43][44]. The results of statistical analysis are presented in Table 2. From the table 2, the methylene carbon chemical shifts (δ, ppm) of Tröger's bases with Hammett σ, σ + and σ I constants were correlated satisfactorily. The remaining substituent constants, F and R parameters were failed in correlation. This is due to the reason stated earlier and associated with the resonance conjugative structure shown in Fig. 2. All correlation gave positive ρ values. This means that there is a normal substituent effect operates in all systems.
The correlations of methylene carbon chemical shifts (ppm) of Tröger's bases were fails with some Hammett substituent constants, F and R values in single parameter regression analysis. When seeking the multi linear regression, it is worthwhile that these frequencies correlated satisfactorily with Inductive, Resonance and Swain-Lupton's [44] constants collectively and the correlated equations are given in 6 and 7.

CONCLUSIONS
A series of Tröger's bases have been synthesized by electrophilic substitution reaction of substituted anilines and paraformaldehyde in presence Lewis acid catalyst anhydrous AlCl 3 . The purities of these Tröger's bases were checked by their physical constants and spectroscopic data published earlier in the literature. The NMR spectroscopic frequencies (δ, ppm) of methylene protons and carbons were assigned. The assigned chemical shifts (δ, ppm) of methylene protons and carbons have been correlated with Hammett substituent constants, F and R parameters using single and multi-regression analyses. From the results of statistical analyses, the effects of substituents on methylene protons and carbon were discussed.