6-Chloro-3-methyluracil
[CAS 4318-56-3]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound >> Urinary (urea) pyrimidine
• Name: 6-Chloro-3-methyluracil
• Synonyms: 3-Methyl-6-chlorouracil
• Molecular Formula: C₅H₅ClN₂O₂
• Molecular Weight: 160.55
• CAS Registry Number: 4318-56-3
• EC Number: 610-113-2
• SMILES: CN1C(=O)C=C(NC1=O)Cl

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*
• Melting point: 278 - 280 (Decomposes) °C (Expl.)
• Index of refraction: 1.581 (Calc.)^*

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

Safety Data

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

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2A	H319
Skin sensitization	Skin Sens.	1	H317

Discovery and Applications

6-Chloro-3-methyluracil is a halogenated and alkylated derivative of uracil, a naturally occurring pyrimidine nucleobase. It belongs to the class of substituted pyrimidine-2,4-diones and contains a six-membered aromatic heterocycle with two ring nitrogen atoms and two carbonyl groups. The compound is structurally related to nucleic acid bases but is chemically modified through chlorine substitution and N-methylation.

The core structure is the uracil ring system, which is a planar, conjugated pyrimidine heterocycle containing nitrogen atoms at the 1 and 3 positions and carbonyl groups at the 2 and 4 positions. This arrangement creates a strongly polarized system in which the carbonyl oxygens act as hydrogen-bond acceptors and the ring nitrogens can participate in tautomeric equilibria under certain conditions.

In 6-chloro-3-methyluracil, a chlorine atom is attached at the 6-position of the pyrimidine ring. Chlorine is an electron-withdrawing substituent through inductive effects and influences the electron density distribution of the heterocycle. This substitution also increases the chemical reactivity of the C6 position toward nucleophilic substitution reactions, a common feature of halogenated pyrimidines used in synthetic chemistry.

The second modification is methylation at the N3 position of the uracil ring. The N-methyl group replaces the hydrogen atom normally present at this position, forming an N–CH3 bond. This substitution reduces hydrogen-bond donating capability at that nitrogen atom and alters the tautomeric behavior of the uracil system. N-methylation also increases hydrophobic character relative to unsubstituted uracil.

The uracil ring system remains aromatic in the sense of a conjugated planar π-electron network, stabilized by resonance between carbonyl and ring nitrogen atoms. The carbonyl groups at positions 2 and 4 are highly polarized, with significant electron density on oxygen atoms, making them key sites for hydrogen bonding and dipolar interactions.

From a structural perspective, the molecule is largely planar due to the conjugation within the pyrimidine ring and the partial double-bond character of the C–N bonds. This planarity is important for its potential interactions with biological systems, particularly nucleic acid-related environments, although the specific substitutions significantly alter its natural base-pairing behavior.

Physicochemically, 6-chloro-3-methyluracil exhibits moderate polarity. The carbonyl groups and ring nitrogens contribute hydrophilicity and hydrogen-bonding capacity, while the methyl and chloro substituents introduce hydrophobic and lipophilic elements. The overall balance results in limited water solubility compared with unsubstituted uracil.

Chemically, the most reactive site is typically the carbon at position 6 bearing the chlorine substituent. Halogenated pyrimidines are known to undergo nucleophilic substitution reactions, particularly in the presence of strong nucleophiles, where chlorine can act as a leaving group. The carbonyl groups are relatively stable but participate in tautomeric equilibria and hydrogen bonding interactions.

The N3-methyl substitution stabilizes the molecule against tautomerization at that nitrogen site and reduces its ability to participate in hydrogen bonding as a donor, which can influence both chemical reactivity and biological recognition.

Overall, 6-chloro-3-methyluracil is a substituted pyrimidine derivative based on the uracil scaffold, featuring a chlorine atom at position 6 and a methyl group on N3. These modifications alter its electronic properties, hydrogen-bonding behavior, and chemical reactivity while maintaining the fundamental planar heteroaromatic structure characteristic of pyrimidine nucleobases.

References

2024. Synthesis, design, biological evaluation, and computational analysis of some novel uracil-azole derivatives as cytotoxic agents. BMC Chemistry.
DOI: 10.1186/s13065-023-01106-x

2023. Developments of pyridodipyrimidine heterocycles and their biological activities. Molecular Diversity.
DOI: 10.1007/s11030-023-10623-9

2023. Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells. Biochemical and Biophysical Research Communications.
DOI: 10.1016/j.bbrc.2023.08.050