Received 15 April 2016; accepted 30 April 2016; published 4 May 2016

ABSTRACT

The structure of the condensation products of 2-hydroxybenzohydrazide, 2-aminobenzohydrazide, and N-methyl-N-(2-aminobenzo) hydrazide with a series of aldoses (L-arabinose, D-ribose, L- rhamnose, D-galactose, D-glucose, and D-mannose) was studied by ¹H- and ¹³C-NMR spectroscopy. The condensation products of aldoses with 2-hydroxybenzohydrazide and 2-aminobenzohydra- zide in DMSOd₆ solutions exist as equilibrium mixtures of linear acylhydrazone and cyclic pyranose and furanose forms. The aldoses condensation products with N-methyl-N-(2-aminobenzo)hy- drazide in the crystalline state and in DMSOd₆ solutions have cyclic benzo-1,2,4-triazepin structure.

Keywords:

Aldoses 2-Hydroxy- and 2-Aminobenzohydrazides, Benzo-1,2,4-Triazepines, Ring-Chain-Ring Tautomerism

Subject Areas: Organic Chemistry

1. Introduction

Condensation products of aldoses with acylhydrazines and their derivatives have been reported to possess significant activity as antimicrobial, antifungal [1] , and anti-HIV [2] agents. Among aldoses acylhydrazones con- taining in their structure a functional 2-hydroxybenzoyl and 2-aminobenzoyl group is known only 2-hydroxy- benzoylhydrazones of arabinose, glucose and mannose [3] , the structure of which is not proved. The presence of a functional nucleophilic NH₂-group in the aldosohydrazone fragment could give rise in appearance of new structural possibilities in further transformations. Intermolecular nucleophilic attacks of NH₂-fragments at the C=N polar bond contained in the linear structure can lead to repeated cyclization with the formation of new cyclic forms. Condensation products of N-methyl-N-(2-aminobenzo) hydrazide with monocarbonyl compounds tend to undergo intramolecular cyclization via nucleophilic addition of the NH₂-group at the C=N bond with formation of seven-membered benzo-1,2,4-triazepin ring [4] [5] . In some cases, this process is reversible, so that equilibrium mixture of linear hydrazone and cyclic benzotriazepin tautomer may exist in solution.

The aim of the present work was to study of the structure of the condensation products of aldoses with hydrazides of 2-hydroxybenzoic (2-HOC₆H₄CONHNH₂), 2-aminobenzoic (2-H₂NC₆H₄CONHNH₂), and N-methyl- N-2-aminobenzoic (2-H₂NC₆H₄CONMeNH₂) acids by ¹H- and ¹³C-NMR spectroscopy methods.

2. Results and Discussion

Compounds 1a-1j and 2a-2d were synthesized in yields 55% - 90% by heating equimolar amounts of the corresponding aldose (L-arabinose, D-ribose, L-rhamnose, D-galactose, D-glucose, D-mannose) and corresponding acylhydrazine: 2-hydroxybenzohydrazide, 2-aminobenzohydrazide, and N-methyl-N-(2-aminobenzo) hydrazide in boiling methanol for a period of 1 - 3 h (Figure 1, Figure 2 and Table 1).

In all experiments, the ¹H- and ¹³C-NMR spectra were recorded at definite time intervals starting from the moment of dissolution until the end of transformations. In addition, the structure of the compounds under study in the crystalline state was confirmed by solid-phase high-resolution ¹³C-NMR spectroscopy (CPMAS). For example, pyranose form B was expected to give a signal from the anomeric C-1 atom at δ 85 - 90 ppm; analogous signal from five-membered furanose tautomer C is located at δ 95 - 100 ppm [6] [7] . The C-1 signal of possible benzo-1,2,4-triazepin tautomer D should appear in a stronger field, at δ 70-75 ppm, which is typical of sp³-hybridized carbon atom in seven-membered ring, located between two nitrogen atoms [4] [5] . Hydrazone structure A should give rise to a downfield signal at δ 145 - 155 ppm (C=N) in the ¹³C-NMR spectrum. The for- mation of analogous seven-membered cyclic benzo-1,3,4-oxadiazepin tautomers for 2-hydroxybenzohydrazones 1a-1f via attack by the OH group on the C=N bond should be ruled out. It is known that condensation products

of 2-hydroxybenzohydrazide with aldehydes and ketones have exclusively linear structure and they do not tend to undergo the above cyclization [8] .

The ¹H- and ¹³C-NMR spectra of the condensation product of 2-hydroxybenzoic acid hydrazide with L-ara- binose 1a, recorded in DMSOd₆ immediately after dissolution, contained one set of signals corresponding to cyclic pyranose structure B. It is characterized by two downfield singlets at δ 10.22 and 12.20 ppm in the ¹H- NMR spectrum from protons in the NHCO group and phenolic OH group, respectively, and the sp³-hybridized C-1 atom gives a signal at δ 90.80 ppm in the ¹³C-NMR spectrum. Taking into account that the ¹H- and ¹³C-NMR spectra were recorded immediately after dissolution, i.e., possible tautomeric and configurational transformations had no time to occur, we presumed that the observed spectral parameters reflect the structure of compound 1a in the crystalline state. The ¹H- and ¹³C-NMR spectra of 1a changed with time, and signals assignable to the second stereoisomer of six-membered structure A, as well as to linear tautomer A and furanose structure C, appeared. Structure A is characterized by a doublet at δ 7.74 ppm in the ¹H-NMR spectrum from the N=CH azomethine proton and a signal at δ 155.05 ppm (C=N) in the ¹³C-NMR spectrum. The presence of five-membered furanose tautomer C in a solution of 1a in DMSOd₆ follows from the presence of signals at δ 84.63 (C-4) and 95.55 ppm (C-1) in the ¹³C-NMR spectrum. After some time, the NMR spectra of compound 1a no longer changed, indicating establishment of ring-chain-ring equilibrium. The equilibrium tautomer mixture consists of 45% of pyranose tautomer B, 30% of linear structure A, and 25% of furanose form C (Table 1).

Analogous pattern was observed for a solution of compound 1b (condensation product of 2-hydroxybenzo­hydrazide and D-ribose) in DMSOd₆; the fractions of structures A, B, and C in the equilibrium tautomer mixture of 1b differ insignificantly from those found for compound 1a. Unlike arabinose and ribose derivatives 1a and 1b, the condensation products 1c-1f derived from 2-hydroxybenzohydrazide and hexoses do not give rise to cyclic furanose form C. Compounds 1c-1f in the crystalline state have cyclic structure B. The cyclic pyranose structure of crystalline compound 1e (condensation product of 2-hydroxybenzohydrazide with glucose) was confirmed by its solid-phase ¹³C-NMR spectrum. In going to solutions in DMSOd₆, compounds 1c-1f undergo partial transformation into linear hydrazone tautomer A. Insofar as the fraction of the linear tautomer for all the examined condensation products of 2-hydroxybenzohydrazide with aldoses did not exceed 30% - 40%, the term “2-hydroxybenzoyl hydrazone” should be regarded as arbitrary as applied to such systems.

A single set of signals corresponding to cyclic pyranose form B is observed for the condensation product of 2-aminobenzohydrazide with L-arabinose 1g immediately after dissolution. As in the case of compound 1a, we may assume that the spectral data reflect the structure of compound 1g in the crystalline state. Sets of signals corresponding both to the five-membered furanose form C and linear aldosohydrazone form A gradually arise in the ¹³C-NMR spectrum in DMSOd₆. The ¹³C-NMR signal at δ 151.35 ppm for the C=N carbon is characteristic for linear form A (Table 1). One set of signals belonging to linear form A is observed in the ¹³C NMR spectrum of the 2-aminobenzohydrazide condensation product with ribose 1h taken immediately after dissolution. This finding suggests that compound 1h has the same structure in the crystalline state. After 2 days, sets of signals arise corresponding to the cyclic pyranose form B and furanose form C in the ¹³C-NMR spectrum of the solution. The ¹³C-NMR signal for atom C-1 at δ 88.13 ppm is characteristic for form C. The presence of the five-mem- bered furanose form C in ¹³C-NMR spectra of compounds 1g, 1h is indicated by the signals for C-4 and C-1 at δ 83 and 95 ppm, respectively. The spectrum of compound 1h stops changing after some time, indicating the establishment of a ring-chain equilibrium in which linear form A (60%) exists along with the cyclic pyranose B (25%) and furanose C forms (15%).

Thus, in contrast to the results of a study of El-Barbary et al. [1] on the structure of a series of 3,5-disubsti- tuted 2-aminobenzohydrazones of aldoses, in which the linear aldosohydrazone structure was adopted, we have shown that in the case of aldose 2-aminobenzoylhydrazones 1g, 1h, these compounds may convert to alternative cyclic pyranose and furanose forms, as well as both ring-chain and ring-linear-ring tautomeric equilibria are possible.

Going from arabinose derivative 1g and ribose derivative 1h to products of condensation with hexoses 1i, 1j is accompanied by disappearance of the cyclic furanose form C and linear aldosohydrazone form A from the equilibrium. In the crystalline state compounds 1i, 1j have pyranose structure B, while the ¹³C-NMR spectra indicate that these compounds in DMSOd₆ solution are represented by geometric a, b-isomers of this form.

Different behavior is found for compounds 2a-2d, which are the products of the condensation of aldoses with N-methyl-N-(2-aminobenzo)hydrazide (Figure 2). The change in the ¹³C-NMR spectra of all these products indicates that they have the cyclic benzo-1,2,4-triazepin structure D in the crystalline state. The ¹³C-NMR signal for atom C-1 at δ 75 - 80 ppm characteristic for sp³-hybridized carbon atom in a seven-membered ring attached to two nitrogen atoms [4] [5] is diagnostic for benzo-1,2,4-triazepin form D. Signals corresponding to a second configurational isomer of the benzo-1,2,4-triazepin form D’ are found in the ¹H- and ¹³C-NMR spectra of compounds 2a-2d in DMSOd₆. It was impossible to determine the 2R- or 2S-configuration of these derivatives. The ¹H- and ¹³C-NMR spectra of solutions of the aldoses condensation products with N-methyl-N-(2-aminobenzo)- hydrazide stop changing after 4 - 7 days, indicating that transition to the possible linear form A and cyclic pyranose form B does not occur. A tendency to cyclize with formation of a seven-membered benzo-1,2,4-triazepin ring through attack of the nitrogen atom at the C=N bond is a common feature of compounds 2a-2d.

3. Conclusion

The ability to undergo ring-chain or ring-chain-ring tautomeric transformation involving two different cyclic structures was found for the aldoses condensation products with 2-hydroxy- and 2-aminobenzohydrazides. The aldoses condensation products with N-methyl-N-(2-aminobenzo) hydrazide were found to strongly tend to form seven-membered benzo-1,2,4-triazepin form via intramolecular nucleophilic addition of the NH₂ group at the hydrazone C=N bond.

4. Experimental Part

¹Н- and ¹³С-NMR spectra in DMSOd₆ were registered on a spectrometer Bruker AV-400 at operating fre­quencies 400 and 100 MHz respectively (internal reference hexamethyldisiloxane). The solid-phase ¹³C-NMR spectra were obtained on a Bruker AM-500 spectrometer (125 MHz) using a standard procedure utilizing cross polarization and magic angle spinning (CPMAS) technique (frequency 4.5 kHz; internal reference hexamethyl­benzene). The tautomeric composition of obtained compounds was estimated by the integration of the appropriate signals in the ¹Н NMR spectra. Elemental analysis of newly obtained compounds was carried out on a CHN Analyzer Hewlett Packard 185B. The purity of prepared compounds was checked by TLC on Silufol UV-254 plates, eluent butanol-water-acetone, 8:1:1.

Synthesis of aldoses 2-hydroxy- and 2-aminobenzoylhydrazones (1a-1j) and (2a-2d). To a solution of 0.01 mol of 2-hydroxybenzohydrazide or 2-aminobenzohydrazide in 25 ml of methanol, 0.01 mol of an appro- priate aldose was added, and the mixture was boiled for a period of 1 - 3 h. The solvent was removed at a reduced pressure, the residue was washed with ether (3 × 50 ml), and the colorless crystalline substance was filtered off on a glass filter funnel (40 - 100 μm), dried and stored in a desiccator over P₂O₅.

4.1. L-Arabinose 2-Hydroxybenzoylhydrazone (1a)

Yield 65%, m.p. 191˚C - 192˚C (lit. [3] m.p. 191˚C). ¹H-NMR spectrum (DMSOd₆): δ = form A (30%): 7.74 (d, J = 4.4 Hz, HC=N), 11.60 (br.s, NHCO), 12.11 (br.s, OH); form α-B (20%): 10.22 (br.s, NHCO), 12.50 (br.s, OH); form β-B (25%): 10.22 (br.s, NHCO), 12.20 (br.s, OH); form α-C (25%): 10.35 (br.s, NHCO), 11.96 (br.s, OH) ppm. ¹³C-NMR spectrum (DMSOd₆): δ = form A: 63.88 (C-5), 65.52 (C-2), 70.29 (C-3), 71.13 (C-4), 155.05 (C-1), 159.50 (ArC-O), 165.33 (C=O); form α-B: 63.55 (C-5), 67.92 (C-4), 69.52 (C-3), 70.32 (C-2), 85.85 (C-1), 159.05 (ArC-O), 166.05 (C=O); form β-B: 65.30 (C-5), 69.01 (C-4), 72.35 (C-3), 73.65 (C-2), 90.80 (C-1), 159.31 (ArC-O), 166.65 (C=O); form α-C: 61.83 (C-5), 84.63 (C-4), 95.55 (C-1), 117.44 - 134.04 (Ar in A-C) ppm. Found, %: C 50.63; H 5.84; N 9.78. C₁₂H₁₆N₂O₆. Calculated, %: C 50.70; H 5.67; N 9.85.

4.2. D-Glucose 2-Hydroxybenzoylhydrazone (1e)

Yield 70%, m.p. 196˚C - 198˚C (lit. [3] m.p. 198˚C). ¹H-NMR spectrum (DMSOd₆): δ = form A (5%): 7.76 (d, J = 4.6 Hz, HC=N), 11.60 (br.s, NHCO), 11.95 (br.s, OH); form α-B (30%): 10.09 (br.s, NHCO), 12.00 (br.s, OH); form β-B (65%):10.22 (br.s, NHCO), 11.87 (br.s, OH) ppm. ¹³C-NMR spectrum (solid phase): δ = form β-B (100%): 59.70 (C-6), 68.23 (C-4), 69.04 (C-2), 74.96 (C-5), 79.24 (C-3), 90.93 (C-1), 112.50, 118.91, 120.57, 128.66, 136.71 (Ar), 160.44 (ArC-O), 172.12 (C=O) ppm. ¹³C-NMR spectrum (DMSOd₆): δ = form A: 63.50 (C-6), 159.47 (ArC-O); form α-B: 60.95 (C-6), 70.22 (C-4), 71.15 (C-5), 71.25 (C-2), 73.72 (C-3), 87.98 (C-1), 159.00 (ArC-O), 166.95 (C=O); form β-B: 61.42 (C-6), 70.50 (C-4), 71.55 (C-2), 76.85 (C-5), 78.18 (C-3), 91.05 (C-1), 158.55 (ArC-O), 166.95 (C=O), 114.37-135.26 (Ar in A and B) ppm. Found, %: C 49.62; H 5.80; N 8.96. C₁₃H₁₈N₂O₇. Calculated, %: C 49.68; H 5.77; N 8.91.

4.3. L-Arabinose 2-Aminobenzoylhydrazone (1g)

Yield 75%, m.p. 189˚C - 191˚C. ¹³C-NMR spectrum (DMSOd₆): δ = form A (25%): 63.78 (C-5), 68.98 (C-2), 70.80 (C-3), 71.17 (C-4), 151.35 (C-1), 147.22 (ArC-N), 165.69 (C=O); form β-B (65%): 65.08 (C-5), 69.05 (C-4), 72.75 (C-3), 73.65 (C-2), 89.13 (C-1), 145.33 (ArC-N), 168.74 (C=O); form α-C (10%): 61.82 (C-5), 76.89 (C-3), 78.81 (C-2), 85.53 (C-4), 95.94 (C-1), 145.80 (ArC-N), 168.01 (C=O), 114.67 - 147.22 (Ar in A-C) ppm. Found, %: C 57.71; H 5.76; N 13.39. C₁₂H₁₇N₃O₅. Calculated, %: C 57.67; H 5.81; N 13.45.

4.4. L-Arabinose N-Methyl-N-(2-Aminobenzoyl)Hydrazone (2a)

Yield 50%, m.p. 168˚C - 171˚C. ¹³C-NMR spectrum (DMSOd₆): δ = form D (65%): 38.35 (CH₃), 63.96 (C-5), 65.35 (C-2), 70.21 (C-3), 71.52 (C-4), 75.37 (C-1), 145.42 (ArC-N), 172.33 (C=O); form D’ (35%): 38.60 (CH₃), 63.75 (C-5), 65.35 (C-2), 70.30 (C-3), 71.52 (C-4), 76.88 (C-1), 145.50 (ArC-N), 172.15 (C=O), 117.65 - 145.50 (Ar in D and D’) ppm. Found, %: C 52.59; H 6.50; N 14.06. C₁₃H₁₉N₃O₅. Calculated, %: C 52.52; H 6.44; N 14.13.

Spectral characteristics of compounds 1b, 1c, 1d, 1f , and 2b-2d were described in works [6] [7] .

Acknowledgements

This work received financial support from the Ministry of Education and Science of Russian Federation (contract 14.574.21.0002, No. RFMEFI57414X0002).

Cite this paper

Igor V. Lagoda,Andrei Yu Ershov,Stanislav I. Yakimovich,Marina Yu Vasileva,Valery A. Polukeev,Ludmila Yu Kuleshova,Irina S. Korovina,Valery V. Shamanin, (2016) Structure of Aldoses Condensation Products with 2-Hydroxy- and 2-Aminobenzohydrazides. Open Access Library Journal,03,1-6. doi: 10.4236/oalib.1102636

References

NOTES

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