Crystal Structure of a Chiral Sec-Amine, 4-Chloro-N-(1-(pyridin-2-yl)ethyl)aniline

Abstract

In this communication, we present the crystal structure of a secondary amine: 4-chloro-N-(1-(pyridin-2-yl)ethyl)aniline (L_b) obtained from a stepwise reduction of an imine, (E)-N-(4-chlorophenyl)-1-(pyridin-2-yl)ethan-1-imine (L_a) with sodium borohydride. The structure was characterized by FT-IR, ¹H and ¹³C NMR, Mass Spectroscopy and X-ray diffraction.

1. Introduction

Schiff bases are a significant ligand in synthetic chemistry due to their numerous applications [1,2,3]. The capacity of the Schiff bases C=N double bond to be reduced to a C-N single bond to generate their corresponding secondary amine is one of their most intriguing properties. Sec-amines are crucial synthesis intermediates in the pharmaceutical [4], polymer [5] and agricultural [6] sectors. Most sec-amines can be made either by direct reductive amination of carbonyl compounds or via a stepwise reaction that starts with the synthesis of imines and then reduces them to amines. The stepwise procedure in reducing imines to amines is a commonly used approach to avoid overalkylation and direct reduction of carbonyl compounds to the appropriate alcohol. It requires the use of various metal hydrides reagents such as Bu₂SnClH [7], LiAlH₄ [8], (g-C₅H₅)₂MoH₂ [9], CaH₂/ZnX₂ [10] and NaBH₄ [11]. Most of these metal hydrides have chemoselective limitations, low yields and are expensive. As a result, most studies utilize sodium borohydrides [12] or its modified compounds such as Na(CH₃COO)₃BH [13], NaBH₃CN [14], NaBH(OAc)₃ [15] and Zn(BH₄)₂ [16] to reduce imines to sec-amines. The choice of sodium borohydride is related to it being a highly selective reducing agent that won’t attack other functional groups in a molecule. As such, sodium borohydride (NaBH₄) was employed in this study to reduce (E)-N-(4-chlorophenyl)-1-(pyridin-2-yl)ethan-1-imine Schiff base to the title sec-amine.

2. Results

The reduction of imine (E)-N-(4-chlorophenyl)-1-(pyridin-2-yl)ethan-1-imine (L_a) with NaBH₄ in methanol solvent led to the formation of a yellow crystal sec-amine of 4-chloro-N-(1-(pyridin-2-yl)ethyl)aniline (L_b). The known compound [17] was obtained in a simple stepwise reductive process with a high yield. The formation of the compound was revealed by the appearance of a new quartet in the ¹H NMR spectrum of L_b (Figure S1), which was attributed to the proton attaching to the methyl group at δ 4.57 ppm. The ¹³C NMR spectrum (Figure S2) further confirmed the formation of L_b. In the FT-IR spectrum of the title amine (Figure S3), the appearance of strong absorption bands at 3264 cm⁻¹ assigned to the -NH group clearly shows the successful reduction of the imine C=N double bond to amine C-N single bond. The peak at 1339, 1286 and 1235 cm⁻¹ corresponding to the vibrational signals of the C-N single bond also confirm the presence of the new C-N single bond. The peak at 741 cm⁻¹ can be assigned to the C-Cl vibration signal.

The molecular structure of L_b was further confirmed by X-ray crystallography. L_b was crystallized from methanol to obtain yellow needle-like crystals suitable for X-ray crystallography. The crystal structure of L_b (Figure 1) revealed that it belongs to the monoclinic system with the space group P21/c. The plane of the pyridinyl moiety is connected to that of the phenyl ring by an NH-CH-CH₃ linker with a torsional angle of 63.0 (2)° between them. The bond length of the amino N1-C4 (1.38 (2) Å) and the phenyl ring C, as well as the bond length of the amino N1-C5 (1.45 (2) Å) (

Table 1. Selected geometric parameters for L_b.

Atom	Length/Å	Atom	Angle/°
N(1)-C(5)	1.45 (2)	C(12)-C(5)-N(1)	108.34 (12)
H(6)-C(5)	1.00	H(6)-C(5)-C(6)	108.43
C(12)-C(5)	1.53 (2)	H(6)-C(5)-N(1)	108.43
C(6)-C(5)	1.53 (2)	H(6)-C(5)-C(12)	108.43
C(1)-Cl(1)	1.76 (2)	C(6)-C(5)-C(12)	110.18 (12)
		N(1)-C(5)-C(6)	112.93 (12)
D-H…A       d(D-H)/Å    d(H…A)/Å  d(D…A)/Å   <D-H-A/° N(1)-H(1)…N(21)    0.88      2.25    3.08 (17)    158.3 C(2)-H(2)…Cl(12)     0.95      2.97    3.88 (15)    160.5 C(10)-H(10)…Cl(13)    0.95      2.91    3.75 (15)    148.3 C(13)-H(13)…Cl(14)    0.95      2.99    3.91 (16)    163.8      12-x, -y, 1-z; 21-x, -y, 2-z; 3+x, ½-y, -½ + z; 41 + x, +y, +z

) and the chiral center, are both close to the average C-N single bond length [18,19]. The chiral sec-amine L_b has a distorted tetrahedral structure, and its geometrical parameters (Table 1) are similar to the literature report [20]. The packing structure of L_b (Figure 2a) also showed strong H-N⋯⋯N_py intermolecular interactions forming its dimer structure (Figure 2b). Notable weak C-H⋯⋯Cl and N_py⋯⋯H-N intermolecular hydrogen bonds were also seen.

3. Materials and Methods

Methanol 99.5% (Aldrich, St. Louis, MO, USA), ethyl acetate 99.8% (Aldrich, St. Louis, MO, USA), 2-pyridinecarboxaldehyde 99% (Aldrich, St. Louis, MO, USA), 4-chloroaniline 99% (Aldrich, St. Louis, MO, USA) and NaBH₄ ≥ 98% (Aldrich, St. Louis, MO, USA) were purchased from local suppliers. All chemicals were of analytical grade and were used as they were given to us. On a BRUKER 400 MHz spectrometer (Karlsruh, German), ¹H NMR and ¹³C NMR spectra in CDCl₃ were recorded. Chemical shift values in CDCl₃ are expressed in parts per million (ppm) in relation to the solvent residual peaks; 7.26 ppm for ¹H NMR and 77.16 ppm for ¹³C NMR. In ¹H NMR spectrum, the splitting pattern is designated as s for singlet, d for doublet, m for multiplet and J for joint (the coupling constant is given in Hertz). The infrared spectrum was recorded using a PerkinElmer Spectrum 100 FT-IR spectrometer (Waltham, MA, USA), and the data were reported as percentage transmittances at the respective wavenumbers (cm⁻¹), between 4000 and 650 cm⁻¹. Only molecular ions (M+) and major fragmentation peaks were reported in the mass spectrum, with intensities expressed as percentages of the base peak, using the Shimadzu LCMS-2020 instrument (Kyoto, Japan).

3.1. Synthesis of 4-chloro-N-(1-(pyridin-2-yl)ethyl)aniline L_a

A known ligand (E)-N-(4-chlorophenyl)-1-(pyridin-2-yl)ethan-1-imine (L_a) [21] was first synthesized using methods similar to our earlier reports [22,23]. Afterward, L_a was reduced to a secondary ligand 4-chloro-N-(1-(pyridin-2-yl)ethyl)aniline (L_b) (Scheme 1) using a modified method from the literature [24].

Synthesis of the secondary amine L_b: The yellow (E)-N-(4-chlorophenyl)-1-(pyridin-2-yl)ethan-1-imine, L_a (1.15 g, 5 mmol) was dissolved in methanol (100 mL) with vigorous stirring and NaBH₄ (0.19 g, 5 mmol) was added gradually within 15 min until the solution became colorless. The resulting solution was further stirred for another 2 h at room temperature. Afterward, the methanol was removed in vacuo. The residue was dissolved in Ethyl acetate washed with cold water (3 × 100 mL). The Ethyl acetate was dried with MgSO₄, filtered and the solvent removed in vacuo to afford an oil product. The resultant yellow oil was heated in a small amount of methanol and allowed to slowly evaporate at room temperature, yielding a crystalline product that was recrystallized from methanol. M.p. 105 °C [17], Yield: 0.91 g, 78%, ¹H-NMR (400 MHz, CDCl₃, δ ppm): 8.56 (d, J = 4.0 Hz, 1H, Hd-py), 7.61 (dd, J = 8.0 Hz, J = 7.9 Hz, 1H, Hb-py), 7.30 (d, J = 7.9 Hz, 1H, Ha-py), 7.15 (dd, J = 8.0 Hz, J = 4.0 Hz, 1H, Hc-py), 7.09 (d, J = 8.8 Hz, 1H, Hi or Hj), 7.05 (d, J = 8.8 Hz, 1H, Hi or Hj), 6.60 (d, J = 8.9 Hz, 1H, Hh or Hk), 6.48 (d, J = 8.9 Hz, 1H, Hh or Hk), 4.57 (q, J = 6.7 Hz, 1H, He-CH), 1.53 (d, J = 6.7 Hz, 3H, Hf-CH₃). ¹³C-NMR (100 MHz, CDCl₃, 25 °C): δ = 149.34 (C5-py), 145.77 (C8-C₆H₄), 145.10 (C1-py), 129.23 (C11-C₆H₄), 129.11 (C12-C₆H₄), 123.29 (C3-py), 122.29 (C4-py), 122.14 (C13-C₆H₄), 120.54 (C2-py), 116.35 (C10-C₆H₄), 114.67 (C9- C₆H₄), 54.87 (C7-CH), 23.17 (C6-CH₃). FT-IR (cm⁻¹): 3264, 3052, 1598, 1339, 1286, 1235, 743.

3.2. X-ray Crystallography

A Bruker Apex Duo diffractometer with an Oxford Instruments Cryojet running at 100 (2) K and an Incoatec micro source working at 30 W power was used to evaluate and collect data of L_b. The data were collected with Mo Kα (λ = 0.71073 Å) radiation at a crystal-to-detector distance of 50 mm using omega and phi scans. The data were reduced with the program SAINT [25] using outlier rejection, scan speed scaling, as well as standard Lorentz and polarization correction factors. A SADABS [26] semi-empirical multi-scan absorption correction was applied to the data. The structure of the ligand L_b was solved by the direct method using the SHELXS [27] program and refined. The visual crystal structure information was performed using ORTEP-3 [28], program. Non-hydrogen atoms were first refined isotropically and then by anisotropic refinement with a full-matrix least-squares method based on F² using SHELXL [29]. All hydrogen atoms were positioned geometrically, allowed to ride on their parent atoms and refined isotropically. The crystallographic data and structure refinement parameters of the sec-amine L_b are given in

Table 2. Crystal data and structure refinement for L_b.

	Lb
Chemical formula	C13H13ClN2
Formula Weight	232.70
Crystal system	Monoclinic
Space group	P 21/c
a (Å)	9.4547 (5)
b (Å)	16.2237 (8)
c (Å)	7.9004 (4)
α (°)	90
β (°)	104.169 (3)
γ (°)	90
V (Å3)	1174.98 (10)
Z	4
ρcalc (g cm−3)	1.315
µ (mm–1)	0.298
F (000)	488.0
Crystal size (mm3)	0.660 × 0.280 × 0.220
θ range for data collection (°)	2.222 to 26.718
Index ranges	–11 ≤ h ≤ 11, –19 ≤ k ≤20, –9 ≤ l ≤9
Reflections collected	16177
Independent reflections	2480 [R (int) = 0.0341]
Completeness to theta = 25.242	99.9%
Data/restraints/parameters	2480/0/146
Goodness-of-fit on F2	1.101
R indices [I > 2sigma (I)]	R1 = 0.0332, wR2 = 0.0800
R indices (all data)	R1 = 0.0375, wR2 = 0.0829
Largest diff. peak and hole (e Å–3)	0.433 and –0.467

.

4. Conclusions

In a two-step approach, we were able to produce a sec-amine with halogen functionality. Because of its high chemo-selectivity, the use of an equimolar amount of sodium borohydride in methanol aids in the effective synthesis of the chlorine-containing sec-amine. The sec-amine possesses a chiral center and forms a distorted tetrahedral structure with the chiral center.