STRUCTURE–ACTIVITY RELATIONSHIPS IN HYDROXYLAMINE DERIVATIVES

Structure–Activity Relationships in Hydroxylamine Derivatives

Structure–Activity Relationships in Hydroxylamine Derivatives

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N,O-Dimethylhydroxylamine Hydrochloride (DMHA HCl): Structure, Reactivity, and Synthetic Utility

Introduction

In synthetic organic chemistry, few compounds offer the unique dual reactivity and ease of use provided by N,O-Dimethylhydroxylamine Hydrochloride (DMHA HCl). This compound, a stable crystalline salt, is a key reagent and intermediate in the synthesis of pharmaceutical agents, agrochemicals, and fine chemicals.

Its structure, featuring both methylated nitrogen and oxygen atoms, allows it to participate in selective and predictable transformations—a property that makes it highly attractive in modern organic synthesis, especially in medicinal chemistry.

Chemical Identity and Structure

IUPAC Name: N-Methoxy-N-methylamine hydrochloride
Synonyms:

  • N,O-Dimethylhydroxylamine hydrochloride

  • Methoxymethylamine hydrochloride

  • N-Methyl-O-methylhydroxylamine HCl

Molecular Formula: C₂H₈ClNO
Molecular Weight: 97.55 g/mol

Structural Description:

The molecule contains a hydroxylamine backbone (R–NHOH), with both the nitrogen and oxygen atoms substituted by methyl groups. The hydrochloride (HCl) salt form ensures stability, easier crystallization, and water solubility.

CH3–N(OCH3)H · HCl

This dual methylation introduces interesting electronic effects that make DMHA a unique nucleophile and mild base under certain conditions.

Physicochemical Properties

  • Appearance: White to off-white crystalline powder

  • Solubility: Soluble in water, methanol, ethanol; slightly soluble in organic solvents like ethyl acetate

  • Melting Point: ~142–144°C (with decomposition)

  • Boiling Point (free base): Not distillable due to decomposition

  • Odor: Slightly amine-like

  • Stability: Hygroscopic; stable under dry, refrigerated conditions

Its aqueous solutions are acidic due to the presence of the protonated amine from the HCl salt.

Synthetic Applications

1. Pharmaceutical Chemistry

DMHA HCl is frequently used as a protecting group reagent and formylation agent in medicinal chemistry. It is especially useful in the synthesis of:

  • Formamides, via reaction with acyl chlorides or isocyanates.

  • Peptidomimetics, where N,O-dimethyl protection prevents side reactions.

  • Hydroxamic acids, by forming intermediates that can be easily hydrolyzed.

  • Prodrug synthesis, where the N,O-dimethyl group serves as a cleavable handle.

One well-known application is in the synthesis of N,N-dimethylhydrazones and oxime ethers, which are used in heterocyclic scaffolds found in kinase inhibitors and CNS-active agents.

2. Agrochemical Manufacturing

In agrochemical synthesis, DMHA HCl serves as a precursor to biologically active structures such as:

  • Herbicide precursors

  • Fungicide intermediates

  • Plant growth regulators

It provides chemoselectivity and reproducibility in reactions with isocyanates and acid chlorides that are commonly used in agrochemical formulation.

3. Formylation and Amide Bond Formation

DMHA HCl can react with acylating agents such as:

  • Acid chlorides

  • Anhydrides

  • Isocyanates

These reactions result in N-formylated or N-acylated derivatives, which are crucial for stepwise peptide synthesis or medicinal analog development.

Reaction Example:

R–COCl + HN(OCH3)CH3 · HCl → R–CON(CH3)OCH3 + HCl

This reaction forms Weinreb amides when the hydrochloride is neutralized—highly useful intermediates that can undergo selective one-carbon additions from organometallics (like Grignards or lithium reagents) without over-addition.

Mechanism of Action (in Synthesis)

The lone pairs on nitrogen and oxygen make DMHA a bifunctional nucleophile. Under acidic or neutral conditions:

  • The nitrogen prefers to attack electrophiles like acyl or alkyl halides.

  • The oxygen, when deprotonated, can form methoxy adducts or participate in ether bond formation.

This dual pathway allows for chemoselective transformations, especially in stepwise multicomponent synthesis or where protecting group strategy is crucial.

Safety and Handling

DMHA HCl is not classified as highly toxic but must be handled with care due to its amine-based structure:

Hazards:

  • Skin and eye irritation

  • Respiratory tract irritation if inhaled as dust

  • Mild corrosive properties in moist environments due to HCl

Safety Guidelines:

  • Use under a fume hood

  • Wear gloves, safety goggles, and lab coat

  • Store in a cool (2–8°C), dry, airtight container

  • Avoid moisture, as it may hydrolyze or become sticky

First aid: In case of skin contact, rinse with plenty of water. If inhaled, move to fresh air and seek medical attention if irritation persists.

Environmental Impact

DMHA HCl is not a persistent organic pollutant and readily degrades under typical waste treatment conditions. However, it should not be released into water systems or soil. Follow all applicable chemical waste disposal regulations.

Conclusion

N,O-Dimethylhydroxylamine Hydrochloride is a small yet powerful synthetic building block that plays a vital role in the production of fine chemicals, pharmaceuticals, and agrochemicals. Its unique reactivity, high solubility, and excellent stability make it a staple reagent in the chemist’s toolbox.

From the lab bench to industrial reactors, DMHA HCl facilitates clean, selective reactions that drive innovation in medicinal chemistry, crop science, and beyond. As research continues to explore new applications for versatile nitrogen-oxygen compounds, DMHA remains a reliable choice for precise molecular transformations.

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