6-Aza-2-thiothymine
[CAS 615-76-9]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound
• Name: 6-Aza-2-thiothymine
• Synonyms: 6-methyl-3-sulfanylidene-2H-1,2,4-triazin-5-one
• Molecular Formula: C₄H₅N₃OS
• Molecular Weight: 143.17
• CAS Registry Number: 615-76-9
• EC Number: 210-445-4
• SMILES: CC1=NNC(=S)NC1=O

Properties

• Density: 1.6$+/-$0.1 g/cm³ Calc.^*
• Melting point: 218 - 221 $degree$C (Expl.)
• Index of refraction: 1.749 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H312-H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P270-P271-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P317-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Eye irritation	Eye Irrit.	2A	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335
Skin irritation	Skin Irrit.	2	H315
Acute toxicity	Acute Tox.	4	H312

Discovery and Applications

6-Aza-2-thiothymine is a heterocyclic pyrimidine derivative belonging to the class of thiopyrimidines, in which a sulfur atom replaces the oxygen atom at the 2-position of the pyrimidine-2,4-dione (thymine-like) framework, and one ring carbon is replaced by nitrogen at the 6-position (“aza” substitution). Its structure is based on a modified pyrimidine ring system containing multiple heteroatoms that significantly influence its electronic and hydrogen-bonding properties.

The core scaffold is derived from the thymine family of nucleobases, which are naturally occurring pyrimidine derivatives found in DNA. In 6-aza-2-thiothymine, the canonical thymine structure is altered in two ways: first, the oxygen atom at the 2-position is replaced by sulfur, forming a thione (C=S) functionality; second, the carbon atom at position 6 of the ring is replaced by a nitrogen atom, introducing additional heteroaromatic character. These modifications change both the tautomeric behavior and hydrogen-bonding pattern of the molecule.

The presence of the 2-thione group (C=S) instead of a carbonyl group (C=O) significantly affects the chemical properties of the compound. Sulfur is larger and less electronegative than oxygen, resulting in weaker hydrogen-bond accepting ability but increased polarizability. This substitution also alters tautomeric equilibria between thione and thiol forms, although the thione form is typically dominant.

The “6-aza” substitution introduces an additional nitrogen atom into the heterocyclic ring system. This modification affects electron distribution in the ring, increasing its electron deficiency and altering its acidity and coordination behavior. The additional nitrogen can participate in hydrogen bonding and may influence stacking interactions in nucleic acid-related systems.

Compounds of this type are of interest in nucleic acid chemistry and medicinal chemistry because modified nucleobase analogues can mimic or interfere with natural base pairing. Structural modifications such as sulfur substitution and ring nitrogen incorporation can alter hydrogen-bonding patterns with complementary bases, affecting recognition and pairing behavior.

From a chemical perspective, 6-aza-2-thiothymine can undergo typical reactions of thiopyrimidines, including oxidation of the thione group, alkylation at sulfur or nitrogen sites, and tautomerization under different pH conditions. The heteroaromatic ring system is electronically activated toward substitution and coordination reactions.

The compound can participate in hydrogen bonding both as a donor (via NH groups) and as a weak acceptor (via sulfur and ring nitrogens). These properties make it relevant in studies of molecular recognition, supramolecular chemistry, and nucleobase analog interactions.

Synthesis of thiopyrimidine derivatives generally involves cyclization of appropriate urea or thiourea precursors with carbonyl-containing reagents, followed by functional group modifications to introduce specific substitutions such as nitrogen incorporation at ring positions. The introduction of “aza” substitution typically requires pre-functionalized heterocyclic intermediates or ring transformation strategies.

From a physicochemical standpoint, 6-aza-2-thiothymine is expected to be polar due to the presence of multiple heteroatoms (nitrogen, sulfur, oxygen equivalents in functional analogs), and capable of strong intermolecular hydrogen bonding. These interactions influence its solid-state structure and solubility behavior in polar solvents.

Historically, modified pyrimidine bases such as thiothymine analogs have been studied in the context of nucleic acid chemistry, enzyme inhibition, and the development of nucleobase analogs for biochemical and pharmacological research. Such compounds help probe the role of hydrogen bonding and electronic structure in genetic base pairing.

Overall, 6-aza-2-thiothymine is a heteroatom-modified pyrimidine derivative featuring a thiocarbonyl group and an additional ring nitrogen. Its altered electronic structure and hydrogen-bonding characteristics distinguish it from natural thymine and make it of interest in nucleobase analog research, heterocyclic chemistry, and molecular recognition studies.

References

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DOI: 10.1007/s00604-025-07668-y

2025. Ultrasensitive detection of imidacloprid in fruits and vegetables using a lateral flow immunoassay based on highly luminescent Au nanoclusters. Analytical and Bioanalytical Chemistry.
DOI: 10.1007/s00216-025-06118-1

2025. Aptamer-regulated colorimetric and electrochemical dual-mode sensor for the detection of uranyl ions utilizing AuNCs@COF composite. Microchimica Acta.
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