2-(2-Chloroethoxy)ethanol
[CAS 628-89-7]

Identification

• Classification: Chemical reagent >> Organic reagent >> Fatty alcohol
• Name: 2-(2-Chloroethoxy)ethanol
• Synonyms: Diethylene glycol monochlorohydrin
• Molecular Formula: C₄H₉ClO₂
• Molecular Weight: 124.57
• CAS Registry Number: 628-89-7
• EC Number: 211-059-9
• SMILES: C(COCCCl)O

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*, 1.18 g/mL (Expl.)
• Boiling point: 182.5 °C 760 mmHg (Calc.)^*, 245.1 - 248 °C (Expl.)
• Flash point: 90.6 °C (Calc.)^*, 90 °C (Expl.)
• Solubility: water: soluble (Expl.)
• Index of refraction: 1.436 (Calc.)^*, 1.452 (Expl.)

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

Safety Data

• Hazard Symbols: GHS05;GHS07 Danger
• Risk Statements: H315-H318-H319-H335
• Safety Statements: P261-P264-P264+P265-P271-P280-P302+P352-P304+P340-P305+P351+P338-P305+P354+P338-P317-P319-P321-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Serious eye damage	Eye Dam.	1	H318
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319
Carcinogenicity	Carc.	2	H351

chemBlink Chemical Story

2-(2-Chloroethoxy)ethanol, CAS 628-89-7, is a bifunctional chloroalkoxy alcohol used as an intermediate in organic and pharmaceutical synthesis. It is also known as diethylene glycol monochlorohydrin, diglycol chlorohydrin, or 2-chloroethyl 2-hydroxyethyl ether. Its molecular formula is C₄H₉ClO₂ and its molecular weight is 124.57. Its structure can be written as ClCH₂CH₂OCH₂CH₂OH.

The molecule is chemically interesting because its two ends perform very different jobs. One end contains a primary alkyl chloride, which can undergo nucleophilic substitution. The other end contains a primary alcohol, which can be esterified, oxidized, converted into other derivatives, or retained in a final molecule. Between them lies an ether oxygen that introduces flexibility and polarity.

This gives 2-(2-chloroethoxy)ethanol the character of a molecular linker. A nucleophile can replace chloride at one end, attaching the chain to a larger molecular framework, while the terminal hydroxyl group remains available for later chemistry.

One of the clearest pharmaceutical examples is the synthesis of quetiapine.

Quetiapine is a dibenzothiazepine antipsychotic containing a piperazine ring substituted with a 2-(2-hydroxyethoxy)ethyl side chain. Published manufacturing processes prepare this side chain directly from 2-(2-chloroethoxy)ethanol.

In an established route, 11-(1-piperazinyl)dibenzo[b,f][1,4]thiazepine is reacted with 2-(2-chloroethoxy)ethanol in the presence of base. One of the piperazine nitrogens acts as the nucleophile and attacks the carbon bearing chlorine.

Chloride leaves, and a new carbon-nitrogen bond forms.

The transformation can be represented in simplified form as:

Piperazine-NH + ClCH₂CH₂OCH₂CH₂OH

→

Piperazine-N-CH₂CH₂OCH₂CH₂OH

The terminal hydroxyl group remains untouched.

This is an important synthetic design feature. The chlorine provides a temporary leaving group whose purpose is to create the new C-N bond, while the hydroxyl group is already in the form required for the final quetiapine side chain.

In other words, nearly the entire four-carbon oxygen-containing chain of 2-(2-chloroethoxy)ethanol survives into the pharmaceutical molecule. Only chlorine is discarded during the attachment step.

This makes the reagent different from a catalyst or protecting group. It is a true structural building block: most of its atoms become part of the final drug.

The reaction also illustrates why alkyl chlorides are useful in medicinal chemistry. A chlorine atom attached to an sp³ carbon can serve as a leaving group, allowing nitrogen, oxygen, sulfur, or other nucleophiles to replace it. The resulting bond can connect two previously separate molecular fragments.

The ether oxygen in 2-(2-chloroethoxy)ethanol contributes another useful property. Ether bonds provide conformational flexibility and hydrogen-bond-accepting ability without introducing an ionizable group. In a pharmaceutical structure, this can influence polarity, molecular shape, and interaction with solvent and biological environments.

The terminal alcohol introduces still another level of functionality. Hydroxyl groups can form hydrogen bonds and can also be chemically modified if a later synthetic route requires esterification, oxidation, or substitution.

Thus, a molecule containing only four carbon atoms already contains three different chemical elements of design: a leaving group, an ether spacer, and a terminal alcohol.

Process chemistry around quetiapine has paid considerable attention to this alkylation step. Earlier preparations required relatively long reaction times and could generate impurities. Later processes introduced phase-transfer catalysts, modified solvent systems, and water-containing reaction media to improve conversion and impurity control.

One patented quetiapine process specifically reports that the reaction of the piperazine intermediate with 2-(2-chloroethoxy)ethanol in the presence of water reduced impurity formation and gave quetiapine with chromatographic purity greater than 99.7%.

This illustrates a recurring problem in pharmaceutical manufacturing. A reaction that is straightforward on paper may become difficult on scale because excess alkylating reagent, competing substitution, hydrolysis, unreacted starting material, and closely related impurities must all be controlled.

The reagent itself can consequently appear in two very different contexts.

During synthesis, it is intentionally added as a starting material.

After synthesis, residual 2-(2-chloroethoxy)ethanol may become an impurity that must be monitored and removed.

A 2007 analytical study developed a gas chromatographic method specifically for measuring residual 2-(2-chloroethoxy)ethanol in quetiapine. This is a good example of how the same chemical can be desirable at one stage of pharmaceutical manufacture and undesirable at another.

The compound also has uses outside quetiapine synthesis. Commercial literature records its conversion to 2-(2-azidoethoxy)ethanol by nucleophilic substitution. In that reaction, azide replaces chloride while the hydroxyl group remains available, producing another bifunctional linker useful for further synthetic transformations.

This reinforces the central identity of 2-(2-chloroethoxy)ethanol: it is a compact two-ended molecular connector.

One end is designed to react.

The other is designed to remain available.

The ether in between provides spacing and flexibility.

Its synthesis itself can be traced to diethylene glycol chemistry. Industrial patent literature describes production from reaction mixtures containing diethylene glycol and hydrogen chloride, followed by extraction and distillation purification.

2-(2-Chloroethoxy)ethanol therefore demonstrates how a seemingly simple industrial chemical can become part of sophisticated pharmaceutical architecture. Its value does not come from a complex ring system or unusual stereochemistry. It comes from having two different functional ends separated by exactly the right length of flexible chain.

In quetiapine synthesis, chlorine marks the point of attachment, the ether remains in the linker, and the alcohol survives at the end of the chain.

Four carbons, two oxygens, and one temporary chlorine are enough to build a recognizable piece of a modern drug molecule.

References

1. NIST Chemistry WebBook. Ethanol, 2-(2-chloroethoxy)-, CAS 628-89-7. Molecular formula C₄H₉ClO₂; molecular weight 124.566.

2. WO 2008/121415 A2. Improved process for preparing quetiapine fumarate. Reaction of a piperazine intermediate with 2-(2-chloroethoxy)ethanol.

3. WO 2010/100623 A1. Process for the preparation of quetiapine fumarate. Process optimization and impurity control in the reaction with 2-(2-chloroethoxy)ethanol.

4. Stolarczyk, E. U.; Groman, A.; Kaczmarek, L. S.; Golebiewski, P. (2007). "GC method for quantitative determination of residual 2-(2-chloroethoxy) ethanol (CEE) and N-methyl-2-pyrrolidinone (NMP) in quetiapine." Acta Poloniae Pharmaceutica, 64, 187-189.

5. JPS58109441A. Preparation of 2-(2'-chloroethoxy)ethanol. Industrial isolation and purification of the compound.