2-Chloro-3-cyanopyridine (CAS 6602-54-6) is one of the most useful small heterocyclic building blocks in the catalogue, and one of the most frequently mis-ordered. The molecule carries two functional groups on adjacent ring positions, and their arrangement is what makes it valuable: the chlorine sits ortho to the ring nitrogen, which means it is displaced by nucleophiles under remarkably mild conditions, while the nitrile one position away can be hydrolysed, reduced or cyclised in a separate step. Buy one starting material, run two independent chemistries.
Two things go wrong commercially. First, the compound is sold under at least four names – 2-chloro-3-cyanopyridine, 2-chloronicotinonitrile, 2-chloropyridine-3-carbonitrile and 2-chloro-3-pyridinecarbonitrile – and several positional isomers exist under confusingly similar names. Second, purity specifications for this material are usually written as “99% min, single impurity 0.2% max”, which bounds the largest peak but not the total. This article covers the identity problem, the manufacturing routes, the reactivity that makes the molecule worth buying, the analytical methods that actually distinguish it from its isomers, and the specification logic a buyer should impose.
The material is catalogued on our 2-chloro-3-cyanopyridine product page.
1. Identity: one compound, four names, several isomers
| Item | Value |
|---|---|
| Preferred name | 2-chloropyridine-3-carbonitrile |
| Common trade names | 2-chloro-3-cyanopyridine; 2-chloronicotinonitrile; 2-chloro-3-pyridinecarbonitrile |
| CAS | 6602-54-6 |
| Formula / MW | C6H3ClN2 / 138.55 |
| Elemental composition | C 52.01%, H 2.18%, Cl 25.58%, N 20.22% |
| InChIKey | JAUPUQRPBNDMDT-UHFFFAOYSA-N |
| PubChem CID | 81079 |
| Melting point | 105-108 degC |
The “nicotinonitrile” name in commercial use refers to the 3-cyano-2-substituted arrangement, following the pyridine numbering convention in which the carboxyl-derived position becomes 3. That convention is a trap for anyone reading a catalogue quickly, because “2-chloronicotinonitrile” and “2-chloro-3-cyanopyridine” sound like different molecules from different numbering systems and are in fact the same compound. The only safe purchasing practice is to order by CAS.
The reason the naming matters is that the positional isomers are all real, all commercially available, and all isobaric at m/z 138.5. 2-Chloro-5-cyanopyridine, 2-chloro-4-cyanopyridine and 6-chloro-2-cyanopyridine differ from this compound only in where the two substituents sit on the ring. They cannot be distinguished by molecular weight, by nominal mass spectrometry, or by elemental analysis. They differ in melting point, in retention time, in NMR chemical shifts, and in the chemistry they will do for you – which is exactly why a supplier substitution is both easy to make and expensive to discover late.
The selection logic between the chlorocyanopyridine isomers, and the four tests that prove which one is in the drum, are set out in Chlorocyanopyridine Isomer Selection.
2. Why the substitution pattern matters chemically
Pyridine is electron-poor, and the ring nitrogen activates the ortho and para positions towards nucleophilic attack. In this molecule the chlorine at C-2 is ortho to the nitrogen, so it is activated twice: once by the ring’s general electron deficiency and once specifically by the adjacent nitrogen, which stabilises the Meisenheimer intermediate. A 3-chloro isomer would be roughly an order of magnitude less reactive under the same conditions; a 4-chloro isomer would be intermediate.
| Chlorine position | Activation relative to the ring nitrogen | Practical consequence |
|---|---|---|
| C-2 (this product) | ortho – strongest | displacement by amines, alkoxides, thiolates and cyanide at 60-100 degC in ordinary solvents |
| C-3 | meta – weakest | needs harsher conditions or palladium catalysis |
| C-4 | para – intermediate | useful but slower; often best done by cross-coupling |
That is the entire commercial logic of the C-2 isomer: it is the position where the chlorine is cheapest to remove, and removing it is how you install the substituent you actually want.
3. Manufacturing routes
Four route families appear in patents and in the process literature. They differ in starting material, in step count and in the impurity they leave behind.
3.1 From 2-aminonicotinonitrile by diazotisation
The most direct: 2-aminonicotinonitrile is diazotised and the diazonium group replaced by chloride – Sandmeyer conditions with copper(I) chloride and hydrochloric acid, or a modern nitrite/halide system. The chemistry is textbook and the yield is good, but the economics depend entirely on the availability of the aminonitrile, which in turn comes from ammonia displacement on this very compound. In practice plants run the pair as a cycle: some of the 2-chloro product is converted to the 2-amino compound, and some of the 2-amino compound is converted back.
3.2 From 2-chloronicotinic acid by amidation and dehydration
2-Chloronicotinic acid is converted to the amide – through the acid chloride with ammonia, or by an ammonia/activating-agent route – and the amide is dehydrated to the nitrile with a reagent such as phosphorus oxychloride, thionyl chloride in dimethylformamide, or trifluoroacetic anhydride. The dehydration step is the one that decides the impurity profile, because over-conditions chlorinate the ring further and under-conditions leave amide in the product. Residual amide is the impurity to look for in this route: it is close in retention to the product and it hydrolyses onward to the acid, so a lot with a 0.5% amide peak will drift on storage.
3.3 From 2-chloropyridine by directed metalation
2-Chloropyridine can be deprotonated at C-3 with a strong hindered base such as lithium diisopropylamide at low temperature, and the resulting aryllithium quenched with dimethylformamide to give 2-chloropyridine-3-carbaldehyde. Conversion of the aldehyde to the nitrile follows by oxime formation and dehydration, or by direct oxidative amination. This route is elegant, avoids the acid, and is the one most often used for isotopically labelled or otherwise special batches, because it builds the carbon skeleton from cheap chloropyridine.
3.4 From 3-cyanopyridine via the N-oxide
3-Cyanopyridine is oxidised to the N-oxide and treated with phosphorus oxychloride or with trimethylsilyl cyanide under Reissert-Henze conditions to introduce the 2-chloro (or 2-cyano) substituent. This family is closest to the classical heterocycle literature and is used where 3-cyanopyridine is cheaper than 2-chloropyridine.
Whichever route is run, the final product is isolated by crystallisation or by distillation and the melting point is the last identity gate: the 105-108 degC window is narrow enough that a wrong isomer or a heavily contaminated lot rarely lands inside it.
4. Specification logic
| Parameter | Our specification | What it controls |
|---|---|---|
| Appearance | White or off-white crystalline powder | general cleanliness; colour in this product usually means ring chlorination or iron |
| Assay (HPLC) | 99.0% min | total UV-active purity |
| Single impurity | 0.2% max | largest single peak; bounds the worst case, not the total |
| Moisture (KF) | 0.2% max | hydrolysis margin for the nitrile |
| Melting point | 105-108 degC | identity and crystalline purity in one number |
Two of these lines deserve a closer look.
Moisture at 0.2% is a stability specification, not a cosmetic one. The nitrile group hydrolyses to the amide in the presence of water, and the rate rises steeply with temperature. At 0.2% moisture the drum has a large margin; at 1% moisture a warm warehouse will convert measurable amounts of product to amide over months, and the customer will see a new peak in front of the main one. If the material is destined for a long sea freight or for storage in a tropical climate, a moisture limit of 0.2% plus a moisture-barrier liner is worth insisting on.
Assay 99.0% with 0.2% single impurity leaves up to 1.0% unaccounted, distributed across smaller peaks. If your next step is a regioselective displacement, that unspecified fraction matters: any residual positional isomer will react at the wrong position and produce an isomeric impurity that can be very hard to purge downstream. Ask for a total-impurity limit of 0.5% and an unspecified-impurity limit of 0.1% when the material feeds a regulated process.
5. Reactivity and downstream products
The two functional groups are orthogonal in practice, which is why the compound sells.
| Chemistry | Conditions (typical) | Product | Use of the product |
|---|---|---|---|
| Ammonolysis (S-NAr) | ammonia in methanol or aqueous ammonia, 60-90 degC, pressure | 2-aminonicotinonitrile | precursor to pyrido[2,3-d]pyrimidines and other fused heterocycles |
| Alkoxide displacement | sodium alkoxide in the corresponding alcohol | 2-alkoxynicotinonitriles | agrochemical and pharmaceutical intermediates |
| Thiolate displacement | thiol plus base, or thiolate salt | 2-alkylthionicotinonitriles | sulfur-containing heterocycle libraries |
| Cyanide displacement | sodium or potassium cyanide in a polar aprotic solvent | pyridine-2,3-dicarbonitrile | tetradentate ligand precursors and dinitrile chemistry |
| Nitrile hydrolysis | controlled acid or base, then pH adjustment | 2-chloronicotinic acid or 2-chloro-3-carbamoylpyridine | the acid is itself a major building block |
| Nitrile reduction | hydrogen with a nickel or cobalt catalyst, or a hydride | 3-(aminomethyl)-2-chloropyridine | benzylic amine for reductive amination |
| Cyclisation | hydrazine, amidines or amidinium salts | fused pyridine heterocycles | kinase-inhibitor and herbicide cores |
The sequence worth memorising is the one that gives 2-aminonicotinonitrile: it is the gateway to the largest family of fused-ring products, and it is the reason the C-2 chlorine is a better leaving group to have than a C-3 or C-4 chlorine. Note also that hydrolysis and displacement compete when water is present and the pH is wrong – a common cause of a batch of “2-chloronicotinic acid” contaminated with 2-aminonicotinic acid.
6. Analytical control
Four techniques cover everything a buyer needs to defend.
- HPLC-UV. C18, water-acetonitrile or methanol gradients, detection near 254 nm. The pyridine nitrile absorbs strongly; a 20 minute gradient resolves the amide, the acid and the positional isomers.
- Melting point. The 105-108 degC window is a cheap identity gate, and a depressed or wide range is the first sign of an isomer or a wet lot.
- 13C NMR. The carbon bearing the chlorine and the nitrile carbon have characteristic shifts; comparing the six aromatic carbons against an authentic spectrum distinguishes the positional isomers unambiguously.
- Karl Fischer. Because moisture is the stability specification, it should be measured on every lot rather than on a composite.
Elemental analysis – chlorine near 25.6% and nitrogen near 20.2% – is a useful independent check when a supplier’s identity is in question, since no isomer differs in composition but a blend, a hydrate or a different heterocycle will.
7. Storage, packaging and handling
Store cool and dry, below 25 degC, in a closed container. The two enemies are water and amine vapour: moisture drives nitrile hydrolysis, and ammonia or amine vapours from nearby materials can displace the chlorine on the surface of the powder. Keep the material away from acids, bases and strong nucleophiles, and do not store it in the same cabinet as ammonia solutions.
Standard packaging is 25 kg net in fibre drums with a polyethylene liner; 1 kg and 5 kg packs are available for development. The solid is a fine organic powder and should be handled with dust control and local exhaust ventilation; an SDS accompanies every shipment.
8. Applications
8.1 Pharmaceutical intermediates
The dominant use is as an early-stage building block for heterocyclic drug candidates. Its attraction is that it delivers a pyridine ring with two differentiated handles in one cheap, crystalline, high-purity solid, so a medicinal chemistry route can branch late.
8.2 Agrochemical intermediates
2-Substituted nicotinonitriles and the acids derived from them appear in the synthesis of nicotinyl insecticides and herbicidal pyridinecarboxylates. For the agricultural side of this chemistry see From 2-Chloronicotinonitrile to 2-Aminonicotinonitrile.
8.3 Ligands and materials
Displacement of the chlorine with cyanide gives pyridine-2,3-dicarbonitrile, a precursor to tetradentate nitrogen ligands used in catalysis and in coordination chemistry.
9. Purchasing guide
- Order by CAS 6602-54-6 and require the CAS to appear on the certificate and on the drum label.
- Require a melting point on every lot; it is the cheapest isomer test available.
- Require named impurities where the downstream chemistry is regioselective: residual amide, residual acid, and total unspecified.
- Set the moisture limit against the shipping route and the storage climate, not against habit.
- For regulated processes, agree an analytical method transfer and a retained-sample protocol before the first commercial lot.
10. Frequently asked questions
Is 2-chloro-3-cyanopyridine the same as 2-chloronicotinonitrile?
Yes – one compound, three naming conventions, one CAS 6602-54-6. The “nicotinonitrile” name follows pyridine numbering from the carboxyl position; the “3-cyanopyridine” name describes the substituent directly.
How do I know I have the right isomer?
Melting point (105-108 degC for this isomer), HPLC retention against an authentic standard, and 13C NMR. Molecular weight, nominal mass and elemental analysis cannot distinguish positional isomers.
Why does the specification stop at a single-impurity limit?
Because most commercial product is sold into general synthesis, where a 1% total impurity is acceptable. For a regulated downstream step, add a total-impurity limit and an unspecified-impurity limit; both are standard requests and both are quotable.
What happens if the material picks up moisture in storage?
The nitrile hydrolyses to the amide, which shows up as a new peak just before the main one in HPLC and as a depressed, widened melting range. Store dry and keep the drum closed; if the material is old, re-test rather than assume.
What quantities are available?
Kilogram to multi-tonne, with development samples from 100 g. Each lot ships with a certificate covering assay, impurities, moisture and melting point, plus SDS.
References and scope note
Formula and elemental arithmetic are reproducible from standard atomic weights; identity data are cross-checked against public chemical databases (PubChem CID 81079). Reaction conditions quoted are typical literature and industrial ranges for orientation, not validated process instructions. No claims are made about the safety of any downstream product.
This article is technical and commercial orientation only. It is not a substitute for process validation, hazard assessment or regulatory advice.
PolyBlueChem supplies 2-chloro-3-cyanopyridine 99% with lot-specific certificates. Contact polybluechem@163.com for pricing, samples or a specification written against your downstream step.