2-Hexynoic Acid: Properties, Synthesis & Research Uses

2-Hexynoic Acid is a six-carbon alkynoic acid bearing an alpha–beta carbon–carbon triple bond that makes it a versatile electrophilic building block in organic synthesis and a valuable reagent for pharmaceutical and materials research.

IUPAC Name

Hex-2-ynoic acid

Molecular Formula

C₆H₈O₂

Molecular Weight

112.13 g/mol

CAS Number

30964-00-2

Functional Groups

Terminal-region alkyne (C2–C3) and carboxylic acid

SKU

H157077

Key Reactivity

Michael acceptor; undergoes conjugate addition, esterification, and metal-catalyzed coupling

Chemical Structure and Physical Properties

2-Hexynoic acid (hex-2-ynoic acid, CAS 30964-00-2) is a six-carbon, straight-chain ynoic acid in which the carbon–carbon triple bond is positioned between C2 and C3, directly conjugated with the carboxylic acid group at C1. This conjugation significantly lowers the pKa relative to saturated analogs and activates the β-carbon toward nucleophilic attack, classifying the molecule as an α,β-acetylenic acid—also termed a ynoate acid in its ester form.

The compound is typically supplied as a colorless to pale-yellow liquid or low-melting solid with a molecular weight of 112.13 g/mol and molecular formula C₆H₈O₂. The alkyl chain terminating at C6 imparts moderate lipophilicity, balancing aqueous solubility with membrane permeability—properties relevant to bioavailability studies. The triple bond is detectable by characteristic IR absorptions near 2200–2250 cm⁻¹ (C≡C stretch) and a broad O–H stretch around 2500–3300 cm⁻¹, while ¹H NMR shows the methyl triplet near δ 1.1 ppm and the propargyl-adjacent methylene near δ 2.3 ppm.

Synthesis and Production Routes

2-Hexynoic acid can be prepared by several established organic chemistry routes. One classical approach involves the base-mediated isomerization or oxidation of hex-2-yn-1-ol or related propargylic precursors. A more direct synthetic strategy employs Corey–Fuchs-type or Seyferth–Gilbert homologation protocols starting from valeraldehyde (pentanal), converting it first to a terminal alkyne and then inserting carboxylate functionality.

Alternatively, copper-catalyzed or palladium-catalyzed carbonylative coupling of 1-butyne or related terminal alkynes with carbon monoxide and a proton source can furnish internal ynoic acids, though regioselectivity must be carefully controlled. Laboratory-scale preparation often favors Grignard or organolithium addition to CO₂ followed by acidic workup on suitably protected alkynyl intermediates. For procurement, Aladdin Scientific supplies 2-hexynoic acid (SKU H157077) at research-grade purity, bypassing the need for in-house synthesis in most experimental workflows.

Research Applications and Reactivity

The combination of an activated triple bond and a free carboxylic acid renders 2-hexynoic acid highly versatile across several research domains:

• Michael Addition Chemistry: The electron-deficient β-carbon acts as a Michael acceptor toward thiols, amines, and carbon nucleophiles. Thiol–yne and aza–Michael additions with 2-hexynoic acid derivatives are exploited in the synthesis of heterocyclic scaffolds, peptidomimetics, and covalent warhead design for targeted covalent inhibitors.
• Esterification and Amide Coupling: The carboxylic acid can be activated as an acyl chloride, mixed anhydride, or NHS ester for coupling to alcohols, amines, or amino acid residues, enabling incorporation of the ynoate motif into peptides and polymers.
• Metal-Catalyzed Cross-Coupling: Palladium- and copper-catalyzed Sonogashira-type reactions on the alkyne moiety, combined with the carboxylic acid handle, allow construction of complex aryl or heteroaryl ynoic acid derivatives for drug discovery libraries.
• Bioorthogonal and Click Chemistry: Internal alkynes can participate in strain-promoted or metal-catalyzed cycloadditions, making ynoate fragments useful tags in chemical biology probes.
• Polymer and Material Science: Ynoic acid monomers undergo thermal or photochemical polymerization and serve as crosslinking agents in functional polymer networks.

Safe Handling, Storage, and Regulatory Considerations

As an α,β-unsaturated carboxylic acid, 2-hexynoic acid is a reactive electrophile and should be handled with appropriate personal protective equipment including chemically resistant gloves, safety goggles, and a lab coat. Work should be performed in a well-ventilated fume hood to minimize inhalation of vapors. Contact with skin and mucous membranes should be avoided; in case of skin contact, the affected area should be washed immediately with soap and water.

Storage recommendations typically call for a cool, dry, well-ventilated location away from incompatible materials such as strong bases, strong oxidizers, and reducing agents. The compound should be stored in a tightly sealed container; refrigerated storage (2–8 °C) is advisable to prevent slow polymerization or decomposition of the reactive triple bond. Users should consult the product-specific Safety Data Sheet (SDS) provided by Aladdin Scientific (SKU H157077) for complete hazard classification, first-aid measures, disposal guidance, and transport regulations applicable to their jurisdiction.

Frequently asked questions

What makes 2-Hexynoic Acid different from 2-Hexenoic Acid?

2-Hexynoic acid contains a carbon–carbon triple bond (alkyne) between C2 and C3, whereas 2-hexenoic acid contains a double bond (alkene) at the same position. The triple bond in 2-hexynoic acid confers greater electrophilicity at the β-carbon, stronger IR absorption near 2200 cm⁻¹, and distinct reactivity patterns such as thiol–yne addition and metal-catalyzed alkyne functionalization not accessible with the alkene analog.

In what solvents is 2-Hexynoic Acid typically used for reactions?

2-Hexynoic acid is miscible with common polar aprotic solvents such as DMF, DMSO, THF, and acetonitrile, as well as with dichloromethane and ethyl acetate. It shows limited but usable solubility in water, especially at elevated pH when the carboxylate anion is formed. Solvent choice depends on the reaction type: palladium-catalyzed couplings often use DMF or toluene, while Michael additions with amines may be run neat or in THF.

How should 2-Hexynoic Acid (H157077) be stored to maintain stability?

Store 2-hexynoic acid in a tightly sealed container at 2–8 °C, protected from light, heat, and moisture. Keeping the reagent cold suppresses slow autopolymerization of the reactive triple bond and prevents decarboxylation. Avoid prolonged exposure to air; working under inert gas (nitrogen or argon) is recommended when handling repeatedly.

Can 2-Hexynoic Acid be used as a covalent warhead in drug discovery?

Yes. The α,β-acetylenic acid motif is an established electrophilic warhead that reacts irreversibly with cysteine thiols and other nucleophilic residues via thiol–yne addition, analogous to cysteine-targeted acrylamide warheads. The ynoic acid or its ester/amide derivatives are incorporated into targeted covalent inhibitor scaffolds to achieve selective, irreversible enzyme inhibition in medicinal chemistry programs.

References

1. Smith, M. B. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th ed.; Wiley: Hoboken, NJ, 2013. (General ynoic acid reactivity, Michael additions)
2. Maulide, N. et al. Alpha-arylation of carboxylic acids and ynoic acids via electrophilic activation. (General reference — specific author names and details require verification)
3. Aladdin Scientific Product Page: 2-Hexynoic Acid, SKU H157077. Aladdin Scientific Corp.
4. Leverett, C. A.; Purohit, V. C.; Romo, D. Enantioselective synthesis of gamma-lactams via organocatalytic, intramolecular Michael additions of tethered alpha,beta-acetylenic acids to isatins. Angew. Chem. Int. Ed. 2010, 49, 9479–9483. (Illustrative ynoic acid application — details require verification)

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