Cyclobutanecarboxylic acid
[CAS 3721-95-7]

Identification

• Classification: Organic raw materials >> Carboxylic compounds and derivatives
• Name: Cyclobutanecarboxylic acid
• Molecular Formula: C₅H₈O₂
• Molecular Weight: 100.12
• CAS Registry Number: 3721-95-7
• EC Number: 223-072-7
• SMILES: C1CC(C1)C(=O)O

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*, 1.047 g/mL (Expl.)
• Melting point: -7.5 °C (Expl.)
• Boiling point: 195.3±8.0 °C 760 mmHg (Calc.)^*, 195 °C (Expl.)
• Flash point: 83.9 °C (Calc.)^*, 83 °C (Expl.)
• Index of refraction: 1.502 (Calc.)^*, 1.444 (Expl.)

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

Safety Data

• Hazard Symbols: GHS05;GHS07 Danger
• Risk Statements: H302-H312-H314-H318-H332
• Safety Statements: P260-P261-P264-P264+P265-P270-P271-P280-P301+P317-P301+P330+P331-P302+P352-P302+P361+P354-P304+P340-P305+P354+P338-P316-P317-P321-P330-P362+P364-P363-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin corrosion	Skin Corr.	1B	H314
Acute toxicity	Acute Tox.	4	H332
Acute toxicity	Acute Tox.	4	H312
Acute toxicity	Acute Tox.	4	H302
Serious eye damage	Eye Dam.	1	H318
Specific target organ toxicity - single exposure	STOT SE	3	H335
Substances or mixtures corrosive to metals	Met. Corr.	1	H290
Skin corrosion	Skin Corr.	1C	H314
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Chronic hazardous to the aquatic environment	Aquatic Chronic	4	H413

chemBlink Chemical Story

Cyclobutanecarboxylic acid, CAS 3721-95-7, is a small cyclic carboxylic acid used as a building block in organic synthesis and medicinal chemistry. Its molecular formula is C₅H₈O₂ and its molecular weight is 100.12. Structurally, the compound consists of a four-membered cyclobutane ring bearing a carboxylic acid group. This simple combination provides two useful features in one molecule: a compact, conformationally restricted carbon framework and a carboxyl group that can be readily converted into many other functional groups.

Cyclobutane occupies an interesting position among the small carbon rings. Cyclopropane forces three carbon atoms into a triangle with bond angles close to 60°, producing exceptionally high angle strain. Adding one carbon atom creates cyclobutane, but this does not produce an ordinary strain-free ring. A planar square would require carbon-carbon-carbon angles near 90°, still far from the preferred tetrahedral angle of approximately 109.5°.

Cyclobutane responds to this problem in a clever way: it does not normally remain perfectly planar. Instead, the ring adopts a puckered or folded conformation. This movement reduces unfavorable eclipsing interactions between neighboring C-H bonds, although it cannot eliminate the substantial angle strain imposed by the four-membered ring.

The result is a useful compromise between strain and stability. Cyclobutane contains considerably more strain than larger cycloalkanes, yet the ring is stable enough to be isolated, stored, chemically modified, and incorporated intact into complex molecules. This combination has made cyclobutane chemistry important both in fundamental studies of molecular structure and in practical synthesis.

In Cyclobutanecarboxylic acid, the carboxyl group provides the main synthetic handle. Like other carboxylic acids, it can be converted into esters, amides, acid chlorides, and related derivatives. Reduction can transform the carboxyl group into other oxidation states, while decarboxylative and coupling chemistry can use it as an entry point to additional carbon-carbon or carbon-heteroatom bond formation.

This makes the compound useful as a source of the cyclobutylcarbonyl or related cyclobutane-containing fragment. Instead of constructing a strained four-membered ring late in a complicated synthesis, chemists can begin with a molecule in which that difficult structural feature already exists and use the carboxyl group to connect it to the rest of the target molecule.

This strategy has become increasingly relevant in medicinal chemistry. Drug molecules were historically dominated by flat aromatic rings because aromatic compounds are synthetically accessible and easy to diversify. Modern medicinal chemistry has increasingly explored saturated, three-dimensional fragments as a way to expand molecular shape and reduce excessive dependence on planar aromatic structures.

Small rings are particularly attractive for this purpose. A cyclobutane can place several carbon atoms into a compact region of space while restricting rotation. Attaching a substituent to the ring therefore creates a geometry quite different from that produced by a flexible open-chain butyl group.

The difference is not merely visual. Molecular conformation influences how functional groups are presented to a biological target. Restricting flexibility can alter binding affinity, selectivity, lipophilicity, solubility, and susceptibility to metabolic transformation. No single effect is guaranteed, but these possibilities explain why cyclobutane-containing building blocks are frequently explored during optimization of biologically active molecules.

Cyclobutanecarboxylic acid is especially convenient because the carboxyl group can form amide bonds. Amide formation is one of the most widely used transformations in medicinal chemistry. Coupling this acid with different amines provides a straightforward route to families of cyclobutanecarboxamides in which the strained ring is retained while the remainder of the molecule is systematically varied.

The four-membered ring also offers opportunities for further substitution. Chemists can prepare derivatives carrying additional groups at other positions of the cyclobutane, creating cis and trans relationships and introducing stereochemical information into otherwise compact structures. In this way, the cyclobutane ring can serve not merely as a hydrophobic spacer but as a small three-dimensional platform for arranging substituents.

Ring strain, however, means that cyclobutane chemistry can also behave differently from ordinary acyclic chemistry. Under appropriate conditions, reactions can exploit the stored energy of the strained ring to promote ring opening, ring expansion, or skeletal rearrangement. Whether the ring is preserved or deliberately broken depends on the synthetic objective and reaction conditions.

This dual character is one reason small-ring chemistry is so useful. The cyclobutane ring can be treated as a stable structural element when the desired molecule requires it, yet its strain can also become a source of reactivity when chemists want to transform the carbon framework.

Cyclobutanecarboxylic acid itself is a liquid under ordinary laboratory conditions. Reference data report a boiling point around 195 °C and a melting point below room temperature. Commercial specifications describe it as a clear, colorless to pale-yellow liquid. These ordinary physical properties contrast with the unusual geometry stored inside its four-membered carbon ring.

The compound therefore illustrates an important principle of molecular design. Adding a single carbon atom to cyclopropane does much more than enlarge a ring. The geometry, conformational behavior, strain, and three-dimensional presentation of substituents all change.

For synthetic and medicinal chemists, Cyclobutanecarboxylic acid packages this unusual four-membered geometry together with one of organic chemistry's most versatile functional groups. The cyclobutane supplies shape; the carboxylic acid supplies connectivity. Together they make a deceptively simple five-carbon molecule into a useful starting point for building considerably more complex structures.

References

1. NIST Chemistry WebBook. Cyclobutylcarboxylic acid, CAS 3721-95-7. Molecular formula C₅H₈O₂; molecular weight 100.1158.
https://webbook.nist.gov/cgi/cbook.cgi?ID=C3721957

2. PubChem. Cyclobutanecarboxylic acid, CID 19494. Chemical identity and physicochemical information.
https://pubchem.ncbi.nlm.nih.gov/compound/Cyclobutanecarboxylic-acid

3. Wiberg, K. B. Studies of strain energies, structures, and bonding in small-ring cycloalkanes.

4. Liebman, J. F.; Greenberg, A. (eds.). Molecular Structure and Strain. Studies of structural and energetic effects in strained organic molecules.

5. Lovering, F.; Bikker, J.; Humblet, C. (2009). "Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success." Journal of Medicinal Chemistry, 52, 6752-6756.