Synthesis and X-Ray analysis of new 1,5-benzo-diazepinium picrates

Article abstract of DOI:10.3987/COM-03-9873

1,2-Diaminobenzenes react with pentane-2,4-dione in ethanol in the presence of picric acid to give 1,5-benzodiazepinium picrates. In the single crystal, the benzodiazepinium molecules form layers with overlapped 7-membered rings in head-to-tail arrangemen

Full text of DOI:10.3987/COM-03-9873

HETEROCYCLES, Vol. 60, No.12, 2003, pp. 2645 - 2651
Received, 28th July, 2003, Accepted, 22nd September, 2003, Published online, 25th September, 2003
SYNTHESIS AND X-RAY ANALYSIS OF NEW 1,5-BENZO-
DIAZEPINIUM PICRATES
Andreas Schmidt,a* Abbas Gholipour Shilabin,a and Martin Niegerb
a Technical University of Clausthal, Institute of Organic Chemistry,
Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany
b Rheinische Friedrich-Wilhelms-University of Bonn, Institute of Inorganic
Chemistry, Gerhard-Domagk-Strasse 1, D-53121 Bonn, Germany
Abstract – 1,2-Diaminobenzenes react with pentane-2,4-dione in ethanol in the
presence of picric acid to give 1,5-benzodiazepinium picrates. In the single crystal,
the benzodiazepinium molecules form layers with overlapped 7-membered rings
in head-to-tail arrangement. Hydrogen bonds to the picrate connect the 1,5-
benzodiazepinium molecules of two layers.
1,5-Benzodiazepines continue to be an interesting class of compounds both from a chemical and a
biological point of view. Whereas nonprotonated 1,5-benzodiazepines form a diimine (2) to avoid an
annular conjugation of 4n π-electrons around the diazepine (8 π-electrons) or benzodiazepine ring (12 π-
electrons) as in 1, protonation results in the formation of intensively colored salts (3) which possess a
stabilizing vinamidinium chromophor. This chromophor causes stabilisation energies of the order of 20
Kcalmol-1.1 In stronger acids the colorless diprotonated species (4) are produced.1 Depending on the
substitution pattern 1,5-benzodiazepines display interesting physiological effects.2
H
N
H
N
N
N
N
+H
-H
+H
-H
N
H
N
H
3
N
H
4
2
1
Scheme 1
In continuation of our work on ionic heterocycles3 and mesomeric betaines4 we became interested in 1,5-
benzodiazepinium salts. We describe here the syntheses of new compounds and the interesting results of
an X-Ray structure analysis. We chose 2,3-diaminophenol (5a), 3,4-diaminophenol (5b), 4-methoxy-1,2-
diaminobenzene dihydrochloride (5c), and 3,4-diaminobenzoic acid (5d) as starting materials. The new
diamine (5b) was prepared by reduction of the readily available 4-amino-3-nitrophenol (6) with Raney-
nickel in the presence of 98% hydrazine hydrate in quantitative yield (Scheme 2).

R1
R2
NH2
NH2
HO
NO2
NH2
Ra-Ni, N2H4
5b
5a: R1 = OH, R2 = H
5b: R1 = H, R2 = OH
5c: R1 = H, R2 = OMe
5d: R1 = H, R2 = COOH
6
Scheme 2
Reaction of the 1,2-diaminobenzenes (5a-d) with pentane-2,4-dione in ethanol in the presence of picric
acid gave the 1,5-benzodiazepinium picrates (7a-d) as intensely violet crystals. The presence of picric
acid proved to be advantageous in comparison with other acids because the resulting salts readily
precipitate from the reaction mixture and are analytically pure after washing with diethyl ether (Scheme
3). Not unexpected, the products are protonated due to the strong acidity of picric acid (pKa 0.25).
O
O
R1
H
N
O
Me
Me
R2
Me
Me
O2N
NO2
5a-d
OH
N
H
O2N
NO2
NO2
7a: R1 = OH, R2 = H
7b: R1 = H, R2 = OH
NO2
7c: R1 = H, R2 = OMe
7d: R1 = H, R2 = COOH
Scheme 3
Single crystals of 1,5-diazepinium picrate (7a) suitable for an X-Ray analysis were obtained by slow
evaporation from a concentrated solution in acetone.5 The compound crystallizes triclinic with one
molecule of acetone of crystallisation (Figure 1).
Figure 1: ORTEP plot of 7a.

The dihedral angles C(3)-C(4)-N(5)-C(6) = 13(2)° and C(11)-N(1)-C(2)-C(3) = –10.3(2)° confirm the
slightly helical structure of the diazepinium moiety which was also found in 2,3-dihydro-1,4-diazepines8
and mixed crystals consisting of 2,4-dimethylbenzodiazepinium and benzene-1,2-diammonium cations
and chloride anions.9 2,4-Dimethylbenzodiazepinium chloride10 and hexafluorophosphate11 as well as the
hydrochloride of 2,4-dimethylnaphthodiazepine12 are planar. As expected, the bond distances in the
vinamidinium chromophor N(1)-C(2)-C(3)-C(4)-N(5) are in agreement with the extensive delocalisation
of 6 π-electrons,13 but they are slightly longer than reported in other systems mentioned above.9-12 By
contrast, the bond lengths N(1)-C(11) and N(5)-C(6) are 142.48(18) pm and 142.38(18) pm, respectively,
and thus separate the benzene moiety from the 7-membered ring. Thus, the molecule avoids a conjugation
of 4n π-electrons around the periphery of the rings by isolation of the two parts of the molecule. The bond
angles in the 7-membered ring are larger than the 120° expected for sp2-hybridized carbon atoms. Some
selected bond lengths and dihedral angles of 7a are given in Table 1.
Table 1. Atom Nos. / Selected bond lengths [pm], bond angles [°], and torsion angles [°] of 7a.
N(1)-C(2) 133.07(18)
C(2)-C(3) 138.5(2)
C(3)-C(4) 138.8(2)
C(4)-N(5) 132.58(18)
C(2)-C(12) 149.8(2)
C(4)-C(13) 150.0(2)
C(10)-O(1) 135.38(17)
C(10)-C(11) 139.7(2)
C(9)-C(10) 139.4(2)
C(6)-C(11) 139.46(19)
C(2)-N(1)-C(11)
N(1)-C(2)-C(3)
C(2)-C(3)-C(4)
C(3)-C(4)-N(5)
C(4)-N(5)-C(6)
N(5)-C(6)-C(11)
C(6)-C(11)-N(1)
N(1)-C(11)-C(10) 114.87(13)
O(1)-C(10)-C(11) 116.49(13)
C(9)-C(10)-C(11) 121.16(13)
129.86(13)
126.42(14)
129.37(14)
127.10(13)
130.07(12)
125.10(13)
126.26(13)
C(11)-N(1)-C(2)-C(3)
C(11)-N(1)-C(2)-C(12)
N(1)-C(2)-C(3)-C(4)
C(2)-C(3)-C(4)-N(5)
C(3)-C(4)-N(5)-C(6)
C(4)-C(5)-C(6)-C(11)
C(4)-N(5)-C(6)-C(7)
C(6)-C(7)-C(8)-C(9)
C(8)-C(9)-C(10)-O(1)
-10.3(2)
170.71(13)
-13.6(3)
11.6(3)
13.0(2)
-19.7(2)
160.18(14)
-0.1(2)
-179.64(12)
O(1)-C(10)-C(11)-N(1) 1.47(17)
Several hydrogen bonds are formed between the three molecules. One intramolecular hydrogen bond is
detected between N(1)-H and the oxygen atom of the 6-hydroxy group (Figure 1). The hydrogen atom of
this group forms a hydrogen bond to the carbonyl oxygen atom of the acetone molecule of crystallisation.
The hydrogen bonds between the acidic N(1)-H group of the diazepinium moiety and the olate group of
the picrate anion on one hand, and between N(1)-H and one of the oxygen atom of one of the ortho-nitro
groups of the picrate on the other stabilize the layers of 1,5-benzodiazepines (Figure 2). The individual
molecules are in the layers head-to-tail orientated in such a way, that the 7-membered rings are
overlapped (Figure 3). The olate group and two oxygen atoms of the ortho-nitro groups of the picrate
combine two stacked 1,5-benzodiazepine molecules by hydrogen bonds through N(1)-H and N(5)-H.

Figure 2.
Table 2. Hydrogen bonds of 7a: Distances [pm] and angles [°].
D-H.....A
d(D-H)
d(H.....A)
d(D.....A)
<(DHA)
N(1)-H(1N).....O(1´)
N(1)-H(1N).....O(61´)
N(1)-H(1N)…..O(1)
N(5)-H(5N)…..O(1´)#1
N(5)-H(5N)…..O(21´)#1
O(1)-H(10)…..O(1A)
87.2(12)
87.2(12)
87.2(12)
86.1(13)
86.1(13)
90.2(14)
224.2 (14)
243.9(14)
217.4(16)
205.0(13)
253.4(15)
180.2(14)
296.71(16)
315.48(16)
260.12(16)
287.73(15)
313.61(17)
269.37(15)
140.5(13)
139.7(12)
109.7(13)
160.9(14)
127.7(13)
169.7(17)
symmetry transformations used to generate equivalent atoms:
#1 -x+2, -y+1, -z+1
Figure 3

The distance between two molecules of 1,5-benzodiazepinium in two layers is 368 pm which is larger
than the two-fold van-der-Waals radii of carbon [rvdW = 165 –170 pm] and nitrogen [rvdW = 155 pm],
respectively (Figure 4).
Figure 4
ACKNOWLEDGEMENTS
We are thankful to Prof. E. Niecke, Prof. K.-H. Dötz and Prof. F. Vögtle for providing the X-Ray facilities.
The Deutsche Forschungsgemeinschaft (DFG) and the Fonds der chemischen Industrie (FCI) is gratefully
acknowledged for financial support.
EXPERIMENTAL
1
13
General methods: The H and C NMR spectra were recorded on a Bruker ARX-400 and DPX-200 in
DMSO-d6 and CDCl3 at 400 and 200 MHz, respectively. The chemical shifts are reported in ppm relative
to internal tetramethylsilane (δ = 0.00 ppm). FT-IR spectra were obtained on a Bruker Vektor 22 in the
range of 400 to 4000 cm-1 (2.5 % pellets in KBr ). The GC-MS spectra were recorded on a GC Hewlett-
Packard 5980, Serie II in combination with a MS Hewlett-Packard 5989 B and on a Varian GC3900 with
SAT2100T mass spectrometer.
Synthesis of 3,4-Diaminophenol (5b).
To a suspension of activated Raney nickel (200 mg) and hydrazine hydrate (98%, 2 mL) in ethanol (40
mL) was cautiously added a solution of 1.54 g (10 mmol) of 4-amino-3-nitrophenol (6) in ethanol (10
mL) and the mixture was stirred for 30 min at rt. The catalyst was then removed by filtration through
Celite and the solvent was distilled off under reduced pressure to give 3,4-diaminophenol (5b) as a light
brown pure solid (1.19 g, 96%), mp 155 °C; 1H NMR (DMSO-d6) δ 8.12 (br s,1H), 6.31 (d, J = 8.14 Hz,
1H), 6.03 (d, J = 2.65 Hz, 1H), 5.81 (dd, J = 8.14/2.65 Hz, 1H), 4.21 (br s, 4H); 13C NMR (DMSO-d6) δ
102.2, 103.2, 115.8, 126.8, 136.7, 149.7; IR (KBr) 3398, 3353, 3272, 3024, 2931, 1621, 1606, 1510, 1486,
1382 cm-1; UV λmax(MeOH) 343 nm; MS m/z (rel. int.) 124 (M+ , 100), 96(28), 68(11), 52(12); Anal.
Calcd for C6H8N2O : C, 58.05; H, 6.50; N, 22.57. Found: C, 57.75; H, 6.32; N, 22.35.

General procedure for the preparation of the 1,5-benzodiazepinium picrates. Solutions of 1.0 mmol
of the diaminobenzene derivatives in 20 mL of ethanol were treated with pentane-2,4-dione (0.1 g; 1.0
mmol), and 0.5 g of picric acid (50% water). The reactions started immediately whereupon the color
changed to dark violet. The mixtures were stirred for 30 min at rt. By addition of ether the precipitation of
the solids was completed. The compounds were filtered off and washed with ether to give intensely violet
fine analytically pure solids.
6-Hydroxy-2,4-dimethyl-5H-benzo[b][1,4]diazepin-1-ium picrate (7a).
2,3-Diaminophenol (0.372 g, 3.0 mmol) was used, yield 0.75 g (61%), mp 198-200 °C; H NMR
1
(DMSO-d6) δ = 10.70 (s, 1H), 9.55 (s, 1H), 9.07 (s, 1H), 8.60 (s, 2H), 6.78 (d, J = 8.15 Hz, 1H), 6.51 (dd,
J = 8.15/7.83 Hz, 1H), 5.96 (d, J = 7.83 Hz, 1H), 4.30 (s, 1H), 1.89 (s, 3H), 1.80 (s, 3H); 13C NMR
(DMSO-d6): δ = 24.1, 24.2, 95.7, 113.8, 116.2 , 120.2, 124.1, 125.2, 129.8, 136.1, 141.8, 149.9, 160.8,
175.1, 176.5; IR (KBr) 3313, 3083, 1609, 1566, 1542, 1429 cm-1; UV λmax(H2O) 218, 256, 358 nm;
λ
max(MeOH) 356, 590 nm; λmax(EtOH) 258, 360 nm; MS m/z (rel. int.) 188 (M+-1, 100), 173(33), 148(29),
91(46), 77(29), 62(85), 52(64); Anal. Calcd for C17H15N5O8: C, 48.93; H, 3.62; N, 16.78. Found: C,
48.97; H, 3.53; N, 16.87.
7-Hydroxy-2,4-dimethyl-5H-benzo[b][1,4]diazepin-1-ium picrate (7b).
3,4-Diaminophenol (0.248 g, 2.0 mmol) was used, yield 0.59 g (71%), mp 228-230 °C; H NMR
1
(DMSO-d6) δ = 9.97 (s, 1H), 9.78 (s, 1H), 9.09 (s, 1H), 8.60 (s, 2H), 6.29 (d, J = 8.59 Hz, 1H), 6.18 (dd, J
= 8.59/2.40 Hz, 1H), 5.92 (d, J = 2.40 Hz, 1H), 4.06 (s, 1H), 1.73 (s, 3H), 1.70 (s, 3H); 13C NMR
(DMSO-d6): δ = 23.7, 23.8, 94.2, 110.7, 113.0, 123.5, 124.1, 125.2, 135.2, 141.8, 158.3, 160.7, 172.6,
173.6; IR (KBr) 3424, 3306, 3080, 1612, 1541, 1480, 1432 cm-1; UV λmax(H2O) 204, 262, 352 nm;
λ
max(MeOH) 284, 348 nm; λmax(EtOH) 268, 286, 354 nm; MS m/z (rel. int.) 188 (M+-1, 100), 173 (10),
146 (23), 106 (7), 77 (88), 5 (11); Anal. Calcd for C17H15N5O8: C, 48.93; H, 3.62; N, 16.78. Found: C,
48.65; H, 3.79; N, 16.78.
7-Methoxy-2,4-dimethyl-5H-benzo[b][1,4]diazepin-1-ium picrate (7c).
4-Methoxy-1,2-diaminobenzene dihydrochloride (1.056 g, 5.0 mmol) was used, yield : 1.83 g (86%), mp
210-212 °C; 1H NMR (DMSO-d6): δ = 9.83 (s, 1H), 9.20 (s, 1H), 8.61 (s, 2H), 6.39 (d, J = 1.26 Hz, 2H),
6.02 (m, 1H), 4.09 (s, 1H), 3.64 (s, 3H), 1.75 (s, 3H), 1.71 (s, 3H); 13C NMR (DMSO-d6): δ = 24.5, 24.6,
56.2, 95.3, 110.8, 111.6 , 124.9, 125.7, 125.9, 126.0, 136.0, 142.5, 160.4, 161.5, 173.6, 174.7; IR (KBr)
3321, 1630, 1609, 1559, 1521, 1481, 1365 cm-1; UV λmax(H2O) 214, 264, 350 nm; λmax(MeOH) 350, 524
nm; λmax(EtOH) 266, 284, 358 nm; MS m/z (rel. int.) 202(M+-1, 100), 187(54), 159(10), 147(18), 118(11),
91(13), 77(7), 62(7); Anal. Calcd for C18H17N5O8: C, 50.12; H, 3.97; N, 16.24. Found: C, 50.15; H, 3.92;
N, 15.93.
7-Carboxy-2,4-dimethyl-5H-benzo[b][1,4]diazepin-1-ium picrate (7d).
3,4-Diaminobenzoic acid (1.52 g, 10.0 mmol) was used, yield 3.87 g (88%), mp 205-207 °C; H NMR
1
(DMSO-d6): δ = 13.15 (br s, 1H), 9.85 (s, 1H), 9.63 (s, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 7.40 (d, J = 8.14
Hz, 1H), 6.99 (s, 1H), 6.48 (d, J = 8.14 Hz, 1H), 4.23 (s, 1H), 1.77 (s, 3H), 1.75 (s, 3H); 13C NMR
(DMSO-d6): δ = 24.1, 96.1, 96.2, 123.1, 124.0, 124.1, 125.2, 130.6, 133.5, 133.5, 138.2, 141.8, 165.1,
175.3, 176.5; IR (KBr) 3310, 3071, 3003, 1692, 1631, 1600, 1568, 1554, 1520, 1435 cm-1; UV λmax(H2O)
268, 354 nm; λmax(MeOH) 352, 524 nm; λmax(EtOH) 242, 270, 360 nm; MS m/z (rel. int.) 216(M+-1, 100),
199(16), 171(21), 159(13), 130(29), 103(13), 91(31), 77(28), 63(52), 53(29); Anal. Calcd for
C18H15N5O9: C, 48.55; H, 3.39; N, 15.73. Found: C, 48.56; H, 3.40; N, 15.41.

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5
Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as
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application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44)1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk). Some crystal data of 3a: C11H13N2O + C6H2N3O7 + C3H6O; M = 475.42;
space group P-1 (no. 2); dimensions 0.50 x 0.40 x 0.25 mm3, a = 8.0073(2) Å, b = 9.6532(3) Å, c =
14.6882(5) Å; α = 81.282(2)°, β = 82.257(2)°, γ = 71.068(2)°; V = 1057.06(6) Å3, Dc = 1.494 MG
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diffractometer (2Θmax. = 56.5°, -10 ≤ h ≤ 10, -12 ≤ k ≤ 12, -18≤ l ≤ 18), 4708 symmetry
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hydrogen atoms were refined using a riding model, other free; wR2 (all data) = 0.1058 [R1 = 0.0393
for 3484 I>2σ(I)].
6
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