Nucleophilic Substitution, Elimination Reactions & Polyhalogen Compounds

Nucleophilic Substitution Reactions

Haloalkanes (alkyl halides) undergo three broad types of reactions:

• Nucleophilic substitution
• Elimination reactions
• Reactions with metals

Chemical behaviour of alkyl halides

Organic compounds in which an sp³-hybridised carbon is bonded to an electronegative atom or group may undergo two main types of transformations. In substitution reactions, the electronegative atom or group is replaced by another atom or group. In elimination reactions, the electronegative atom or group is removed together with a hydrogen from an adjacent carbon, giving a pi bond. The group that departs is called the leaving group.

Nucleophilic substitution reactions occur because the polar C-X bond (X = F, Cl, Br, I) gives the carbon a partial positive charge while the halogen bears partial negative charge. This polarity makes the carbon susceptible to attack by electron-rich species (nucleophiles).

General mechanistic pathways

Two general mechanistic patterns for nucleophilic substitution are observed:

• Concerted bimolecular attack where the nucleophile and substrate participate in a single rate-determining step and the C-X bond breaks as the new bond forms (S_N2 type).
• Stepwise unimolecular ionisation where the C-X bond breaks first to give a carbocation intermediate; the nucleophile then attacks the carbocation (S_N1 type, often assisted by polar protic solvents - solvolysis).

(i) Bimolecular nucleophilic substitution - S_N2

The S_N2 mechanism is a single-step, concerted process in which the nucleophile attacks the electrophilic carbon from the side opposite the leaving group, giving a simultaneous bond formation and bond breaking through a high-energy arrangement called the transition state.

Characteristics of S_N2 reactions

• It is bimolecular and occurs in one step.
• Kinetics: second order overall. Rate ∝ [alkyl halide][nucleophile]; rate = k[alkyl halide][nucleophile].
• No stable intermediates are formed; the reaction proceeds via a transition state.
• Stereochemistry: nucleophilic attack occurs from the backside relative to the leaving group, causing Walden inversion (inversion of configuration at the reaction centre).
• Energetics: single barrier in free-energy diagram; reaction coordinate shows one transition state (illustrated in figure).

Factors affecting S_N2 rate

The rate of an S_N2 reaction depends mainly on the following factors:

• Structure of the substrate: Reactivity order - CH₃X > 1° > 2° >> 3° (3° is usually unreactive due to steric hindrance). Bulky groups near the reaction centre raise the transition-state energy and slow the reaction.
• Concentration and strength of the nucleophile: A stronger / more nucleophilic species increases the rate. Negatively charged nucleophiles are generally more reactive than their neutral conjugate acids (for example HO^- > H₂O, RO^- > ROH).
• Effect of solvent: Polar aprotic solvents (e.g., DMSO, DMF, acetone) do not solvate anions strongly and therefore increase the reactivity of anionic nucleophiles; nucleophilicity in polar aprotic solvents follows F^- > Cl^- > Br^- > I^-. In polar protic solvents, small nucleophiles are strongly solvated and their nucleophilicity is reduced; in such solvents the nucleophilicity order often becomes I^- > Br^- > Cl^- > F^-.
• Nature of the leaving group: The better the leaving group (the more stable after leaving), the faster the S_N2 reaction. Typical order for halide leaving ability: I^- > Br^- > Cl^- > F^-. Weak bases make good leaving groups.

Relative substrate reactivity (example values)

Steric effects on nucleophilicity

Relative nucleophilicity and solvent

In polar protic solvents, nucleophilicity is affected by solvation; small anions (such as F^-) are heavily solvated and become poorer nucleophiles. In such media the observed nucleophilicity order for halides is I^- > Br^- > Cl^- > F^-. In polar aprotic solvents, anions are less solvated and nucleophilicity generally follows basicity; for halides: F^- > Cl^- > Br^- > I^-.

Example relative nucleophilicity list (polar protic solvent): SH^- > CN^- > I^- > OH^- > N₃^- > Br^- > AcO^- > Cl^- > F^- > H₂O.

Examples of SN₂ substitution with various nucleophiles

Nucleophile	Alkyl halide	Product	Class
		R -	Alkyl halide
		R -	Alcohol
		R -	Ether
		R -	Thiol (mercaptan)
		R -	Thioether (sulphide)
		R -	Amine
		R -	Azide
		R -	Alkyne
		R -	Nitrile
		R - COO - R	Ester
		[R - PPh3]+	Phosphonium salt

Question 1: Complete the following reactions with mechanism

(a) 

Sol. 

(b) 

Sol.

(p-Nitroanisole)

(c)

Ph - CH₂Cl

Sol. CH₃-CH₂-O^! is present in excess and it is a stronger nucleophile than Ph - O^!, so the product is Ph-CH₂-OEt

(d) CH₃ - C ≡ CH

X

Y

Sol.

(e) 

Ph₃ → Salt

Sol. 

Question 2: When the concentration of alkyl halide is tripled and the concentration of OH^- ion is reduced to half, the rate of S_N² reaction increases by :

(A) 3 times (B) 2 times (C) 1.5 times (D) 6 times

Ans: c

(ii) Unimolecular nucleophilic substitution - S_N1

The S_N1 mechanism proceeds in two steps. First, the C-X bond breaks to give a carbocation and a leaving group (rate-determining ionisation). Second, the nucleophile rapidly attacks the carbocation to give the substitution product.

Characteristics of S_N1 reactions

• It is unimolecular in the rate-determining step and normally a two-step process with a carbocation intermediate.
• It follows first-order kinetics: Rate ∝ [alkyl halide]; rate = k[R-X].
• Stereochemistry: the carbocation intermediate is planar (sp²) and can be attacked from either face, leading to racemisation if the centre is chiral.
• Carbocation rearrangements (hydride or alkyl shifts) are possible and common when they produce a more stable carbocation.
• Polar protic solvents stabilise ions and therefore increase the rate of ionisation.

Factors affecting S_N1 rates

• Structure of substrate: Reactivity order for S_N1 is 3° > 2° > 1° > CH₃-X because more substituted carbocations are more stable.
• Concentration and nature of nucleophile: Rate of S_N1 is largely independent of the nucleophile (since nucleophile attacks after the rate-determining ionisation).
• Effect of solvent: Polar protic solvents stabilise the charged transition state and intermediate and therefore increase the S_N1 rate.
• Nature of leaving group: Better leaving groups stabilise the developing negative charge in the transition state and increase the rate.

Comparison of S_N1 and S_N2

Question 3: Predict the compound in each pair that will undergo solvolysis (in aqueous ethanol) more rapidly.

Sol. (a) II > I (b) II > I (c) I > II (d) II > I (e) II > I

Question 4: Give the solvolysis products expected when each compound is heated in ethanol

(a)

(b)

(c)

(d)

Sol. (a)

(b)

(c)

(d)

Question 5: The rate of SN¹ reaction is fastest with

Ans. (A)

The reaction of R-X with aqueous KOH

• R-X + KOH → R-OH + KX (hydrolysis to give alcohol)
• Example: CH₃-CH₂-Cl + KOH → CH₃-CH₂-OH + KCl
• Under some conditions elimination or oxidation products may form depending on substrate and conditions (examples often shown with scheme illustrations).

Other nucleophilic reactions of R-X

Williamson Ether Synthesis (S_N2)

The Williamson ether synthesis forms ethers by reaction of an alkoxide ion with an alkyl halide via an S_N2 mechanism. Primary alkyl halides (and methyl halides) are most suitable because steric hindrance is minimal; tertiary halides usually fail because S_N2 is hindered and elimination predominates.

• 
• EtONa + MeCl → EtOMe + NaCl
• Reactivity depends on steric hindrance: a methyl or primary halide gives higher rate than a secondary or tertiary.
• Example: MeONa + PhCl - no reaction (aryl halides do not undergo S_N2 displacement under these conditions).
• Some attempted combinations lead to competing elimination, rearrangement or other pathways rather than the desired ether.

Hydrolysis of ethers (acid-catalysed)

• Ethers are generally cleaved by strong acids (HI, HBr) to give alcohols or alkyl halides depending on the conditions and the nature of the groups on oxygen.
• Primary alkyl groups normally undergo S_N2 cleavage, while tertiary give carbocations and may lead to substitution or rearrangement depending on conditions.

Reaction of ether with HI

• For unsymmetrical ethers, the bond that breaks follows the pathway leading to the more stable carbocation (or the path favourable for S_N2 if primary centre is involved).

Reactions with moist and dry Ag₂O

• Halides can be converted into ethers by treatment with silver oxide (Ag₂O) under suitable conditions with mixing of alkyl halides; mixture of ethers may result.

(iii) Intramolecular nucleophilic substitution - SNi (Darzens type)

Darzens process

Some intramolecular substitutions proceed with retention of configuration; this is sometimes represented as an SNi process where the nucleophile and leaving group are in the same molecule and reaction proceeds through a concerted intramolecular pathway.

Mechanism:

Note : (1) In SNi retention of configuration takes place.

(2) In presence of pyridine above reaction may follow an S_N2 mechanism.

(iv) Neighbouring Group Participation (NGP or Anchimeric Assistance)

Neighbouring group participation (NGP) or anchimeric assistance is the acceleration of a substitution reaction by an internal nucleophile that participates in the reaction mechanism. The internal nucleophile forms a temporary bond to the reaction centre, stabilising an intermediate or transition state and thereby increasing the rate.

Requirements and features:

• An internal nucleophile (e.g., lone pair on an adjacent heteroatom) must be present within reach of the reaction centre.
• The internal group is often anti to the leaving group to permit effective orbital overlap in forming a bridged intermediate.

Elimination Reactions

In elimination reactions two atoms or groups (Y and Z) are removed from adjacent atoms of a substrate to form a double bond (alkene or other unsaturated species). Depending on the mechanism, eliminations are classified as E₁ or E₂.

Dehydration of alcohol (E₁)

Characteristics of E₁

• Unimolecular, two-step process; first step is formation of a carbocation (rate-determining).
• First-order kinetics: Rate ∝ [substrate].
• Carbocation intermediate allows rearrangements.
• Second step: base removes a proton from the β-carbon to form the alkene.

E₂ elimination

Characteristics of E₂

• Bimolecular concerted (single-step) mechanism; second-order kinetics.
• The base abstracts a proton while the leaving group departs; both events are synchronous in the transition state.
• Shows kinetic isotope effects and requires the proton and the leaving group to be antiperiplanar (coplanar but opposite) for the most favourable orbital alignment.
• Rearrangements do not occur because no discrete carbocation is formed.
• Product distribution generally follows Saytzeff (Zaitsev) rule: the more substituted (and hence more stable) alkene is usually the major product, unless steric or geometrical constraints favour the Hofmann product.
• E₂ is favoured by strong bases (RO^-, alkoxide), polar aprotic solvents, high base concentration and higher temperature.

Typical reactivity of haloalkanes toward E₂: R-I > R-Br > R-Cl > R-F

Question 1: Predict the elimination products of the following reactions.

(a) Sec-butyl bromide +

(b) 3-Bromo-3-ethylpentane + CH₃OH

(c) 2-Bromo-3-ethylpentane + MeONa

(d) 1-Bromo-2-methylcyclohexane + EtONa

Sol. (a) CH₃-CH=CH-CH₃

(b)

(c)

(d)

Question 2:

major + minor

Write the structure of major and minor product.

Sol. 

(minor)

(major)

Question: Compare rate of elimination (dehydrohalogenation in presence of alcoholic KOH) i.e., E₂ reaction in the following:

1. (a)

(b)

(c)

(d)

Ans: c > b > a > d

2. (a)

(b)

(c)

Ans: c > b > a

3. (a)

(b)

(c)

Ans: c > b > a

4. (a)

(b)

(c)

Ans: b > a > c

Dehalogenation (-X₂) via E₂

E_c or E_i (Intramolecular or cyclic elimination)

Features:

• The base and leaving group are part of the same molecule; elimination proceeds via a cyclic transition state.
• Overall syn-elimination is typical for these intramolecular processes.
• Hofmann product may predominate because the cyclic transition state often favours the least hindered β-hydrogen.
• No rearrangement occurs.

Example - pyrolysis of esters (a typical intramolecular elimination)

Comparison of E₁ and E₂

Question 3:

P + Q + R

Sol.
P is

Q is

R

Question 4: Arrange the compounds of each set in order of reactivity towards dehydrohalogenation by a strong base

(a) 2-Bromo-2-methylbutane, 1-Bromopentane, 2-Bromopentane

(b) 1-Bromo-3-methylbutane, 2-bromo-2-methylbutane, 2-Bromo-3-methylbutane

(c) 1-Bromobutane, 1-Bromo-2,2-dimethylpropane, 1-bromo-2-methylbutane, 1-Bromo-3-methylbutane

Haloalkanes - Reactions with Metals

Reactions of haloalkanes/haloarenes with sodium or other active metals give coupling products. Two classical reactions are listed below.

Wurtz-Fittig reaction

A mixture of an alkyl halide and an aryl halide reacts with sodium in dry ether to give an alkyl arene (mixed coupling) along with other coupling by-products. Reaction conditions and substituents determine the product mixture.

Fittig reaction

A mixture of haloarenes reacts with sodium in dry ether to give diaryl compounds (aryl-aryl coupling). This is analogous to the Wurtz reaction but involves aryl halides.

Polyhalogen Compounds

The hydrocarbons or other carbon compounds containing more than one halogen atom are called polyhalogen compounds. Many polyhalogen derivatives have industrial, agricultural or laboratory uses. A few important polyhalogen compounds are described here.

1. Trichloromethane (chloroform), CHCl₃

Chloroform or trichloromethane is a colourless, sweet-smelling dense liquid. It was first prepared in 1831 and was once widely used as an anaesthetic. Large-scale industrial production and use increased in the 20th century, although many uses have declined for safety and environmental reasons.

Preparation (stepwise chlorination of methane)

CH₄ + Cl₂ → CH₃Cl + HCl (chloromethane)

CH₃Cl + Cl₂ → CH₂Cl₂ + HCl (dichloromethane)

CH₂Cl₂ + Cl₂ → CHCl₃ + HCl (trichloromethane)

CHCl₃ + Cl₂ → CCl₄ + HCl (tetrachloromethane)

These chlorinated methane products can be separated by fractional distillation.

Uses of chloroform

• Historically used as an anaesthetic and in dentistry for some procedures.
• Used as a solvent for certain analysis techniques (for example, in spectroscopic sample preparation where chloroform is an appropriate solvent).
• Previously used as an extraction solvent for fats, greases and oils; many such applications have declined due to toxicity concerns.
• Used as an ingredient or intermediate in manufacture of other chemicals and as an indirect additive in some packaging processes (subject to regulation).

2. Triiodomethane (iodoform)

• Iodoform (CHI₃) was used earlier as an antiseptic. Its activity is due to release of free iodine rather than iodoform itself, and its strong, unpleasant odour has led to replacement by other iodine-containing formulations.

3. Tetrachloromethane (carbon tetrachloride, CCl₄)

• Carbon tetrachloride has been used in refrigerant and aerosol propellant production and as a precursor to freons and other chlorinated derivatives.
• Its use has been drastically reduced because of toxicity (liver damage, central nervous system effects) and environmental effects (ozone depletion when converted to CFCs).

4. Freons

• Freons are chlorofluorocarbons prepared from chlorinated methanes/ethanes and used in refrigeration and as propellants. They are chemically stable and non-flammable.
• Freon-12 (commonly, CCl₂F₂) is produced via reactions such as the Swarts reaction from chlorinated precursors. Large-scale production was common in the mid-20th century, but freons are now regulated because of their ozone-depleting potential.

5. DDT (dichlorodiphenyltrichloroethane)

• DDT was first synthesised in 1873 and its insecticidal properties were discovered by Paul Müller of Geigy (Switzerland) in 1939; Müller was awarded the Nobel Prize in Physiology or Medicine in 1948 for this discovery.
• After WWII DDT saw wide global use because it was effective against vectors of malaria and typhus. Problems such as insect resistance and toxicity to non-target organisms (notably fish and birds) were reported in the late 1940s onward.
• DDT is chemically stable and lipid-soluble so it bioaccumulates in fatty tissues and persists in the environment. These issues led to bans and restrictions; the US banned DDT in 1973, though limited uses continue in some regions for public-health purposes under controlled conditions.