Carbon–carbon bond formation

In a nutshell

Most organic reactions swap one functional group for another but leave the carbon skeleton alone. The reactions in this subtopic are different: each one forms a new C-C bond, so the product has a longer carbon chain (or a carbon group on a benzene ring).

You need four of them: haloalkane + CN^-, carbonyl + HCN, then turning the nitrile made into an amine or a carboxylic acid, and the Friedel-Crafts reactions of arenes.

Assumed knowledge: Haloalkanes, Carbonyl compounds, Aromatic compounds.

Core content

Extending carbon chain length: why forming a C-C bond matters in synthesis

In synthesis you often need a product with more carbon atoms than the starting material. Swapping functional groups cannot do that. You need a reaction that forms a C-C bond.

The first two give a nitrile (-C≡N). A nitrile is useful because it can then be converted into:

• a primary amine, by reduction with H₂/Ni
• a carboxylic acid, by acid hydrolysis

Both keep the extra carbon.

Extending carbon chain length: haloalkanes with cyanide ions

A haloalkane reacts with cyanide ions to form a nitrile. The cyanide ion is a nucleophile, so this is nucleophilic substitution: CN^- replaces the halogen.

CH₃CH₂CH₂Br + CN^- → CH₃CH₂CH₂CN + Br^- (1-bromopropane to butanenitrile)

Why ethanol and not water: with water present, the haloalkane is also hydrolysed to an alcohol, so you get a mixture. Ethanol also dissolves the haloalkane.

The mechanism is the same shape as hydrolysis with OH^- at AS, with CN^- as the nucleophile:

1. The C-X bond is polar: C^δ+-X^δ-.
2. A curly arrow goes from the lone pair on the carbon of :CN^- to the C^δ+.
3. A curly arrow goes from the C-X bond to the X. The bond breaks by heterolytic fission.
4. Products: the nitrile and the halide ion, X^-.

Naming nitriles. The C of the C≡N is part of the chain and is carbon 1. Count it, then add -nitrile to the alkane name:

• CH₃CN: ethanenitrile (2 carbons)
• CH₃CH₂CH₂CN: butanenitrile (4 carbons, from a 3-carbon haloalkane)

Still don't get it? · counting carbons in a nitrile

Picture a train of carriages. Swapping the seats inside one carriage changes what the train is for, but it is still the same length. Coupling a brand-new carriage onto the end makes the train longer, and that carriage stays on the train however you refit it later.

Now the chemistry, one step at a time:

1. 1-Bromopropane has 3 carbons in a chain, with Br on the end carbon.
2. CN^- brings its own carbon. The new bond is between the end carbon of the chain and the C of CN^-.
3. So the chain now has 3 + 1 = 4 carbons: CH₃CH₂CH₂-C≡N.
4. When you name it, you count all 4, with the nitrile carbon as carbon 1: butanenitrile, not "propanenitrile" or "propyl cyanide".
5. Later reactions only refit that last carriage. Reduction turns C≡N into CH₂NH₂; hydrolysis turns it into COOH. Either way the carbon stays, so the amine or acid is still 4 carbons long.

Exam wording: the reaction forms a C-C bond and increases the length of the carbon chain by one carbon; the nitrile is named counting the C of C≡N as carbon 1.

What an examiner checks on this mechanism:

• δ+ on C and δ- on the halogen.
• First arrow starts at the lone pair on the C of CN^- (not the N) and ends at the C^δ+.
• Second arrow starts at the C-X bond and ends at X.
• Products include the halide ion with its charge, and the new bond on the nitrile is C-C.

Extending carbon chain length: carbonyl compounds with HCN

Aldehydes and ketones add HCN across the C=O to form hydroxynitriles. This is nucleophilic addition, and you met it in Carbonyl compounds. Here the point is that it forms a C-C bond.

CH₃CHO + HCN → CH₃CH(OH)CN (ethanal to 2-hydroxypropanenitrile)

NaCN supplies the CN^- nucleophile; the acid supplies the H⁺ for the second step. HCN itself is a very toxic gas, and cyanide salts are toxic too, so this is done in a fume cupboard.

The mechanism, in two steps:

1. Curly arrow from the lone pair on the C of :CN^- to the C^δ+ of C=O, and from the C=O bond to the O.
2. The intermediate has O^-. A curly arrow goes from a lone pair on O^- to H⁺ (H₂O can be used instead).

The two cyanide routes side by side. Students mix up their conditions, so learn this table:

Extending carbon chain length: reducing nitriles to amines

A nitrile is reduced to a primary amine by hydrogen with a nickel catalyst (H₂/Ni). The C≡N becomes -CH₂NH₂.

CH₃CH₂CH₂CN + 2H₂ → CH₃CH₂CH₂CH₂NH₂ (butanenitrile to butylamine)

General: RCN + 2H₂ → RCH₂NH₂

Each C≡N needs 2H₂: two H go onto the carbon and two onto the nitrogen.

Butylamine is also called butan-1-amine. Compare the routes to amines:

• haloalkane + ammonia gives an amine with the same number of carbons (Amines)
• haloalkane + CN^-, then H₂/Ni, gives an amine one carbon longer

Extending carbon chain length: hydrolysing nitriles to carboxylic acids

A nitrile is hydrolysed to a carboxylic acid by heating under reflux with dilute aqueous acid, e.g. HCl(aq). The C≡N becomes -COOH and the nitrogen ends up as ammonium ions.

CH₃CH₂CH₂CN + 2H₂O + HCl → CH₃CH₂CH₂COOH + NH₄Cl (butanenitrile to butanoic acid)

Ionic form: RCN + 2H₂O + H⁺ → RCOOH + NH₄⁺

Points that carry the equation mark:

• 2H₂O per C≡N, not one.
• The nitrogen leaves as NH₄⁺ (NH₄Cl with HCl), not as NH₃, because the solution is acidic.
• The acid has the same number of carbons as the nitrile: butanenitrile gives butanoic acid.

Extending carbon chain length: Friedel-Crafts alkylation and acylation

Benzene rings are hard to attach carbon chains to. The Friedel-Crafts reaction does it: an arene reacts with a haloalkane (alkylation) or an acyl chloride (acylation) in the presence of a halogen carrier, forming a C-C bond to the aromatic ring.

Halogen carriers named in the spec are iron, iron halides and aluminium halides. AlCl₃ is the usual one here.

Overall equations:

C₆H₆ + CH₃CH₂Cl → C₆H₅CH₂CH₃ + HCl (ethylbenzene)

C₆H₆ + CH₃COCl → C₆H₅COCH₃ + HCl (phenylethanone)

The halogen carrier makes the electrophile:

CH₃CH₂Cl + AlCl₃ → CH₃CH₂⁺ + AlCl₄^-

CH₃COCl + AlCl₃ → CH₃CO⁺ + AlCl₄^-

And is regenerated at the end, so it acts as a catalyst:

H⁺ + AlCl₄^- → AlCl₃ + HCl

The mechanism follows the same electrophilic substitution pattern as the bromination and nitration of benzene in Aromatic compounds. You can be asked to apply it to these electrophiles:

1. Curly arrow from the delocalised ring to the positive carbon of the electrophile.
2. Intermediate: the ring is broken, drawn as a horseshoe with a + charge, and the carbon under attack carries both H and the new group.
3. Curly arrow from the C-H bond back into the ring, restoring the delocalised ring and releasing H⁺.

For alkylation, draw the same thing with CH₃CH₂⁺ as the electrophile: the arrow goes to the positive carbon of the ethyl group.

Still don't get it? · why Friedel-Crafts needs a halogen carrier

Imagine trying to get someone who is very comfortable on a sofa to stand up. A gentle tap on the shoulder does nothing. You need a real pull.

Benzene is that comfortable person, and the halogen carrier is what turns a gentle tap into a pull:

1. Benzene's delocalised ring is very stable. It will only react with an electrophile that is strongly positive.
2. In a chloroalkane or an acyl chloride, the carbon bonded to Cl is only δ+. That is the gentle tap: not enough to make benzene react.
3. AlCl₃ takes the Cl, together with the bonding pair of electrons, forming AlCl₄^-.
4. That leaves the carbon with a full positive charge: R⁺ or RCO⁺. Now it is a strong electrophile, and the ring attacks it.
5. At the end, the H⁺ lost from the ring meets AlCl₄^-, giving back AlCl₃ and HCl. The AlCl₃ is not used up, so it is a catalyst.

Exam wording: the halogen carrier (e.g. AlCl₃) generates the electrophile (R⁺ or RCO⁺) and is regenerated by H⁺ + AlCl₄^- → AlCl₃ + HCl.

Why it matters in synthesis: a Friedel-Crafts reaction is one of the few ways to make a C-C bond to an aromatic ring. Acylation also puts a reactive C=O group onto the ring, ready for further reactions.

Worked examples

No calculation is listed for 6.2.4, so these examples model the routes, equations, names and mechanism points that the marks are for.

Example 1: a one-carbon-longer acid and amine from a haloalkane

Starting from bromoethane, give the reagents and conditions, and equations, to make (a) propanoic acid and (b) propylamine.

Step 1 is the same for both: make the nitrile. Bromoethane has 2 carbons; both targets have 3, so you need one new C-C bond.

CH₃CH₂Br + CN^- → CH₃CH₂CN + Br^-

Reagents and conditions: NaCN (or KCN) in ethanol, heat under reflux. Product: propanenitrile (count the C of the C≡N).

(a) Acid hydrolysis: dilute HCl(aq), heat under reflux.

CH₃CH₂CN + 2H₂O + HCl → CH₃CH₂COOH + NH₄Cl

(b) Reduction: H₂ with a Ni catalyst.

CH₃CH₂CN + 2H₂ → CH₃CH₂CH₂NH₂

Atom check for (a): left C₃H₁₀NO₂Cl; right C₃H₆O₂ + NH₄Cl = C₃H₁₀NO₂Cl. Balanced.

Where marks go: using aqueous KCN in step 1, writing one H₂O or one H₂, and making ammonia instead of NH₄Cl. Going straight from bromoethane to an amine with NH₃ gives ethylamine, which is one carbon short.

Example 2: a two-step route from an aldehyde

Ethanal is converted into 2-hydroxypropanoic acid, CH₃CH(OH)COOH, in two steps. Give the reagents for each step, the intermediate and the equations.

1. The target has 3 carbons and ethanal has 2, with an OH on the carbon next to the COOH. That points to HCN addition (which gives an OH and a C≡N on the same carbon), then hydrolysis of the C≡N.
2. Step 1, reagents NaCN(aq)/H⁺(aq):

CH₃CHO + HCN → CH₃CH(OH)CN (intermediate: 2-hydroxypropanenitrile)

3. Step 2, dilute HCl(aq), heat under reflux:

CH₃CH(OH)CN + 2H₂O + HCl → CH₃CH(OH)COOH + NH₄Cl

The OH is untouched; only the C≡N changes.

Where marks go: giving "HCN" alone or "KCN in ethanol" as the step 1 reagent. Those are the conditions for a haloalkane, not a carbonyl.

Example 3: model mechanism for 1-iodobutane with cyanide ions

Outline the mechanism for the reaction of 1-iodobutane with cyanide ions, and name the organic product. Each numbered point is something the examiner looks for. Draw it in the same shape as Figure 2.

1. 1-Iodobutane drawn with C^δ+-I^δ- on the C-I bond.
2. :CN^- with its lone pair and charge on the carbon; curly arrow from that lone pair to the C^δ+.
3. Curly arrow from the C-I bond to the I.
4. Products: CH₃CH₂CH₂CH₂CN and I^-.
5. Product name: 4 carbons in the haloalkane + 1 from CN = 5, so pentanenitrile.
6. Mechanism name: nucleophilic substitution.

CH₃CH₂CH₂CH₂I + CN^- → CH₃CH₂CH₂CH₂CN + I^-

Example 4: choosing the Friedel-Crafts reagent

Give the reagents needed to make 1-phenylpropan-1-one, C₆H₅COCH₂CH₃, from benzene. Write equations for the formation of the electrophile and for the overall reaction.

1. The group added to the ring is COCH₂CH₃: it contains C=O, so this is acylation, not alkylation.
2. The acyl chloride with that group is propanoyl chloride, CH₃CH₂COCl. Halogen carrier: AlCl₃.
3. Electrophile:

CH₃CH₂COCl + AlCl₃ → CH₃CH₂CO⁺ + AlCl₄^-

4. Overall:

C₆H₆ + CH₃CH₂COCl → C₆H₅COCH₂CH₃ + HCl

For comparison, ethylbenzene needs a haloalkane: chloroethane + AlCl₃ (alkylation).

Where marks go: forgetting the halogen carrier, writing the by-product as Cl₂ or H₂ instead of HCl, or putting the + charge of CH₃CH₂CO⁺ on the oxygen. The + belongs on the carbonyl carbon.

Example 5: a diamine from a dihaloalkane

1,2-Dibromoethane can be converted into butane-1,4-diamine, H₂N(CH₂)₄NH₂, a monomer for polyamides. Give the two steps.

1. Two carbons in, four out: two new C-C bonds, one at each end. Both Br atoms are substituted.

BrCH₂CH₂Br + 2CN^- → NCCH₂CH₂CN + 2Br^-

Reagents: NaCN in ethanol, heat under reflux. Intermediate: butanedinitrile.

2. Reduce both C≡N groups with H₂/Ni, so 4H₂:

NCCH₂CH₂CN + 4H₂ → H₂NCH₂CH₂CH₂CH₂NH₂

Where marks go: balancing with 2H₂ (that is enough for only one C≡N), or 1 CN^- for two C-Br bonds.

Common exam mistakes

• Cyanide curly arrow from the nitrogen. The arrow starts at the lone pair on the carbon of CN^-, and the new bond is C-C. A product drawn as "-NC" is wrong.
• Missing dipoles or charges. Leave off the δ+/δ- on C-X, or the charge on X^- in the products, and the mechanism loses marks.
• Aqueous cyanide for a haloalkane. The reagent is CN^- in ethanol. With water present the haloalkane is also hydrolysed to an alcohol.
• Swapping the two cyanide reagents. Haloalkane: NaCN/KCN in ethanol. Carbonyl: NaCN(aq)/H⁺(aq). Each is wrong for the other reaction.
• Calling haloalkane + CN^- "addition", or carbonyl + HCN "substitution". The haloalkane loses X^-, so it is substitution; nothing leaves the carbonyl, so it is addition.
• Forgetting to count the nitrile carbon. 1-Bromopropane gives butanenitrile, not "propanenitrile". The chain is one carbon longer.
• Misspelling the name. It is butanenitrile ("butane" + "nitrile"), not "butannitrile".
• Wrong reducing agent for a nitrile. Nitriles are reduced by H₂/Ni. Sn/conc. HCl is for reducing nitroarenes to aromatic amines.
• Under-counting H₂ or H₂O. Reduction needs 2H₂ per C≡N; acid hydrolysis needs 2H₂O per C≡N.
• Amine product one carbon short. Reducing RCN gives RCH₂NH₂: the nitrile carbon becomes the CH₂. Writing RNH₂ loses the extra carbon.
• Ammonia as the hydrolysis by-product. In acid the nitrogen leaves as NH₄⁺ (or NH₄Cl with HCl), not NH₃.
• Thinking haloalkane + NH₃ lengthens the chain. It does not. To gain a carbon, go via the nitrile.
• No halogen carrier in a Friedel-Crafts reaction. Without AlCl₃ (or another halogen carrier) there is no electrophile and no reaction.
• Mixing up alkylation and acylation. Haloalkane gives an alkylbenzene; acyl chloride gives an aromatic ketone. Check whether the target has a C=O next to the ring.
• Wrong by-product or no catalyst regeneration. Friedel-Crafts gives HCl, and H⁺ + AlCl₄^- → AlCl₃ + HCl shows the carrier is regenerated.
• Positive charge on the oxygen of RCO⁺. The electrophile's + charge is on the carbon, and the ring's curly arrow must end at that carbon.

Key definitions

• Nucleophile: an electron pair donor.
• Electrophile: an electron pair acceptor.
• Nucleophilic substitution: a reaction in which a nucleophile replaces an atom or group in a molecule; here CN^- replaces the halogen of a haloalkane, which leaves as a halide ion.
• Nucleophilic addition: an addition reaction in which a nucleophile attacks the δ+ carbon of a C=O bond, followed by protonation, so that two species join to form one product.
• Electrophilic substitution: a reaction in which an electrophile replaces an atom (usually hydrogen) on an aromatic ring, keeping the delocalised ring.
• Halogen carrier: a substance such as iron, an iron halide or an aluminium halide that reacts with a halogen (or haloalkane or acyl chloride) to produce the electrophile, and is regenerated at the end.
• Nitrile: a compound containing the -C≡N functional group; the C of C≡N is counted as carbon 1 of the chain.
• Hydroxynitrile: a compound containing an -OH group and a -C≡N group on the same carbon atom, formed by nucleophilic addition of HCN to a carbonyl compound.
• Heterolytic fission: bond breaking in which one bonding atom receives both electrons from the bonded pair.
• Curly arrow: the movement of an electron pair, showing either heterolytic fission or formation of a covalent bond.
• Friedel-Crafts reaction: the electrophilic substitution of an arene by a haloalkane (alkylation) or an acyl chloride (acylation) in the presence of a halogen carrier, forming a C-C bond to the aromatic ring.

Specification

• I can explain why C-C bond formation is used in synthesis to increase the length of a carbon chain, and pick out which reactions do it. (6.2.4 a)
• I can write an equation for the reaction of a haloalkane with CN^- in ethanol to form a nitrile, and name the nitrile. (6.2.4 b i)
• I can draw the nucleophilic substitution mechanism for a haloalkane with CN^-. (6.2.4 b i, see 4.2.2 c)
• I can write an equation for the reaction of an aldehyde or ketone with HCN (NaCN(aq)/H⁺(aq)) to form a hydroxynitrile, and draw the nucleophilic addition mechanism. (6.2.4 b ii, see 6.1.2 b-c)
• I can write an equation for the reduction of a nitrile to a primary amine with H₂/Ni. (6.2.4 c i)
• I can write an equation for the acid hydrolysis of a nitrile to a carboxylic acid. (6.2.4 c ii)
• I can describe Friedel-Crafts alkylation (haloalkane) and acylation (acyl chloride) with a halogen carrier, write the equations, including formation of the electrophile, and name the product. (6.2.4 d, see 6.1.1 d)

Related notes

• Haloalkanes: nucleophiles and the nucleophilic substitution mechanism with OH^-
• Basic concepts of organic chemistry: naming, heterolytic fission and curly arrows
• Aromatic compounds: the electrophilic substitution mechanism and halogen carriers
• Carbonyl compounds: nucleophilic addition of HCN in full
• Carboxylic acids and esters: acyl chlorides, and what nitrile hydrolysis produces
• Amines: the other routes to amines, which keep the chain length
• Polyesters and polyamides: where diamines and diacids made this way end up
• Organic synthesis: putting these reactions into multi-stage routes