2,3,5-Collidine: Properties, Uses & Lab FAQs

2,3,5-Collidine is a sterically hindered trimethylpyridine base widely used in organic synthesis as a mild, selective proton scavenger and non-nucleophilic auxiliary base.

IUPAC Name

2,3,5-trimethylpyridine

CAS Number

695-98-7

Molecular Formula

C₈H₁₁N

Molecular Weight

121.18 g/mol

Appearance

Colorless to pale yellow liquid

Aladdin SKU

C109929

What Is 2,3,5-Collidine?

2,3,5-Collidine (IUPAC: 2,3,5-trimethylpyridine; CAS 695-98-7) is an isomer of the collidine family — methylated pyridines bearing three methyl substituents on the aromatic ring. The methyl groups at the 2- and 3-positions create steric bulk around the ring nitrogen, making this compound a non-nucleophilic, hindered base. Its molecular formula is C₈H₁₁N and its molecular weight is 121.18 g/mol.

Like other alkylpyridines, 2,3,5-collidine is a liquid at room temperature. It is miscible with most common organic solvents (dichloromethane, THF, acetonitrile, toluene) and has limited miscibility with water. Its basicity (pKa of conjugate acid approximately 7.1 in water) is slightly higher than pyridine itself, yet the steric environment substantially reduces its nucleophilicity.

Key Applications in Research and Synthesis

The principal role of 2,3,5-collidine in the laboratory is as a non-nucleophilic auxiliary base used to neutralise acid by-products generated during reactions without competing with electrophilic reagents or substrates. Typical applications include:

• Acylation and sulfonylation reactions: Added in excess to scavenge HCl or HBr liberated when acid chlorides, sulfonyl chlorides, or acid anhydrides react with nucleophiles such as alcohols and amines.
• Peptide and nucleotide chemistry: Used as a hindered base where a less nucleophilic auxiliary is needed to avoid side reactions on sensitive intermediates.
• Glycosylation and protecting-group chemistry: Employed to buffer acidic conditions without promoting unwanted elimination or rearrangement.
• Spectroscopic and electrochemical studies: Occasionally used as a ligand or additive in coordination chemistry and as a proton shuttle in mechanistic studies.

Its selectivity advantage over unhindered bases (e.g., triethylamine) lies in a reduced tendency to participate in competing nucleophilic pathways, which can be critical in stereoselective or highly sensitive transformations.

Handling, Safety and Storage

2,3,5-Collidine should be handled in a well-ventilated fume hood. Key safety considerations include:

• Flammability: As a liquid alkylpyridine, it is flammable. Keep away from open flames and oxidising agents.
• Irritant: It may cause skin, eye and respiratory irritation. Use appropriate PPE — chemical-resistant gloves, safety glasses and lab coat.
• Inhalation hazard: The vapour has a characteristic amine-like odour; avoid prolonged inhalation.
• Disposal: Dispose of as halogenated or non-halogenated organic solvent waste according to local regulations.

For storage, keep the reagent in a tightly sealed container under inert atmosphere (nitrogen or argon) if long-term stability is required, at room temperature away from light and heat sources. Always consult the current Safety Data Sheet (SDS) for specific hazard classification and first-aid measures before use.

Purity, Grades and Quality Considerations

For most synthetic applications, a purity of ≥98% (GC) is recommended to minimise interference from isomeric trimethylpyridines (e.g., 2,4,6-collidine or 3,4,5-collidine), which may differ in steric and electronic properties. When ordering from Aladdin Scientific (SKU C109929), check the Certificate of Analysis (CoA) for:

• GC purity (%)
• Water content (Karl Fischer)
• Colour and appearance
• Refractive index (where available)

If the reagent will be used in moisture-sensitive reactions, consider drying over activated molecular sieves (3 Å or 4 Å) prior to use. Freshly opened reagent of high purity is preferable for critical asymmetric or enantioselective transformations.

Comparison with Related Collidine Isomers

The collidine family comprises several trimethylpyridine isomers. Understanding the differences helps researchers select the most appropriate reagent:

• 2,4,6-Collidine (2,4,6-trimethylpyridine): The most commonly encountered isomer in synthesis. Methyl groups flanking nitrogen at 2- and 6-positions provide maximum steric shielding, making it the most hindered and least nucleophilic of the common collodines. Widely used as a non-nucleophilic base in Koenigs–Knorr glycosylation and triflation reactions.
• 2,3,5-Collidine (this product): Intermediate steric bulk — the 2-methyl group provides some nitrogen shielding but the 3- and 5-methyls contribute principally to electronic activation. Useful where a balance of moderate basicity and reduced nucleophilicity is required.
• 3,4,5-Collidine: No methyl substituents adjacent to nitrogen; behaves more like a simple nucleophilic pyridine base.

The choice between isomers should be guided by the reaction mechanism, sensitivity of substrates to nucleophilic attack, and any literature precedent for the specific transformation.

Frequently asked questions

What is 2,3,5-collidine used for in organic synthesis?

2,3,5-Collidine serves primarily as a non-nucleophilic, hindered base to neutralise acid by-products (e.g., HCl, HBr) generated in acylation, sulfonylation, glycosylation, and protecting-group reactions. Its steric profile reduces competitive nucleophilic side reactions that simpler amine bases may cause.

How does 2,3,5-collidine differ from 2,4,6-collidine?

In 2,4,6-collidine, methyl groups are located on both sides of the nitrogen (positions 2 and 6), providing maximum steric shielding and making it the least nucleophilic collidine isomer. In 2,3,5-collidine, only the 2-position is adjacent to nitrogen, yielding intermediate steric bulk and slightly different electronic properties. Researchers should select based on the specific steric and nucleophilicity requirements of their reaction.

Is 2,3,5-collidine soluble in common organic solvents?

Yes. As a liquid alkylpyridine, 2,3,5-collidine is miscible with most common organic solvents including dichloromethane, THF, acetonitrile, ethyl acetate, and toluene. It has limited miscibility with water. This broad organic-solvent compatibility makes it convenient to add directly to most reaction mixtures.

What purity grade should I order for sensitive synthetic work?

For sensitive or stereoselective reactions, a GC purity of ≥98% is recommended to minimise interference from trimethylpyridine isomers. Always verify the Certificate of Analysis (CoA) upon receipt and, if the reaction is moisture-sensitive, dry the reagent over activated molecular sieves before use. Aladdin Scientific offers 2,3,5-collidine under SKU C109929.

How should 2,3,5-collidine be stored to maintain quality?

Store 2,3,5-collidine in a tightly sealed container under an inert atmosphere (nitrogen or argon) at room temperature, away from light, heat, and ignition sources. For long-term storage, periodic quality checks by GC are advisable. Always follow the guidance in the current SDS supplied with the product.

References

1. March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. Wiley, 4th ed. General discussion of pyridine bases and their nucleophilicity.
2. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry. Oxford University Press, 2nd ed. Coverage of hindered amine and pyridine bases in synthesis.
3. Sigma-Aldrich/Merck product documentation for collidine isomers. General physicochemical data.

Products are supplied for research and development use only. Not for use in humans, animals, diagnosis, or therapy.