Methyl 3,3-difluorocyclobutanecarboxylate
[CAS# 1234616-13-7]

Identification

• Classification: Chemical reagent >> Organic reagent >> Ester >> Acid ester compound
• Name: Methyl 3,3-difluorocyclobutanecarboxylate
• Synonyms: 3,3-Difluorocyclobutanecarboxylic acid methyl ester
• Molecular Formula: C₆H₈F₂O₂
• Molecular Weight: 150.12
• CAS Registry Number: 1234616-13-7
• SMILES: COC(=O)C1CC(C1)(F)F

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Boiling point: 130.2±40.0 °C 760 mmHg (Calc.)^*
• Flash point: 32.5±22.2 °C (Calc.)^*
• Index of refraction: 1.396 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS02;GHS07 Danger
• Risk Statements: H315-H319-H225
• Safety Statements: P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P337+P313-P305+P351+P338-P362+P364-P303+P361+P353-P332+P313-P403+P235
• Transport Information: UN 1993

Discovery and Applications

Methyl 3,3-difluorocyclobutanecarboxylate is an organofluorine compound with the molecular formula C₆H₈F₂O₂. It belongs to the class of difluorinated cyclobutane derivatives and features a four-membered cyclobutane ring substituted with two fluorine atoms at the 3-position and a methyl ester group at the 1-position. The incorporation of fluorine atoms into small-ring systems like cyclobutane imparts unique physicochemical properties and makes such compounds valuable intermediates in pharmaceutical and agrochemical research.

The synthesis of methyl 3,3-difluorocyclobutanecarboxylate typically involves difluorocyclopropanation reactions or fluorinated precursor transformations. One established method includes the reaction of 3,3-difluorocyclobutanecarboxylic acid with methanol in the presence of acid catalysts to form the methyl ester via Fischer esterification. Alternatively, a cyclobutane ring can be constructed using difluorinated precursors in a [2+2] cycloaddition or other ring-forming reactions under appropriate conditions, followed by esterification.

The difluoro substitution at the 3-position introduces strong electron-withdrawing effects, increasing the chemical stability of the compound while also modifying its reactivity. These fluorine atoms can significantly affect the compound’s conformational preferences and metabolic stability, properties that are of great interest in medicinal chemistry. The presence of a small, strained cyclobutane ring adds further uniqueness to the molecule, as ring strain influences both the reactivity and binding properties of such structures when incorporated into biologically active compounds.

Methyl 3,3-difluorocyclobutanecarboxylate has been utilized primarily as a synthetic building block. In medicinal chemistry, difluorocyclobutyl groups are used to replace traditional alkyl or cycloalkyl moieties to enhance metabolic resistance and modulate biological activity. The electron-deficient fluorine atoms and ring strain together create a structural motif that can improve ligand–target interactions or influence the bioavailability of drug candidates. Several research efforts have examined similar fluorinated cyclobutane derivatives as peptidomimetic building blocks, enzyme inhibitors, and bioisosteres of carboxylic acid or ketone-containing motifs.

In addition to pharmaceutical applications, such compounds also appear in agrochemical development. The difluorocyclobutane scaffold can be introduced into herbicide or pesticide candidates to improve their environmental persistence, biological selectivity, or efficacy. The fluorinated ring system may also confer resistance to metabolic degradation by enzymes in plants or insects, which is a desirable property in the design of long-lasting active agents.

The methyl ester group provides a functional handle for further synthetic modification. It can undergo saponification to yield the corresponding carboxylic acid, or participate in nucleophilic substitution, amidation, or coupling reactions. These features make methyl 3,3-difluorocyclobutanecarboxylate a flexible intermediate for the preparation of more complex fluorinated molecules.

Characterization of this compound typically involves nuclear magnetic resonance (NMR) spectroscopy, including ²H, ³C, and ¹F NMR, as the presence of two fluorine atoms gives rise to characteristic coupling patterns. Infrared (IR) spectroscopy shows the ester C=O stretch typically around 1735 cm⁻¹. Mass spectrometry provides information on molecular weight and fragmentation pathways, while elemental analysis may be used to confirm the purity and composition.

In summary, methyl 3,3-difluorocyclobutanecarboxylate is a synthetically valuable fluorinated ester that combines the unique properties of a strained cyclobutane ring and difluoro substitution. Its structural features make it an attractive intermediate in the development of pharmaceuticals and agrochemicals, particularly where enhanced metabolic stability, conformational rigidity, or electron-withdrawing effects are desirable.

References

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