Iodoacetamide
[CAS 144-48-9]

Identification

• Classification: Organic raw materials >> Amino compound >> Amide compound
• Name: Iodoacetamide
• Synonyms: 2-Iodoacetamide
• Molecular Formula: C₂H₄INO
• Molecular Weight: 184.96
• CAS Registry Number: 144-48-9
• EC Number: 205-630-1
• SMILES: C(C(=O)N)I

Properties

• Density: 2.4±0.1 g/cm³ Calc.^*
• Melting point: 92 - 95 °C (Expl.)
• Boiling point: 215.8±40.0 °C 760 mmHg (Calc.)^*
• Flash point: 84.3±27.3 °C (Calc.)^*
• Solubility: water: slightly soluble (Expl.)
• Index of refraction: 1.638 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS06;GHS07;GHS08 Danger
• Risk Statements: H301-H317-H334-H413
• Safety Statements: P233-P260-P261-P264-P270-P271-P272-P273-P280-P284-P301+P316-P302+P352-P304+P340-P321-P330-P333+P317-P342+P316-P362+P364-P403-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	3	H301
Skin sensitization	Skin Sens.	1	H317
Respiratory sensitization	Resp. Sens.	1	H334
Chronic hazardous to the aquatic environment	Aquatic Chronic	4	H413
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute toxicity	Acute Tox.	3	H311
Acute toxicity	Acute Tox.	2	H330
Respiratory sensitization	Resp. Sens.	1B	H334
Eye irritation	Eye Irrit.	2A	H319
Skin sensitization	Skin Sens.	1B	H317

• Transport Information: UN 2811

Discovery and Applications

Iodoacetamide is a simple halogenated acetamide compound with the molecular formula C₂H₄INO. Structurally, it consists of an acetamide group in which one hydrogen atom on the methyl carbon is replaced by an iodine atom, producing a highly electrophilic carbon center adjacent to both a carbonyl group and a good leaving group (iodide).

The core functional group is the amide (–CONH₂), which contains a carbonyl carbon double-bonded to oxygen and single-bonded to a nitrogen atom. Amides are generally stabilized by resonance between the nitrogen lone pair and the carbonyl group, which reduces the electrophilicity of the carbonyl carbon compared with other acyl derivatives. However, in iodoacetamide, the presence of the iodine atom significantly alters the reactivity of the molecule.

The iodine substituent is attached to the carbon adjacent to the carbonyl group (the α-carbon). Iodine is a large, highly polarizable halogen with a relatively weak carbon–iodine bond. This bond is more labile than corresponding carbon–chlorine or carbon–bromine bonds, making iodoacetamide a strong alkylating agent under suitable conditions. The electron-withdrawing effect of the carbonyl group further increases the electrophilicity of the α-carbon, facilitating nucleophilic substitution reactions.

Because of this activated α-carbon, iodoacetamide readily undergoes nucleophilic substitution (typically SN2-type reactions) with nucleophiles such as thiol groups (–SH), amines, and other nucleophilic functional groups in biomolecules. In particular, it reacts efficiently with cysteine thiol groups in proteins, forming stable thioether adducts. This reaction irreversibly modifies cysteine residues by alkylation, preventing disulfide bond formation or further redox reactions involving free thiols.

In biochemical contexts, this reactivity makes iodoacetamide a widely used reagent for protein modification and enzymatic sample preparation. It is commonly employed to block free thiols after reduction of disulfide bonds, ensuring that cysteine residues remain in a reduced and chemically inert state during downstream analytical procedures such as mass spectrometry or electrophoresis.

From a physicochemical standpoint, iodoacetamide is a small, polar molecule due to the amide group, but it also contains a strongly polarizable iodine atom that contributes to its reactivity rather than hydrophilicity. The compound is typically water-soluble and can diffuse readily in aqueous biological systems, enabling efficient reaction with accessible nucleophilic sites in proteins and peptides.

Chemically, the most reactive site is the carbon bearing iodine. This carbon is strongly electrophilic due to the combined effects of the electron-withdrawing carbonyl group and the excellent leaving ability of iodide. Under neutral to slightly basic conditions, nucleophiles such as thiolates (RS⁻) react rapidly with iodoacetamide to displace iodide and form stable covalent bonds.

The amide group itself is relatively stable and does not typically undergo hydrolysis under mild conditions. However, under strong acidic or basic conditions, amide bond cleavage can occur, although this is not relevant under typical biochemical usage conditions.

Overall, iodoacetamide is a small, highly reactive alkylating agent characterized by a halogen-activated α-carbon adjacent to an amide group. Its strong electrophilicity toward nucleophiles, especially thiol groups in cysteine residues, underlies its extensive use in biochemical research for covalent modification and thiol blocking in proteins.

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