Structure-Based Evaluation of the Regioselectivity in Binary Hydrogen Bonds

Structure-based evaluation of the regioselectivity in bifurcated hydrogen bonds

Lin Li, Zhuan Fei, Xiang-gao Meng, Li-ping Cao, Tao Pang, Yan-ping Zhu, Anxin Wu*

Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Central China Normal University, Wuhan 430079, P.R. China

* Corresponding authors. (A. X. Wu) Phone: +86 27 67867773. Fax: +86 27 67867773. E-mail: .

Instrumental

All the reagents were obtained from J&K and used as received unless otherwise mentioned. All compounds were characterized by IR and NMR. NMR spectra (δ scale in ppm, J coupling in Hz) were recorded in DMSO-d6 on Varian Mercury 600 spectrometer operating at 600 MHz for 1H and 150 MHz for 13C relative to tetramethylsilane as an internal standard. IR spectras(ν in cm-1) were recorded on a Perkin-Elmer PE-983 infrared spectrometer as KBr pellets. Melting points were determined on an XT–4A Meltemp apparatus and were uncorrected.

Synthesis

A mixture of isocyanate and the appropriate aniline in 1:1 molar ratio in 10 mL of DMF was heated at 70℃ for 4h. The product was isolated after column chromatography in ∼80% yield1.

1-(4-hydroxyphenyl)-3-phenylurea(1) 2

Crystallized from EtOAc/EtOH. m.p.220℃. 1H NMR (DMSO-d6, 600 MHz):  9.08 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.30 (m, 4H), 6.94 (s, 1H), 6. 69 (d, J = 8.5 Hz, 2H). 13C NMR (DMSO-d6, 150 MHz):  157.9, 157.5, 145.1, 136.2, 133.9, 126.7, 125.6, 123.1, 120.3. IR (KBr,cm-1): 3306, 1636, 1595, 1570, 1509, 1463, 1444, 1385, 1224.

1-(4-hydroxyphenyl)-3-phenylthiourea(2) 3

Crystallized from EtOAc/P.E. m.p.164℃. 1H NMR (DMSO-d6, 600 MHz):  9.52 (s, 1H), 9.51 (s, 1H), 9.38 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.30 (t, J = 7.2 Hz, 2H), 7.17 (d, J =8.4 Hz, 2H), 7.10 (m, 1H), 6.72 (d, J = 8.4 Hz, 2H). 13C NMR (DMSO-d6, 150 MHz):  181.9, 157.0, 141.8, 132.6, 130.5, 128.4, 126.3, 125.9, 117.2. IR(KBr,cm-1): 3211, 3022, 1553, 1531, 1451, 1339, 1252, 699.

1-(4-hydroxyphenyl)-3-(4-nitrophenyl)urea(3) 4

Crystallized from CHCl3/MeOH. m.p.230℃. 1H NMR (DMSO-d6, 600 MHz):  9.34 (s, 1H), 9.19 (s, 1H), 8.61 (s, 1H), 8.17 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 7.8Hz, 2H), 6.73 (d, J = 7.2 Hz, 2H). 13C NMR (DMSO-d6, 150 MHz):  158.2, 157.2, 151.8, 145.8, 135.4, 130.2, 126.0, 122.3, 120.4. IR(KBr,cm-1): 3366, 3290, 1660, 1555, 1503, 1458, 1412, 1328, 1222, 654.

1-(4-hydroxyphenethyl)-3-(4-nitrophenyl)urea(4) 5

Crystallized from CHCl3/MeOH. m.p.176℃. 1H NMR (DMSO-d6, 600 MHz):  9.28 (s, 1H), 9.23 (s,1H), 8.14 (d, J = 9 Hz, 2H), 7.62 (d, J =8.4 Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 6.72(d, J = 7.8 Hz, 2H), 6.38 (s, 1H), 3.31 (t, J = 6.6 Hz, 2H), 2.65 (t, J = 6.6 Hz, 2H). 13C NMR (DMSO-d6, 150 MHz):  160.8, 159.4, 152.2, 145.4, 134.7, 134.4, 130.2, 121.8, 120.2, 46.0, 39.8. IR (KBr,cm-1): 3376, 3296, 1663, 1555, 1509, 1448, 1412, 1327, 1232, 653.

1-(4-hydroxyphenethyl)-3-phenylthiourea(5) 6

Crystallized from EtOAc/MeOH. m.p.98℃. 1H NMR (DMSO-d6, 600 MHz):  9.54(s, 1H), 9.52(s, 1H), 7.65 (s, 1H), 7.35 (d, J = 7.2 Hz, 2H), 7.30 (d, J = 7.2 Hz, 2H), 7.09 (m, 1H), 7.04 (t, J = 6.6 Hz, 2H), 6.71 (d, J = 7.2 Hz, 2H), 3.64 (s, 2H), 2.75 (s, 2H). 13C NMR (DMSO-d6, 150 MHz):  180.3, 155.8, 139.2, 129.6, 129.3, 128.7, 124.2, 123.0, 115.2, 45.7, 33.7. IR(KBr,cm-1): 3233, 1574, 1537, 1513, 1449, 1342, 1253, 700.

1-(4-hydroxyphenethyl)-3-phenylurea(6) 7

Crystallized from DMSO/EtOH. m.p.174℃. 1H NMR (DMSO-d6, 600 MHz):  9.24(s, 1H), 8.52 (s, 1H), 7.43 (d, J = 7.8 Hz, 2H), 7.24 (t, J = 7.8 Hz, 2H), 7.05 (d, J = 9 Hz, 2H), 6.90 (m, 1H), 6.75 (t, J = 8.4 Hz, 2H). 6.10(s, 1H), 3.32 (t, J = 6.6 Hz, 2H), 2.66 (t, J = 6.6 Hz, 2H). 13C NMR (DMSO-d6, 150 MHz):  160.8, 160.3, 145.6, 134.6, 133.8, 126.7, 122.7, 120.3. 46.0, 40.1. IR (KBr,cm-1): 3405, 3357, 1681, 1560, 1513, 1441, 1315, 1247, 691.

1-(4-hydroxyphenyl)-3-methylthiourea(7) 8

Crystallized from DMSO/EtOH. m.p.198℃. 1H NMR (DMSO-d6, 600 MHz):  9.44 (s, 1H), 9.23 (s, 1H), 7.27 (s, H), 7.05 (d, J = 7.2 Hz, 2H), 6.74 (d, J = 7.2Hz, 2H) 2.86 (s, 3H). 13C NMR (DMSO-d6, 150 MHz):  186.26, 160.14, 134.7, 131.6, 120.5, 36.4. IR (KBr,cm-1): 3335, 3182, 1562, 1530, 1442, 1223, 655.

1-hexyl-3-(4-hydroxyphenyl)urea(8) 9

Crystallized from CHCl3/MeOH. m.p.134℃. 1H NMR (DMSO-d6, 600 MHz):  8.94 (s, 1H), 8.02(s, 1H), 7.13(d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 2H), 5.93(s, 1H), 3.03 (t, J = 6.6 Hz, 2H), 1.39(d, J = 6.6 Hz, 2H), 1.27(s, 6H), 0.87(t, J = 6 Hz, 3H). 13C NMR (DMSO-d6, 150 MHz):  160.8, 157.0, 137.3, 124.9, 120.2, 36.2, 35.0, 31.3, 27.3, 19.1. IR (KBr,cm-1): 3347, 1660, 1555, 1503, 1458.

Figure S1. X-ray structure of 3. The nitro group is involved in intermolecular C–H···O nitro interaction along the b-axis with a phenyl CH donor.

Figure S2. X-ray structure of 4. The asymmetry urea hydrogen bond and O–H···O interaction

Figure S3. X-ray structure of 6. The hydroxyl group of the tyramine is inserted into the amide chain of the ureas.

Figure S4. X-ray structure of 7. One of the urea -NH groups of 7 is bonded to phenol, while the other -NH group bonds to the urea carbonyl in a pattern similar to that found in secondary amides.

Figure S5. X-ray structure of 8. The solvent molecules interrupt the O–H···O interaction of the hydroxyl groups of 8.

Summary of queries used. Search found structure that:

Match Query 1 and Query 2

Query 1 or

Query 2

Table S1. CSD refcodes and structural summary of N, N’-disubstituted phenolic (thio)ureas extracted from the Cambridge Structural Database (CSD Version 5.32, Nov 2010+2 updates).a

aMix is defined as the hydroxyl groups bond to the urea proton, while the Self-sorting means the phenol and (thio)ureas maintaining in the self-complementary.

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