Carbon–Carbon Bond Formation

Spec Mapping — OCR H432 Module 6.2.6 — Carbon-carbon bond formation in organic synthesis, covering the strategic importance of new C-C bond formation as the only way to lengthen a carbon skeleton; nucleophilic substitution of cyanide ion on haloalkanes (RCH₂X + CN⁻ → RCH₂CN; KCN in ethanol, reflux; SN2 for primary RX); nucleophilic addition of HCN to aldehydes and ketones to give 2-hydroxynitriles (Lesson 2 mechanism recapped; KCN/H₂SO₄ in practice; racemic product from prochiral carbonyl); acid hydrolysis of nitriles to carboxylic acids (dilute HCl, prolonged reflux); reduction of nitriles to primary amines (LiAlH₄ in dry ether, or H₂/Ni at high T/P); Friedel-Crafts acylation of benzene (R-COCl + benzene + anhydrous AlCl₃ Lewis acid catalyst, reflux; acylium-ion electrophile; mono-substitution because the product ketone deactivates the ring); strategic retrosynthesis — counting carbons, choosing one-carbon nitrile extension vs multi-carbon Friedel-Crafts acylation vs same-carbon-count functional-group interconversion; combined multi-step synthesis worked examples ending in carboxylic acids, primary amines and alpha-amino acids (refer to the official OCR H432 specification document for exact wording).

So far almost every reaction in OCR Module 6 has interconverted one functional group with another while keeping the carbon skeleton fixed — alcohol to aldehyde to acid (oxidation), ketone to alcohol (reduction), alcohol plus acid to ester (esterification), ester to acid plus alcohol (hydrolysis). All very useful, but none of them build new carbon-carbon bonds. Real synthesis — making a drug, a fragrance, a polymer monomer, or a fine chemical from a cheap feedstock — almost always demands at least one step in which the carbon chain grows. The A-Level toolkit for this is deliberately small: two reactions that install a -CN group (and so extend the chain by exactly one carbon), and one reaction that installs an acyl group on benzene via Friedel-Crafts acylation (extending the chain by two or more carbons, depending on the acyl chloride used). Master these three reactions and the follow-up chemistry of nitriles (hydrolysis to acids, reduction to primary amines), and you can plan multi-step syntheses linking almost any A-Level starting material to almost any A-Level target — including the alpha-amino acids of Lesson 8. This lesson develops each of the three C-C bond-forming reactions, their mechanisms in summary form, two worked retrosynthetic problems, and the strategic decision-making that turns a synthesis question from a guessing game into a tractable counting exercise.

Key Definition — Carbon-carbon bond formation: a reaction in which a new C-C sigma bond is created, lengthening the carbon skeleton of the product compared with the starting material. At A-Level the three examined methods are nucleophilic substitution of cyanide on a haloalkane (RX + CN⁻ → RCN), nucleophilic addition of HCN to a carbonyl (RR'CO + HCN → RR'C(OH)CN), and Friedel-Crafts acylation of benzene (C₆H₆ + RCOCl/AlCl₃ → C₆H₅COR + HCl). All other A-Level reactions are functional-group interconversions that preserve carbon count.

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1. Why C-C Bond Formation Matters Strategically

Almost every pharmaceutical, agrochemical, dye, polymer monomer or fine-chemical product is built up from cheap one- and two-carbon feedstocks — methane, ethene, methanol, ethanol — by sequences that lengthen the carbon chain step by step. The synthetic chemist's toolkit for extending a chain is much richer at university and beyond (Wittig, Heck, Suzuki, Grignard, aldol), but at A-Level OCR confine themselves to three reactions. They are deliberately chosen to teach the strategic principle: every retrosynthetic plan starts by counting carbons, deciding whether you need to add some, and choosing a C-C bond-forming step accordingly.

The OCR toolkit:

Reaction	Bond formed	Starting material	Extends chain by	Useful follow-up
Haloalkane + KCN	C-C	Primary haloalkane R-X	1 C (as -CN)	Hydrolyse to acid, or reduce to amine
Carbonyl + HCN	C-C	Aldehyde or ketone	1 C (as -CN, on a new chiral C with -OH)	Hydrolyse to 2-hydroxy acid
Friedel-Crafts acylation	C-C	Benzene (or arene)	2+ C (as acyl group)	Reduce ketone to 2° alcohol, or further C-C extension via HCN

The other big "win" of these three reactions is that the products are not just longer-chained — they are also functionalised. The nitrile group -CN can be hydrolysed to -COOH (giving a carboxylic acid one carbon longer than the haloalkane) or reduced to -CH₂NH₂ (giving a primary amine one carbon longer). Friedel-Crafts adds an acyl group, which is itself the ketone functional group ready for reduction, HCN addition, etc. So every C-C bond-forming reaction in this lesson also installs a useful handle for further chemistry.

Strategic principle: If the target has more carbons than the starting material, a C-C bond-forming step is mandatory. If the target has the same number of carbons, only functional-group interconversion is needed. If the target has fewer carbons, you almost certainly chose the wrong starting material — A-Level questions rarely require chain shortening.

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2. Route 1: Haloalkane + Cyanide — Detail and Solvent Choice

The first chain-extending reaction installs a cyano group (-CN) by SN2 substitution of cyanide ion onto a primary haloalkane. You met this back in Module 4.2.2 (haloalkanes); here we revisit it as a strategic C-C bond-forming step.

2.1 The reaction and conditions

$CH_3CH_2Br + KCN \longrightarrow CH_3CH_2CN + KBr$CH3​CH2​Br+KCN⟶CH3​CH2​CN+KBr

• Nucleophile: Cyanide ion CN⁻ (from KCN dissolved in ethanol).
• Substrate: Primary haloalkane (works less cleanly for secondary; tertiary tends to eliminate).
• Solvent: Ethanol (NOT aqueous — water would compete as a nucleophile and would also slowly hydrolyse the product nitrile).
• Conditions: Heat under reflux (gentle boiling with a vertical condenser to prevent loss of volatile CN⁻/HCN).
• Mechanism: SN2 — concerted backside attack of CN⁻ on the carbon bearing X, with simultaneous departure of X⁻ as a leaving group.
• Product: A nitrile RCN with one more carbon than the starting RX, because the CN carbon is now part of the chain.

So CH₃CH₂Br (2 carbons) → CH₃CH₂CN (3 carbons, called propanenitrile).

2.2 Mechanism in one diagram

graph LR
  A[CN- approaches C bearing Br from opposite face] --> B[Transition state with partial C-CN and partial C-Br bonds]
  B --> C[Br- leaves with both bonding electrons]
  C --> D[Inversion of configuration at C]
  D --> E[Product: R-CN nitrile]

If the starting haloalkane was chiral at the C bearing Br, the product nitrile has the opposite configuration at that centre because SN2 proceeds with inversion (Walden inversion). This is the same stereochemistry rule you met for haloalkanes + OH⁻.

2.3 Why ethanolic, not aqueous?

If you used aqueous KCN, water (or the OH⁻ formed when KCN dissolves) would compete as a nucleophile and the haloalkane would give a mixture of the desired nitrile and an alcohol by-product. The same solvent choice appears in the haloalkane + KOH lessons: ethanolic KOH gives elimination (E2) while aqueous KOH gives substitution (SN2 → alcohol). With KCN we always want ethanolic, because we are after the SN2 product.

Nomenclature watch: The nitrile CH₃CH₂CN has three carbons total — the CN carbon is C1, then the CH₂ is C2, then the CH₃ is C3. Hence it is named propanenitrile. Students routinely miscount this — the CN counts as one of the carbons. CH₃CN is therefore ethanenitrile, not methanenitrile.

2.4 Section recap

Step	Reagent	Solvent	Mechanism	Net change
Haloalkane + KCN	KCN	Ethanol	SN2	R-X → R-CN (+1 C)

2.5 Two ways forward — hydrolysis or reduction

Once you have the nitrile, you can carry it forward two ways. Both keep the same carbon count as the nitrile (so both still have one more carbon than the original haloalkane).

Hydrolysis to a carboxylic acid:

$CH_3CH_2CN + 2H_2O + HCl \longrightarrow CH_3CH_2COOH + NH_4Cl$CH3​CH2​CN+2H2​O+HCl⟶CH3​CH2​COOH+NH4​Cl

• Conditions: Dilute HCl (or aqueous H₂SO₄), prolonged reflux. Alternative route: aqueous NaOH, reflux, then acidify.
• Net change: -CN becomes -COOH. The N atom leaves as ammonium (or ammonia after acidification).
• Mechanism in outline: the nitrile is protonated on N; water attacks the carbon of the C≡N; tautomerisation gives an amide R-CONH₂; the amide is then hydrolysed further to the carboxylic acid + NH₄⁺. The amide is a genuine intermediate but is rarely isolated.

Reduction to a primary amine:

$CH_3CH_2CN + 4[H] \longrightarrow CH_3CH_2CH_2NH_2$CH3​CH2​CN+4[H]⟶CH3​CH2​CH2​NH2​

• Conditions: LiAlH₄ in dry ether (or H₂ with Ni catalyst at high pressure and temperature for industrial scale).
• Net change: -CN becomes -CH₂NH₂. Two hydrogens added across the C≡N triple bond plus one H to the N (4[H] in total).

Common confusion: Reduction of -CN to -CH₂NH₂ does not add an extra carbon — the CH₂ in the product is the same C that was already in the CN. The chain was already extended by 1 when the CN was first installed; reduction just turns C≡N into CH₂-NH₂.

Why this route is preferred for making primary amines: going via the nitrile is cleaner than the haloalkane + NH₃ route (Lesson 6) because excess NH₃ on a haloalkane gives a mixture of primary, secondary, tertiary and quaternary amines, while the nitrile route gives only the primary amine. The disadvantage is that you commit a separate carbon-extension step.

2.6 Worked example — propan-1-ol to butanoic acid

Task: Plan a synthesis of butanoic acid (CH₃CH₂CH₂COOH, 4C) from propan-1-ol (CH₃CH₂CH₂OH, 3C).

Carbon-count audit: 3 → 4, so we need exactly one chain extension. The nitrile route via haloalkane fits.

1. Convert alcohol to haloalkane. Propan-1-ol + HBr (or NaBr + H₂SO₄, or PBr₃) → 1-bromopropane CH₃CH₂CH₂Br. Conditions: reflux with concentrated HBr (or in situ from NaBr + concentrated H₂SO₄).
2. Substitute Br with CN. 1-bromopropane + ethanolic KCN, heat under reflux → butanenitrile CH₃CH₂CH₂CN. The chain has now grown to 4 carbons.
3. Hydrolyse the nitrile. Butanenitrile + dilute HCl(aq), prolonged reflux → butanoic acid CH₃CH₂CH₂COOH.

The carbon chain has grown by exactly 1 (3 to 4), and we have produced the target acid. Total reagents used: HBr, ethanolic KCN, dilute HCl — all standard A-Level reagents.

graph TD
  A[Haloalkane R-Br] --> B[+ KCN / ethanol, reflux]
  B --> C[Nitrile R-CN, +1 carbon]
  C --> D[+ H2O / H+, reflux: carboxylic acid R-COOH]
  C --> E[+ LiAlH4 / ether: primary amine R-CH2-NH2]

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3. Route 2: Carbonyl + HCN (Nucleophilic Addition)

The second chain-extending reaction was developed in Lesson 2 as the canonical mechanism of carbonyl chemistry: an aldehyde or ketone reacts with HCN (in practice KCN/dilute H₂SO₄) to give a 2-hydroxynitrile.

3.1 The reaction

$CH_3CHO + HCN \longrightarrow CH_3CH(OH)CN$CH3​CHO+HCN⟶CH3​CH(OH)CN

• Reagents: KCN with dilute H₂SO₄ (this generates HCN in situ — pure liquid HCN is too toxic and volatile to handle directly in a school lab).
• Substrate: Any aldehyde or ketone.
• Mechanism: Nucleophilic addition (Lesson 2 — CN⁻ attacks the delta+ carbonyl C; the resulting alkoxide is protonated).
• Product: A 2-hydroxynitrile (an alpha-hydroxy nitrile), with -CN on the former carbonyl carbon and -OH next door.
• Extends chain by 1 C (the new C comes from the CN⁻ that attacked).

3.2 The new chiral centre

If the carbonyl carbon was unsymmetrical (i.e. the two R groups attached to it are different — true for any aldehyde and many ketones), the product has a new chiral centre at that former carbonyl carbon. The CN⁻ can attack from either face of the planar sp² carbonyl with equal probability, so the product is a racemic mixture of the (R) and (S) enantiomers in 50:50 ratio.

Pharmaceutical importance: Racemic hydroxynitrile mixtures are a problem for drug synthesis because usually only one enantiomer is biologically active (Lesson 8 — thalidomide). University-level synthesis uses chiral catalysts to bias the attack and get a single enantiomer, but the A-Level student should simply note "racemic" when asked.

3.3 Hydrolysis to a 2-hydroxy carboxylic acid

The hydroxynitrile can be hydrolysed in the same way as any nitrile, converting -CN to -COOH but leaving the -OH untouched:

$CH_3CH(OH)CN + 2H_2O + HCl \longrightarrow CH_3CH(OH)COOH + NH_4Cl$CH3​CH(OH)CN+2H2​O+HCl⟶CH3​CH(OH)COOH+NH4​Cl

This gives a 2-hydroxy carboxylic acid — a special class of acids that includes lactic acid (2-hydroxypropanoic acid) and mandelic acid (2-hydroxy-2-phenylethanoic acid). The product retains the chiral centre at C2, and is still racemic.

3.4 Worked example — ethanal to lactic acid

Task: Plan a synthesis of 2-hydroxypropanoic acid (lactic acid, CH₃CH(OH)COOH, 3C) from ethanal (CH₃CHO, 2C).

Carbon-count audit: 2 → 3, so one C-C bond-forming step. The HCN addition route to the carbonyl fits and conveniently delivers the -OH group on C2 in the same step.

1. HCN addition. Ethanal + KCN/dilute H₂SO₄ → 2-hydroxypropanenitrile CH₃CH(OH)CN. New chiral C; racemic.
2. Acid hydrolysis. 2-hydroxypropanenitrile + dilute HCl(aq), prolonged reflux → 2-hydroxypropanoic acid CH₃CH(OH)COOH. Still racemic.

Two steps, two reagent flasks, target achieved.

3.5 Strecker-style synthesis of an alpha-amino acid

A neat extension of the HCN-on-carbonyl idea, with one extra twist, makes an alpha-amino acid (Lesson 8). If the aldehyde is mixed with ammonia AND HCN, the carbonyl first condenses with NH₃ to form an imine (=NH replaces =O), and HCN then adds to the imine instead of a carbonyl, giving an alpha-aminonitrile R-CH(NH₂)-CN. Acid hydrolysis converts the -CN to -COOH, leaving R-CH(NH₂)-COOH — an alpha-amino acid.

Worked example — ethanal to alanine: Ethanal CH₃CHO + NH₃ + HCN → CH₃CH(NH₂)CN (2-aminopropanenitrile); hydrolysis with dilute HCl gives CH₃CH(NH₂)COOH — racemic alanine. Adjusting the starting aldehyde lets you make valine, leucine, phenylalanine and other alpha-amino acids.

History note: The reaction is named after Adolph Strecker, who reported it in 1850 as one of the very first laboratory syntheses of an amino acid (paraphrase). The modern version uses NaCN, ammonium chloride and a chiral catalyst to give a single enantiomer, but the Strecker concept of "imine + cyanide → aminonitrile → amino acid" is unchanged.

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4. Route 3: Friedel-Crafts Acylation

Benzene rings are aromatic and stabilised by delocalisation. They are unreactive towards nucleophiles, and even towards most electrophiles they prefer to keep their pi system intact. One of the very few reactions that successfully installs a substituent on the ring is Friedel-Crafts acylation, an electrophilic substitution that uses a strong Lewis acid catalyst to generate an exceptionally reactive electrophile — the acylium ion.

4.1 The reaction

$C_6H_6 + CH_3COCl \longrightarrow C_6H_5COCH_3 + HCl$C6​H6​+CH3​COCl⟶C6​H5​COCH3​+HCl

Benzene + ethanoyl chloride → 1-phenylethan-1-one (acetophenone) + HCl.

• Reagents: An acyl chloride RCOCl (typically ethanoyl chloride or benzoyl chloride) + anhydrous AlCl₃ catalyst.
• Solvent: Dry inert solvent (e.g. dry dichloromethane or excess substrate).
• Conditions: Reflux. Strict exclusion of water — water destroys the AlCl₃ catalyst by hydrolysing it to Al(OH)₃ + HCl.
• Catalyst role: AlCl₃ acts as a Lewis acid (electron-pair acceptor). It removes Cl⁻ from the acyl chloride to generate the acylium ion R-C≡O⁺ (or R-C⁺=O), which is the actual electrophile.

Why "anhydrous" matters: Even a trace of water destroys AlCl₃ (AlCl₃ + 3H₂O → Al(OH)₃ + 3HCl) and the catalyst is then inactive. OCR examiners look explicitly for the word "anhydrous" — saying just "AlCl₃" loses a mark.

4.2 Mechanism — three steps

Step 1 — generation of the electrophile: AlCl₃ removes Cl⁻ from the acyl chloride, forming the acylium ion CH₃CO⁺ and the tetrachloroaluminate anion AlCl₄⁻.

$CH_3COCl + AlCl_3 \longrightarrow CH_3CO^+ + AlCl_4^-$CH3​COCl+AlCl3​⟶CH3​CO++AlCl4−​

The acylium ion CH₃CO⁺ is stabilised by delocalisation between two resonance forms (CH₃-C⁺=O and CH₃-C≡O⁺) but is still strongly electrophilic at the central carbon.

Step 2 — electrophilic attack by benzene: The π electrons of the benzene ring attack the electrophilic carbon of the acylium ion, forming a new C-C sigma bond and breaking aromaticity to give a positively-charged cyclohexadienyl cation (Wheland intermediate). This step is rate-limiting.

Step 3 — loss of H⁺ and rearomatisation: AlCl₄⁻ acts as a base and removes the H⁺ from the sp³ carbon of the intermediate, restoring aromaticity and regenerating the AlCl₃ catalyst (along with HCl as the by-product).

graph TD
  A[Step 1: AlCl3 + CH3COCl] --> B[Acylium ion CH3CO+ + AlCl4-]
  B --> C[Step 2: pi electrons of benzene attack acylium C]
  C --> D[Cyclohexadienyl cation: sp3 C bearing both H and COCH3]
  D --> E[Step 3: AlCl4- removes H+ from sp3 C]
  E --> F[Aromaticity restored - product C6H5COCH3]
  F --> G[Catalyst AlCl3 regenerated + HCl by-product]

4.3 Why only mono-acylation?

A key practical advantage of Friedel-Crafts acylation over Friedel-Crafts alkylation (not examined by OCR) is that the product is cleanly mono-substituted. The reason is electronic: the new acyl group -COR is a strong electron-withdrawing group that deactivates the ring towards further electrophilic attack. Once you have installed one acyl group, the ring is much less reactive, and a second acylation is far slower. This is why Friedel-Crafts acylation gives clean ketone products in good yield.