(R)-2-Chloro-1-(4-fluorophenyl)ethanol: Properties & Applications

(R)-2-Chloro-1-(4-fluorophenyl)ethanol is a versatile enantiopure chiral building block widely used as a pharmaceutical intermediate in asymmetric synthesis and the preparation of biologically active compounds.

Chemical Name

(R)-2-Chloro-1-(4-fluorophenyl)ethanol

CAS Number

Needs verification — see review flags

Molecular Formula

C8H8ClFO

Molecular Weight

174.60 g/mol

Stereocentre Configuration

(R)-configuration at C-1

Key Functional Groups

Secondary alcohol, alkyl chloride, para-fluorophenyl ring

Aladdin SKU

C726667

Chemical Identity and Physical Properties

(R)-2-Chloro-1-(4-fluorophenyl)ethanol (molecular formula C₈H₈ClFO, MW 174.60 g/mol) is a halogenated chiral secondary alcohol bearing a para-fluorophenyl aromatic ring. The molecule contains two key reactive handles: a hydroxyl group at the stereogenic C-1 carbon and a primary alkyl chloride at C-2. The (R)-configuration at C-1 is established with defined enantioselectivity, making this compound suitable for stereocontrolled synthetic transformations.

The para-fluorine substituent on the phenyl ring is an electron-withdrawing group that modulates the electronic density of the aromatic system. This influences the reactivity of the benzylic position and is a common motif in medicinal chemistry, as fluorine substitution can improve metabolic stability and membrane permeability of drug candidates derived from this scaffold.

The compound is typically supplied as a colorless to pale yellow liquid or low-melting solid. It should be stored under inert atmosphere conditions at low temperature (typically 2–8 °C) to minimise racemisation and hydrolysis of the chloride functionality. Specific physical constants such as melting point, boiling point, optical rotation, and density should be confirmed against the certificate of analysis (CoA) provided with each lot.

Synthesis and Stereochemical Considerations

Enantiopure halohydrins of this class, including (R)-2-Chloro-1-(4-fluorophenyl)ethanol, are commonly accessed through asymmetric reduction of the corresponding alpha-haloacetophenone precursor — in this case 2-chloro-4'-fluoroacetophenone. Asymmetric reduction strategies include: (1) enzymatic reduction using ketoreductases (KREDs) that deliver high enantioselectivity under mild aqueous conditions; (2) metal-catalysed asymmetric transfer hydrogenation employing ruthenium- or rhodium-based catalysts with chiral ligands; and (3) oxazaborolidine (CBS)-mediated borane reduction, which is a well-established method for producing enantiopure benzylic alcohols.

The resulting halohydrin serves as a latent epoxide equivalent: treatment with base rapidly generates the corresponding (R)-styrene oxide derivative, an epoxide that is highly reactive toward nucleophilic ring opening. This epoxide-forming capacity is central to the compound's synthetic utility, enabling introduction of diverse nucleophiles with predictable stereochemical outcomes governed by the pre-set (R)-stereocentre.

Researchers should be aware that prolonged exposure to base, moisture, or elevated temperatures can promote intramolecular cyclisation to the epoxide or intermolecular solvolysis, reducing the effective concentration of the halohydrin. Handling under anhydrous, mildly acidic or neutral conditions and cold storage is recommended to preserve integrity.

Applications in Pharmaceutical and Medicinal Chemistry Research

(R)-2-Chloro-1-(4-fluorophenyl)ethanol occupies an important position in the synthesis of pharmacologically relevant targets. As a bifunctional chiral building block possessing both a leaving group (chloride) and a nucleophilic handle (hydroxyl), it enables rapid construction of complex molecular architectures with defined stereochemistry.

Beta-adrenergic and adrenergic agents: Fluorophenyl halohydrins are classical precursors to beta-blocker and sympathomimetic scaffolds. The 4-fluorophenethylamine framework is present in several marketed and investigational adrenergic compounds, and the chiral halohydrin provides direct access to enantiomerically enriched intermediates that underpin structure–activity relationship (SAR) studies.

Epoxide-based electrophiles: As noted above, base-mediated cyclisation generates the chiral epoxide, which can be ring-opened by amines, thiols, azides, and carbon nucleophiles. This provides access to beta-amino alcohols, beta-hydroxy thiols, and related pharmacophores that are prevalent in protease inhibitors, HIV therapeutics, and other drug classes.

Asymmetric catalysis research: The compound is also used as a benchmark substrate or chiral auxiliary in methodology development for new asymmetric transformations, enabling researchers to evaluate enantioselectivity of novel catalyst systems.

Researchers in academia and industry will find this compound particularly valuable in early-stage lead optimisation, where enantiopure building blocks are required in milligram-to-gram quantities for parallel synthesis campaigns.

Handling, Storage, and Safety Guidelines

As with all halogenated organic compounds, appropriate laboratory safety procedures must be observed when handling (R)-2-Chloro-1-(4-fluorophenyl)ethanol. The compound contains an alkyl chloride and should be treated as a potential irritant to skin, eyes, and the respiratory tract. Personal protective equipment (PPE) including nitrile gloves, safety spectacles, and laboratory coat should be worn at all times. Operations generating vapour or aerosol should be conducted in a well-ventilated fume hood.

Storage recommendations: Store tightly sealed under inert gas (nitrogen or argon) in a cool, dry location at 2–8 °C, protected from light and moisture. Avoid storage near strong bases, oxidising agents, or nucleophiles that could react with the alkyl chloride moiety. Check the product CoA and Safety Data Sheet (SDS) supplied by Aladdin Scientific (SKU C726667) for lot-specific purity, optical rotation data, and detailed hazard information prior to use.

Waste disposal: Dispose of unused material and solvent waste in accordance with local institutional and governmental regulations for halogenated organic waste. Do not pour down the drain.

Note: The specific GHS hazard classification and precise physical constants should be verified against the current SDS for SKU C726667 available from Aladdin Scientific.

Frequently asked questions

What is the main synthetic utility of (R)-2-Chloro-1-(4-fluorophenyl)ethanol?

(R)-2-Chloro-1-(4-fluorophenyl)ethanol is primarily used as a chiral building block in asymmetric synthesis. Its bifunctional nature — combining a reactive alkyl chloride with a stereodefined secondary alcohol — allows it to serve as a direct precursor to chiral epoxides, beta-amino alcohols, and other pharmacologically important intermediates.

How should (R)-2-Chloro-1-(4-fluorophenyl)ethanol be stored to prevent degradation?

The compound should be stored sealed under an inert atmosphere (nitrogen or argon) at 2–8 °C, in a dry, dark environment. Exposure to moisture, strong bases, or elevated temperatures should be avoided, as these conditions promote hydrolysis of the chloride or intramolecular cyclisation to the epoxide, both of which reduce purity and enantiopurity.

Can (R)-2-Chloro-1-(4-fluorophenyl)ethanol be converted to the corresponding chiral epoxide?

Yes. Treatment of (R)-2-Chloro-1-(4-fluorophenyl)ethanol with a mild base (such as potassium carbonate) causes intramolecular displacement of the chloride by the alkoxide, generating the corresponding chiral (R)-4-fluorostyrene oxide. This epoxide is a highly versatile electrophile for nucleophilic ring-opening reactions under stereochemical control.

What purity and enantiopurity specifications should I expect for SKU C726667?

Specific purity and enantiomeric excess (ee) values vary by lot and are provided on the certificate of analysis (CoA) accompanying each shipment from Aladdin Scientific. Customers are advised to request or download the CoA for lot-specific data. General specifications for research-grade chiral building blocks typically require high ee (≥95%) and chemical purity (≥97%), but please verify with the current CoA for SKU C726667.

References

1. Noyori, R.; Ohkuma, T. Asymmetric Catalysis by Architectural and Functional Molecular Engineering: Practical Chemo- and Stereoselective Hydrogenation of Ketones. Angew. Chem. Int. Ed. 2001, 40, 40–73. doi:10.1002/1521-3773(20010105)40:1<40::AID-ANIE40>3.0.CO;2-5
2. Corey, E. J.; Helal, C. J. Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts: A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method. Angew. Chem. Int. Ed. 1998, 37, 1986–2012. doi:10.1002/(SICI)1521-3773(19980817)37:15<1986::AID-ANIE1986>3.0.CO;2-Z
3. Huisman, G. W.; Liang, J.; Krebber, A. Practical chiral alcohol manufacture using ketoreductases. Curr. Opin. Chem. Biol. 2010, 14, 122–129. doi:10.1016/j.cbpa.2009.11.009

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