6-Chlorouracil
[CAS 4270-27-3]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound >> Urinary (urea) pyrimidine
• Name: 6-Chlorouracil
• Synonyms: 6-Chloro-2,4-(1H,3H)-pyrimidinedione; 4-Chloro-2,6-dihydroxypyrimidine
• Molecular Formula: C₄H₃ClN₂O₂
• Molecular Weight: 146.53
• CAS Registry Number: 4270-27-3
• EC Number: 224-258-0
• SMILES: C1=C(NC(=O)NC1=O)Cl

Properties

• Density: 1.6±0.1 g/cm³ Calc.^*
• Melting point: 295 °C (Decomposes) (Expl.)
• Index of refraction: 1.587 (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
Acute toxicity	Acute Tox.	4	H302

chemBlink Chemical Story

6-Chlorouracil, CAS 4270-27-3, is a halogenated derivative of uracil used primarily as an intermediate in heterocyclic, nucleoside, and medicinal chemistry. Its molecular formula is C₄H₃ClN₂O₂ and its molecular weight is 146.53. Structurally, it retains the pyrimidine-2,4-dione framework of uracil but carries a chlorine atom at the 6-position. This apparently simple substitution turns a familiar nucleobase skeleton into a much more versatile synthetic platform. :contentReference[oaicite:1]{index=1}

Uracil is one of the canonical pyrimidine nucleobases of RNA. Its ring contains two nitrogen atoms and two carbonyl groups arranged in a six-membered heterocycle. In biological systems, uracil is incorporated into RNA as the nucleoside uridine after attachment to ribose. 6-Chlorouracil is not itself a natural nucleobase, but it preserves much of the same heterocyclic framework while introducing a carbon-chlorine bond that can be selectively transformed.

The chlorine atom at the 6-position is the key synthetic feature. In electron-deficient pyrimidine systems, chlorine can serve as a leaving group in nucleophilic aromatic substitution. This means that amines, hydrazine, and other nucleophiles can replace chlorine and install new nitrogen- or carbon-containing functionality directly onto the uracil ring.

One particularly well documented transformation is reaction with hydrazine. Published work on fused uracils describes nucleophilic substitution of 6-chlorouracil derivatives with hydrazine hydrate to give 6-hydrazinyluracils. These hydrazino intermediates can then react with additional carbonyl compounds and undergo cyclization, producing more complex fused nitrogen heterocycles such as pyrimidopyridazines and pyrazolopyrimidines. :contentReference[oaicite:2]{index=2}

This sequence illustrates an important principle of heterocyclic synthesis. The chlorine atom is not intended to remain in the final molecule. It acts as a temporary synthetic handle marking one specific carbon atom on the pyrimidine ring. Once a nucleophile replaces chlorine, the newly introduced functional group can become the starting point for an entirely new ring.

In this sense, 6-chlorouracil is a partially activated version of uracil. The parent nucleobase is chemically stable and biologically familiar, whereas the 6-chloro derivative is deliberately equipped with a position that synthetic chemists can manipulate. The rest of the uracil framework can remain intact while the 6-position is diversified.

This has made 6-chlorouracil useful in the preparation of substituted uracils. Alkylation at the ring nitrogens, followed by nucleophilic substitution at C-6, allows chemists to vary several parts of the molecule independently. Such flexibility is particularly valuable in medicinal chemistry, where families of closely related analogues are synthesized to determine how small structural changes affect biological activity.

A notable example appeared in 2007, when Nencka and coworkers reported a series of 5-substituted-6-chlorouracils as inhibitors of human thymidine phosphorylase. Thymidine phosphorylase is an enzyme involved in pyrimidine nucleoside metabolism. The study showed that appropriately substituted 6-chlorouracil derivatives could bind efficiently to the enzyme, demonstrating that the chlorine-containing uracil framework can itself be part of a biologically active molecular design rather than merely a transient synthetic intermediate. :contentReference[oaicite:3]{index=3}

This distinction is important. 6-Chlorouracil itself should not automatically be described as an established therapeutic agent or as possessing the activity of every derivative prepared from it. Biological properties depend strongly on substitution around the uracil ring. The medicinal-chemistry value of the scaffold lies in allowing those substitutions to be explored systematically.

The compound has also been used in nucleoside chemistry. Coupling halogenated pyrimidine bases to protected ribose derivatives provides routes to halogenated uridines and related nucleoside analogues. This chemistry is challenging because pyrimidine bases contain more than one nitrogen that can potentially react, so controlling which nitrogen forms the glycosidic bond is an important synthetic problem.

A 2017 study specifically examined the regiospecific synthesis of 6-halouridine derivatives and noted that direct ribosylation of 6-chlorouracil can favor undesired N-3 attachment. The researchers therefore developed methods to control the coupling and obtain the desired nucleoside regioisomer. This example shows that a seemingly small modification such as chlorine at C-6 can influence not only what reactions are possible but also where those reactions occur. :contentReference[oaicite:4]{index=4}

The relationship between 6-chlorouracil and uracil also highlights the importance of halogens in synthetic design. Chlorine can influence electron distribution within the heterocycle, but more importantly, it can act as a replaceable atom. Chemists often use halogens in precisely this way: not because the halogen itself is the final objective, but because it provides a predictable site for further bond formation.

This strategy is especially powerful in heterocyclic chemistry. Once a complex ring has been assembled, rebuilding it merely to change one substituent would be inefficient. A halogenated intermediate allows the core ring to be prepared once and then diversified at a selected position by substitution or coupling chemistry.

6-Chlorouracil therefore occupies an interesting position between biological chemistry and synthetic chemistry. Its parent compound, uracil, belongs to the molecular vocabulary of life. Adding one chlorine atom converts that stable biological scaffold into a versatile laboratory intermediate that can be transformed into substituted uracils, fused heterocycles, and nucleoside analogues.

The molecule demonstrates how little structural change may be required to alter the role of a compound completely. Uracil is primarily a biological building block. 6-Chlorouracil is primarily a synthetic one. The difference is one chlorine atom, but that atom creates a new point of access through which chemists can redesign the pyrimidine ring.

References

1. NIST Chemistry WebBook. 6-Chlorouracil, CAS 4270-27-3. Molecular formula C₄H₃ClN₂O₂; molecular weight 146.532.
https://webbook.nist.gov/cgi/cbook.cgi?ID=C4270273

2. Nencka, R.; Votruba, I.; Hrebabecky, H.; Jansa, P.; Tloust'ova, E.; Horska, K.; Masojidkova, M.; Holy, A. (2007). "Discovery of 5-Substituted-6-chlorouracils as Efficient Inhibitors of Human Thymidine Phosphorylase." Journal of Medicinal Chemistry, 50, 6016-6023.
https://doi.org/10.1021/jm070644i

3. El-Kalyoubi, S. A. M.; Agili, F. (2016). "A Novel Synthesis of Fused Uracils: Indenopyrimidopyridazines, Pyrimidopyridazines, and Pyrazolopyrimidines for Antimicrobial and Antitumor Evaluation." Molecules, 21, 1714.
https://doi.org/10.3390/molecules21121714

4. Blackburn, D. J.; Kent, G. T.; Wu, W. (2017). "Regiospecific synthesis of 6-halouridine derivatives: An effective method for coupling sterically hindered pyrimidine bases to ribose." Tetrahedron Letters.
https://doi.org/10.1016/j.tetlet.2017.04.024