1. 3-Chloro-4-fluoroaniline (CAS 367-21-5): An Overview
3-Chloro-4-fluoroaniline – also written as 3-chloro-4-fluorobenzenamine (CAS 367-21-5, molecular formula C6H5ClFN, molecular weight 145.56 g/mol) – is a doubly halogenated aniline carrying an amino group at C1, chlorine at C3 and fluorine at C4. It is supplied as a white to off-white crystalline solid, typically at 99% GC purity, and is bought essentially as an intermediate: it is not an end product, and almost all of it is consumed inside a multi-step synthesis of a pharmaceutical or agrochemical active ingredient.
That positioning explains what buyers actually argue about when they negotiate. Nobody buys this product for its own properties. They buy a starting amine that has to survive four or five downstream steps without introducing an impurity they cannot remove, and they buy it on a schedule that matches a campaign start. The three specifications that matter – assay, impurity and moisture – are proxies for that, and the sections below explain what each one is really protecting.
2. Chemical and Physical Properties
| Property | Value / note |
|---|---|
| Chemical name | 3-Chloro-4-fluoroaniline |
| Synonyms | 3-Chloro-4-fluorobenzenamine; 3-chloro-4-fluorophenylamine; 3-chloro-4-fluoro-aniline |
| CAS Registry Number | 367-21-5 |
| Molecular formula | C6H5ClFN |
| Molecular weight | 145.56 g/mol |
| Theoretical chlorine | 24.36% |
| Theoretical fluorine | 13.05% |
| Theoretical nitrogen | 9.62% |
| Appearance | White to off-white crystalline solid |
| Assay (GC) | ≥ 99.00% |
| Water | ≤ 0.10% |
| Solubility | Practically insoluble in water; soluble in most organic solvents (alcohols, ketones, esters, aromatic hydrocarbons) |
| Chemical character | Weak base; typical aromatic amine reactivity (diazotisation, acylation, condensation) |
The three theoretical element percentages are worth keeping at hand. They are the fastest arithmetic check on a CoA that has been copied across suppliers: any halogenated aniline claimed as C6H5ClFN must land on 24.4% Cl, 13.1% F and 9.6% N, and a certificate that reports an element outside rounding distance of those figures is describing a different molecule.
As an aromatic amine it is a weak base with the usual aniline chemistry: it forms stable diazonium salts below about 5 °C in mineral acid, acylates readily with acid chlorides and anhydrides, condenses with aldehydes and with activated heterocycles, and undergoes palladium-catalysed coupling on the aryl chloride. The C–F bond at the para position, by contrast, is essentially inert under nucleophilic conditions that would readily displace a chloride; that difference is why the fluorine is placed early in a route and the chlorine is placed where selectivity is needed.
3. Manufacture: How the 3-Chloro-4-Fluoro Pattern Is Built
There are two commercial ways to arrive at a 3-chloro-4-fluoroaniline, and they differ in where the halogens enter the ring. Both finish with a nitro-group reduction, so the last step is common; the distinguishing decision is upstream.
Route A: halogen exchange on a dichloronitrobenzene
The dominant industrial approach starts from 2,4-dichloronitrobenzene or a closely related isomer and replaces one chlorine with fluorine by halogen exchange (the Halex reaction): potassium fluoride in a polar aprotic solvent such as DMSO or DMF, at roughly 150–200 °C, usually with a phase-transfer catalyst. Fluoride is a poor nucleophile in protic media but a good one in dipolar aprotic media where the cation is poorly solvated, which is why the solvent choice, the water content of the KF and the agitation pattern control the conversion far more than stoichiometry does. The exchange is selective for the position activated by the nitro group, giving a chlorofluoronitrobenzene in which the remaining chlorine sits exactly where the route wants it.
The nitro intermediate is then reduced to the aniline (see below). The advantage of this route is that both halogens come from cheap, high-volume commodity raw materials and the positional pattern is set by the existing substitution of the nitrobenzene rather than by a difficult separation.
Route B: nitration and reduction of a chlorofluorobenzene
Alternatively a chlorofluorobenzene is nitrated and reduced. This avoids the fluorination step but forces the chemist to deal with the fact that nitration of a chlorofluorobenzene gives a mixture of positional isomers, and the isomers must be separated before or after reduction. Because the isomer distribution is governed by the directing effects of the two halogens – which are similar in strength and can act in competition – the crude nitration mixture is rarely clean enough to skip purification.
The reduction step, and the impurity it creates
Almost every commercial route ends with the reduction of a chlorofluoronitrobenzene, and the choice of reductant decides which impurity dominates:
- Bechamp-type reduction (iron plus hydrochloric or acetic acid) – cheap and robust, gives high conversion, but generates a large volume of iron oxide sludge that has to be disposed of, and the strongly acidic, hot conditions are unkind to the remaining chlorine if the reaction is run past conversion.
- Catalytic hydrogenation (Pd/C or Raney nickel) – the cleanest and fastest on a laboratory or pilot scale, and the one that carries the most specific hazard for this molecule: hydrogenolysis of the aryl chloride. On palladium, a fraction of the C–Cl bond at C3 is reduced during the same hydrogenation that reduces the nitro group, producing 4-fluoroaniline as the characteristic by-product. Because 4-fluoroaniline is structurally very close to the target, it survives crystallisation and shows up in the final GC as a shoulder rather than as a separate peak. Controlling catalyst loading, hydrogen pressure and temperature, and stopping at the point of nitro conversion, is the whole art of this route.
- Sodium dithionite or sodium sulfide reduction – selective for the nitro group and much less aggressive towards the aryl chloride, at the cost of a sulfur-containing effluent stream and the need to control sulfide residues.
For a buyer, this matters because the impurity specification (≤ 0.30% in this grade) is mostly a statement about which reduction route the plant runs. A certificate from a hydrogenation plant and a certificate from an iron-reduction plant, both showing 99.0% assay, can describe very different impurity patterns – and only one of them will behave well in the next step if that next step is sensitive to a dehalogenated amine.
4. Grades, Specifications and Quality Control
| Parameter | Typical commercial specification | What it protects |
|---|---|---|
| Assay (GC, area%) | ≥ 99.00% | Overall purity of the batch |
| Single impurity | ≤ 0.30% | Limits the largest single closely-related species |
| Water (Karl Fischer) | ≤ 0.10% | Storage stability, weighing accuracy, downstream water-sensitive steps |
| Appearance | White to off-white crystalline solid | Indicator of oxidation or wet storage |
| Isomer identity | Positional purity of the 3-chloro-4-fluoro isomer | The single most under-specified parameter in the market |
There is a fourth number that buyers increasingly ask for and that is not always on the CoA by default: the positional (isomeric) purity. A GC area percentage tells you how much of the main peak there is; it does not tell you whether 0.4% of the material is 4-chloro-3-fluoroaniline sitting underneath the same integration window. For a building block whose whole value is where the halogens sit, the isomer ratio is the real identity parameter, and a supplier who cannot state it is asking the buyer to trust the plant’s crystallisation.
Water is the second practical control. Halogenated anilines are hydroscopic and, more importantly, wet material darkens: oxidation to coloured oligomers is accelerated by moisture and light, and the resulting batch may still pass assay while failing an appearance or solution-colour specification downstream.
5. The Isomer Landscape: Why 3-Chloro-4-Fluoro Is Not Interchangeable
Halogenated anilines are a family in which several members have almost the same molecular formula, almost the same molecular weight and almost the same chromatographic behaviour, but completely different downstream chemistry. Mixing them up is one of the most common and most expensive mistakes in fine-chemical procurement.
| Isomer | CAS | Distinguishing feature | Practical consequence |
|---|---|---|---|
| 3-Chloro-4-fluoroaniline | 367-21-5 | Cl meta, F para to NH2 | F is inert, Cl is the available handle; the pattern most fluoroquinolone routes need |
| 4-Chloro-3-fluoroaniline | 367-22-6 (isomer entry) | Cl para, F meta | Swaps which halogen can be displaced; changes coupling and cyclisation outcome |
| 3,5-Dichloro-4-fluoroaniline | 2729-34-2 | Two chlorines | Different formula and molecular weight – detectable by mass, not by GC retention |
| 4-Fluoroaniline | 371-40-4 | Only fluorine, no chlorine | The classic dehalogenation by-product of catalytic hydrogenation |
Two consequences follow. First, a molecular formula and a molecular weight will not protect you between positional isomers: 3-chloro-4-fluoro and 4-chloro-3-fluoro have the same C6H5ClFN and the same 145.56, and no mass-based method distinguishes them. Second, GC retention time is a weak identity test on this family, because the isomers differ mainly in electron distribution rather than in volatility; a proper identification needs either an authentic reference standard, an NMR check, or a mass-spectrometric fragmentation pattern compared against a standard.
The practical procurement rule is therefore: specify the CAS number, not the name. Names such as “chlorofluoroaniline” are ambiguous in catalogues, and translated names are worse. The CAS 367-21-5 is the only unambiguous identifier, and it should appear on the purchase order, the CoA and the label.
6. Applications in Pharmaceutical Synthesis
The largest single use is as a building block for fluoroquinolone-type antibacterial structures, where a 3-chloro-4-fluoro-substituted aniline fragment is required. The molecule’s job in those routes is to supply a benzene ring already carrying the right halogen pattern, so that the later cyclisation and side-chain steps do not have to introduce halogens onto an already elaborated scaffold – a transformation that is much harder to do selectively on a complex intermediate.
The practical advantages the aniline offers in a pharmaceutical campaign are:
- A single reactive handle. The amino group is the only strongly nucleophilic site, so acylation, alkylation and condensation steps can be run without protecting the ring.
- A fluorine that stays put. Aryl fluorines are not displaced under the nucleophilic conditions used in most aminations and cyclisations, so the para position remains a spectator while the rest of the molecule is built.
- A chlorine that can be used later. The meta chlorine is a usable leaving group for palladium-catalysed amination or for a second halogen exchange if the route needs it, which gives process chemists a late-stage option.
- Diazotisation as an entry point. The amino group converts to a diazonium salt cleanly, opening routes to aryl hydrazines, azides and azo compounds that are useful in heterocycle construction.
These are the reasons a project team will specify this exact isomer rather than a cheaper chloroaniline: the halogen pattern is doing structural work, not just electronic work.
7. Applications in Agrochemicals, Dyestuffs and Fine Chemicals
In crop-protection synthesis the same logic applies: the aniline supplies a halogenated aromatic fragment into herbicidal and fungicidal active ingredients, and the positional pattern again determines the biological activity of the final molecule. Because agrochemical routes are usually run at much larger tonnage than pharmaceutical routes, the cost of the starting aniline matters more, and the pressure to use an iron reduction rather than a catalytic hydrogenation is stronger – which brings the impurity discussion of Section 3 back into play.
Beyond these two, the molecule appears in:
- Dyestuff chemistry – diazotisation and coupling to azo colourants, and as a precursor to substituted aryl hydrazines.
- Cross-coupling substrates – the aryl chloride accepts palladium-catalysed amination (Buchwald-Hartwig type) and related transformations, which is why this molecule turns up in ligand and catalyst screening work.
- Building-block libraries – medicinal chemistry suppliers stock it because 3-chloro-4-fluoro is a recurring motif in kinase and antibacterial scaffolds.
8. Handling, Safety and Regulatory Notes
Aromatic amines require respect in the plant and in the warehouse. The key points for this material:
- Skin absorption and sensitisation. Anilines penetrate skin readily; repeated exposure can produce sensitisation, and the classic systemic effect of aromatic amines is methaemoglobinaemia. Gloves (nitrile, not latex), goggles and a lab coat are minimum; avoid dust generation when weighing.
- Storage. Keep dry, cool, away from acids, acid chlorides, oxidising agents and direct sunlight. Anilines darken on air and light exposure; close containers promptly and consider nitrogen blanketing for long storage.
- Water and effluent. Halogenated anilines are toxic to aquatic organisms. Do not release to drains; plant effluent treatment must be able to handle the aryl amine load.
- Transport. Classified as a toxic solid on the basis of its amine character; the transport classification, packing group and UN number must be read from the supplier’s SDS for the specific grade rather than assumed.
Hazard notice: 3-Chloro-4-fluoroaniline is a halogenated aromatic amine. It is harmful if swallowed or in contact with skin, causes skin and eye irritation, may cause an allergic skin reaction, and is toxic to aquatic life. Handle with appropriate personal protective equipment and local exhaust ventilation. This page describes industrial use by qualified personnel and is not a substitute for the supplier’s Safety Data Sheet or for a site-specific risk assessment.
On the regulatory side, this is a standard industrial intermediate and not a controlled substance; it is, however, subject to general chemical control regimes in most jurisdictions (inventory listing, transport classification, and in some markets reporting obligations for aromatic amines). Buyers should confirm the import requirements of their own jurisdiction – the fact that a compound is not “controlled” does not mean it moves without documentation.
9. Procurement Guide
| Decision | What to specify | Why it matters |
|---|---|---|
| Identity | CAS 367-21-5 written on the PO, CoA and label | Names are ambiguous across the isomer family |
| Assay | ≥ 99.00% by GC, with the method stated | “99%” without a method is not a specification |
| Impurity | Single impurity ≤ 0.30%; ask whether 4-fluoroaniline is reported separately | Reveals the reduction route and the main risk impurity |
| Water | ≤ 0.10% by Karl Fischer | Storage stability and appearance |
| Isomeric purity | State the 3-chloro-4-fluoro positional purity, or ask for an NMR confirmation | The parameter most often missing and most costly to get wrong |
| Packaging | 25 kg fibre drum with inner liner; confirm pallet and container loading | Anilines need a moisture barrier |
| Documentation | CoA per batch, SDS in the required language, and where needed a non-GMO / allergen / origin statement | Pharma and agro customers audit documentation, not just assay |
| Logistics | Confirm the UN number and packing group before booking | Changes the freight class and the carrier acceptance |
A practical verification on arrival: check that the CoA batch number matches the drum label, that the appearance is white to off-white rather than brown, and that the water content is within spec on your own Karl Fischer. Aniline batches that have absorbed moisture during a long sea freight often pass assay on re-test but have drifted in colour, and colour drift is the leading cause of a rejected lot in the customer’s plant.
10. Frequently Asked Questions
What is 3-chloro-4-fluoroaniline used for?
Mainly as an intermediate: it supplies a 3-chloro-4-fluoro-substituted benzene ring into fluoroquinolone-type antibacterial syntheses and into agrochemical active ingredients, and it also serves dyestuff chemistry and palladium-catalysed coupling work. See the full technical overview for the downstream routes.
Can 4-chloro-3-fluoroaniline be substituted for it?
No. The two are positional isomers with identical molecular formula and molecular weight, but different chemistry: in one the chlorine is the displaceable handle and the fluorine is inert, in the other the roles are reversed. Substitution changes the outcome of coupling and cyclisation steps. Specify the CAS number.
What is the typical impurity in this product?
The characteristic by-product depends on the reduction route. Catalytic hydrogenation over palladium can dehalogenate part of the material to 4-fluoroaniline; iron-acid reduction tends to leave a different profile. Ask the supplier which reduction route the plant runs, and ask for 4-fluoroaniline to be reported separately.
How should it be stored?
Dry, cool, out of direct sunlight, away from acids, acid chlorides and oxidising agents. Keep containers closed; anilines darken on air exposure. For storage beyond a few months, nitrogen blanketing is worth considering.
Is it a controlled substance?
No – it is a standard industrial intermediate, not a narcotic, precursor or scheduled chemical. It is nevertheless a hazardous material for transport and a toxic substance for aquatic life, so normal hazardous-goods documentation applies. Confirm your own jurisdiction’s import requirements.
References and Further Reading
- CAS Registry Number 367-21-5; PubChem CID 9708 (molecular formula C6H5ClFN, molecular weight 145.56 g/mol).
- Halex (halogen exchange) fluorination practice: potassium fluoride in dipolar aprotic media, reviewed in standard organofluorine process literature.
- Aromatic amine reduction routes and the hydrogenolysis of aryl chlorides: see standard catalytic hydrogenation practice for substituted nitroaromatics.
- Related reading on this site: Chlorofluoroaniline Isomers: How to Specify the Right One and Buying Halogenated Anilines.
Disclaimer: this article describes the chemistry and industrial handling of 3-chloro-4-fluoroaniline for qualified professional readers. It is not a safety data sheet, not a substitute for a site-specific risk assessment, and not a recommendation for any particular use. Analytical values quoted are typical commercial specifications; the specification that applies to your order is the one stated on the certificate of analysis for that batch.
Request a quotation for 3-chloro-4-fluoroaniline (CAS 367-21-5): send the quantity, required purity and destination port to polybluechem@163.com. COA and SDS available on request.