6. Doktorat z chemii organicznej

 Promotorem mojej pracy doktorskiej na Wydziale Chemicznym Politechniki Śląskiej był nieodżałowanej pamięci prof. Jerzy Suwiński. Recenzentami byli, prof. Wojciech Zieliński oraz prof. Andrzej Maślankiewicz. Wykonanie badań do doktoratu oraz jego napisanie to była dla mnie przygoda naukowa o niezwykłej wartości merytorycznej i intelektualnej. Obrona odbyła się w czerwcu 1994 roku, tuż po śmierci mojego Ojca. 

Poniżej znajduje się telegraficzny skrót zagadnień chemicznych, które zajmowały mnie w doktoracie i przyniosły mi stopień doktora inżyniera nauk chemicznych. 

Reactions of 1,4-Dinitroimidazoles with Compounds Containing

a Primary Amino-Group 

1. 1,4-Dinitroimidazoles react with selected primary amines to give 1-alkyl-substituted-4-nitroimidazoles:

2. Conditions were very mild in these reactions: 

• Room temperature
• Water or water-methanol solution (or disspersion)
• pH range = 7 - 9.5
• Reaction time from minutes to hours
• Products were usually obtained as precipitates
• Yields were from moderate to high 

3. Scope of products obtained.

3.1. 1,4-Dinitroimidazole (or its 2-methyl- or 5-methyl derivative) reacts with primary aliphatic amines to give 1-alkyl-4-nitroimidazoles. Decreasing of pH level is compensed by addition of 1M potassium hydroxide solution during the reacton, eg:

3.2. 1,4-Dinitroimidazole (or its 2-methyl derivative) reacts with alpha-aminoacids in weak alkaline solution to give α-(4-nitroimidazol-1-yl)alkanecarboxylic acids after acidification with conc. HCl, eg:

Besides histidine, there were used: Gly, (S)-Val, (S)-Asp, (R,S)-Asn, (S),(R,S)-Phe, (S)-Thyr, (R),(S),(R,S)-Ala, (S)-His, (R,S)-Glu and (R,S)-Trp.

α-(4-nitroimidazol-1-yl)alkanecarboxylic acid esthers were obtained in the reaction of 1,4-dinitroimidazoles (14DNI) with α-aminoacid methyl (or ethyl) esther hydrochlorides after addition of sodium bicarbonate to water-methanol suspension of substrates at 0 °C: Besides histidine, there were used methyl esters of: Gly, (R),(S),(R,S)-Ala, [2(R,S),3(R,S)]-Thr, (S)-Ser, (S)-Ileu, (S)-Tyr, (S)-Val, (S)-Phe.

2-Methyl-1,4-initroimidazole reacts with dipeptides under conditions similar to the reaction of 1,4dinitroimidazoles with α-aminoacids. Dipeptide used: Gly-Gly, Gly-(R,S)-Ala, (R,S)-Ala-(R,S)-Ala, Gly-(S)-Ala, (R)-Ala-(R)-Ala (S)-Ala-(S)-Ala, (S)-Ala-Gly.

3.3. 1,4-Dinitroimidazoles react with various anilines to give 1-aryl-4-nitroimidazoles in water-methanol suspension (eventualy with the addition of Britton-Robinson buffer, pH  7): 

R = 2-COOH, 3-COOH, 4-COOH, 4-COOEt, 3-OH, 4-SO₃K, 4-SO₂NH₂.

3.4. 1,4-Dinitroimidazoles react with aminopyridines in two ways:

3.4.1. 2-(or 3)-Aminopyridines give pyrid-2-(or3)-yl-4-nitroimidazoles e.g.: 

3.4.2. With 4-aminopyridine the reaction runs via the cine-substitution:

 3.5. Unusual reaction of 2-methyl-1,4-dinitroimidazole with hydrazine leads to an expansion of the imidazole ring. A derivative of 1,2,4-triazine is formed with an N-N bridge between either triazine rings. This derivative was obtained as a dihydrate of p-toluenesulfonate salt (see an X-ray spectrum):

3.6. In the reaction of 1,4-dinitroimidazoles with t-butoxycarbonylhydrazine (an example of N-monosubstituted hydrazine) the imidazole ring is crashed, and glyoxal dihydrazones are formed:

3.7. A reaction of 1,4-dinitroimidazole with N-aminomorpholine gives two main products, expected ANRORC product and the unexpected product of oxidation of the hydrazine moiety to form the unusual four membered nitrogen chain:

3.8. Other interesting products obtained in the reaction of 1,4-dinitroimidazoles with α-amino-ε-caprolactam or with 4-AMINOTEMPO radical.

3.9. Sepctacular reactions of 1,4-dinitroimidazoles with compounds containing a primary amino-group: Reactons of 1,4-dinitroimidazoles with chiral aminoacids give chiral products wirh retention of chirality:

3.10. Reactions of 1,4-dinitroimidazoles with [¹⁵N]Glycine give products containing [¹⁵N]isotope in the 1-position of the imidazole ring:

3.11. The plausible mechanism consists of: the Addition of Nucleophile (here the primary amino compound) to 1,4-dinitroimidazole, Ring Opening of the imidazole moiety, Ring Closure, and finally the rearomatization reaction with the elimination of nitroamide (so called ANRORC type mechanism):

References:

1. J. Suwiński, W. Szczepankiewicz, „Nitroimidazoles. Part XII. Reactions of 1,4-dinitroimidazoles with aminopyridines”, Polish. J. Chem., 1991, 65, 515-518.

2. J. Suwiński, W. Szczepankiewicz, „Synthesis of methyl esters of (2S or 2R) 2-(4-nitro-1-3imidazolyl)alkanecarboxylic acids”, Tetrahedron: Asymm., 1991, 2, 941-942.

3. J. Suwinski, W. Szczepankiewicz, „Synthesis of (2-methyl-4-nitro-1-[¹⁵N]imidazolyl)acetic acid”, J. Labell. Compd. Radiopharm., 1992, 31, 159-162.

4. J. Suwinski, W. Szczepankiewicz, M Widel, „Nitroimidazoles, XIV: Synthesis of 4-nitroimidazoles with 1-substituent containing acid, ester or phenol functions, and radiosensitizing efficiency of some of these compounds” Arch. Pharm. (Weinheim), 1992, 325, 317-324.

5. H. Llempen, E. Salwińska, J. Suwiński, W. Szczepankiewicz, „Nitroimidazoles. Part XV. Reactions of 1,4-dinitroimidazoles with aromatic amines”, Polish J. Chem., 1992, 66, 943-950.

6. H. Llempen, E. Salwińska, J. Suwiński, W. Szczepankiewicz, E. Dziwiński, „Nitroimidazoles. Part XVIII. EI Mass Spectrometry of 1-Aryl-4-nitroimidazoles in Standard Conditions”, Polish J. Chem., 1993, 67, 1745-1753.

7. J. Suwiński, W. Szczepankiewicz, „Synthesis of 2-methyl-4(5)nitro[¹⁵N1(3)]imidazole from 2-methyl-4(5)-nitroimidazole”, J. Labell. Comp. Radiopharm., 1996, 38, 395-401.

8. J. Suwiński, W. Szczepankiewicz, E. M. Holt, „Reactions of 1,4-Dinitroimidazoles with Hydrazines”, Tetrahedron, 1996, 52, 14905-14916.