Haloalkanes: Chemical Properties and Reactivity

Chemical Properties of Haloalkanes

• Haloalkanes, also known as alkyl halides, feature a halogen atom connected to an sp³ hybridized carbon.
• The polarized carbon-halogen (C-X) bond is key to their reactivity, enabling two primary reaction types.
• Nucleophilic substitution (SN) involves replacing the halogen with a nucleophile.
• Base-assisted β-elimination (E) results in the removal of H-X, forming an alkene.
• Both reaction types utilize heterolytic cleavage of the C-X bond.
• During cleavage, the halogen takes the bonding electrons, departing as a halide ion.

Relative Reactivity of R-X and Halogens

• The reactivity order is R-I > R-Br > R-Cl >>> R-F.
• Iodide (I-), bromide (Br-), and chloride (Cl-) are more effective leaving groups than fluoride (F-).
• I-, Br-, and Cl- are more stable as anions.
• Iodine's large atomic size leads to a weaker carbon bond, facilitating the leaving group's negative charge dispersion over a larger space.

Solvents and Haloalkane Reactivity

• Polar solvents are essential for both nucleophilic substitution and elimination reactions.
• Haloalkanes and reactants are polar compounds.
• Two main types of polar solvents exist: polar protic and polar aprotic solvents.
• Polar protic solvents are water (H₂O), methanol (CH3OH), and ethanol (C2H5OH).
• Polar aprotic solvents are dimethyl sulfoxide ((CH₃)₂S=O), N,N-dimethyl formamide (HCON(CH3)2), acetonitrile (CH3CN), and acetone ((CH3)2CO).

N.S. (Nucleophilic Substitution) Reactions of Haloalkanes

• Reaction with NaOH yields an alcohol (R-OH).
• Reaction with NaSH yields a thioalcohol (R-SH).
• Reaction with RONa yields an ether (R-O-R’).
• Reaction with R`SNa yields a thioether (R-S-R’).
• Reaction with NaCN yields a nitrile (R-C≡N), which can be further hydrolyzed to a carboxylic acid (R-COOH) using H₂SO₄ and H₂O with heat.
• Reaction with RCCNa yields an alkyne (R-C≡C-R’).
• Reaction with R-C=O-ONa yields an ester (R-O-C=O-R').
• Reaction with R3N yields a quaternary ammonium salt (R-NR3X).
• Reaction with NaN3 yields an alkyl azide (R-N3).

Reaction Mechanisms of Nucleophilic Substitution (NS)

• SN1 reactions are unimolecular and proceed through a two-step ionic mechanism.
• SN2 reactions are bimolecular and occur in a single concerted step.

Course and Characteristics of SN1 Reactions

• In the SN1 mechanism, the nucleophile adds to the carbocation intermediate.
• If the nucleophile is neutral water (H₂O), a subsequent proton loss occurs.
• SN1 reactions follow first-order kinetics.
• The rate-determining step depends only on the haloalkane concentration.
• SN1 reactions often result in a mixture of products due to carbocation rearrangement.
• Less stable 2° carbocations rearrange to more stable 3° carbocations via 1,2-hydride or 1,2-alkyl shifts.

Stereochemistry of SN1 Reactions

• SN1 reactions at a chiral carbon in an optically active haloalkane lead to a racemic mixture.
• Hydrolysis of cis-1-bromo-4-methylcyclohexane via SN1 yields equal amounts of cis- and trans-4-methylcyclohexanol.

Course of SN2 Reactions

• SN2 reactions proceed through a concerted mechanism.
• Bond-breaking and bond-forming events happen simultaneously in a single step.
• The nucleophile attacks the electrophilic carbon at a 180° angle from the leaving halogen through a transition state (T.S.).

Factors Affecting SN1 and SN2 Reaction Mechanisms

• Alkyl portion structure of the R-X molecule
• Nucleophile strength
• Polar solvent nature

Effect of Alkyl Portion Structure on SN1 Reactions

• SN1 reaction rates depend on carbocation intermediate stability.
• The reactivity order is: 3° RX > 2° RX > 1° RX > Halomethane.
• 3° R-X compounds are more reactive due to the formation of a more stable 3° carbocation.

Effect of Alkyl Portion Structure on SN2 Reactions

• SN2 reaction rates depend on the ease of nucleophile (Nu) approach to the electrophilic carbon.
• The reactivity order is: Halomethane > 1° RX > 2° RX > 3° RX.
• Bulky alkyl groups hinder nucleophile approach in 3° R-X compounds.

Benzyl and Allyl Halides

• Although benzyl and allyl halides are 1° alkyl halides, they favor both SN1 and SN2 reactions.
• Benzyl and allyl halides favor SN1 reactions due to the formation of resonance-stabilized carbocations.

Strength of Nucleophiles

• Weak, neutral nucleophiles favor SN1 reactions.
• Strong, negatively charged nucleophiles e.g (RS-, N3-, NC-, RCO2-) are essential for SN2 reactions.

Common Nucleophiles

• Neutral ones: water (H₂O), alcohols (CH3OH and C2H5OH), ammonia (NH3), and alkyl amines (1° RNH₂, 2° R₂NH, and 3° R3N).
• Charged ones: metal hydroxides (Na+-OH or K+-OH), metal alkoxides (Na+-OC2H5 and Na+-OCH3), metal cyanides (Na+-CN or K+-CN), metal azides (Na+-N3), metal acetylides (RC≡C-+Na), and potassium or sodium salts of carboxylic acids (RCO₂-+Na).

Solvent Effects on SN1 and SN2 Reactions

• Polar protic solvents (H₂O and ROH) favor SN1 reactions by stabilizing cationic and anionic intermediates through solvation.
• Polar aprotic solvents (dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone) favor SN2 reactions.
• Polar aprotic solvents do not solvate nucleophiles.

Stereochemistry of SN2 Reactions

• SN2 reactions are stereospecific; product configuration is dependent on reactant configuration.
• SN2 reactions at a chiral center result in inversion of configuration to give an optically active product with opposite configuration to the reactant.
• If SN2 reaction takes place at a chiral carbon of optically active haloalkane of R-configuration, an S-chiral optically active pure enantiomer of the product is generated.

SN2 Reaction Example

• SN2 reaction of cis-1-bromo-4-methylcyclohexane with aqueous NaOH gives trans-4-methylcyclohexanol.

Vinyl and Aryl Halides

• Halogens connected to sp² carbons (vinyl and aryl halides) do not undergo either SN1 or SN2 reactions.
• Vinyl and aryl halides cannot undergo SN1 reactions due to their inability to form stable carbocation intermediates.
• Vinyl and aryl halides cannot undergo SN2 reactions due to the pi electron cloud of sp² carbons that repels Nu.

Base-Induced β-Elimination of HX from Haloalkanes

• The removal of H-X from adjacent carbons to form an alkene is β-elimination (E).

Types of Bases that Induce β-Elimination

• Sterically hindered bases are sodium or potassium t-butoxide ((CH3)3C-O-+Na), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1,8-diazobicylo[5.4.0]undec-7-ene (DBU).
• Non-sterically hindered bases are sodium or potassium ethoxide (C2H5O-+K or +Na) and sodium or potassium methoxide(CH3O-+Kor+Na).

Reaction Mechanisms of β-Elimination (E)

• E1 reactions are unimolecular and involve a two-step ionic mechanism.
• E2 reactions are bimolecular and occur via a single-step concerted process.

E1 Reaction Characteristics

• E1 reactions consist of two steps.
• The first step involving haloalkane ionization is slower and rate-determining.
• The second, faster step involves base attack on β-H of the C+ intermediate and formation of a C=C double bond.
• E1 reactions follow first-order kinetics.

Regiochemistry of E1 Reactions

• E1 reactions follow Zaitsev's rule.
• If alkyl halides have multiple β carbons, the major product is the more substituted alkene.

E2 Reaction Characteristics

• It is a concerted process in which bonds are broken and formed in a single step.
• E2 reactions are 2nd order reactions.

Regiochemistry of E2 Reactions

• E2 reactions that utilize non-sterically hindered bases follow Zaitsev’s rule.
• E2 reactions that utilize bulky bases favor the least substituted alkene.
• Bulky bases abstract a less hindered beta-hydrogen.
• E2 reaction of Fluoroalkane gives the least substituted alkene even with non-bulky base such as potassium methoxide.
• In E2 reactions, a bad leaving group, a carbanion T.S. takes place rather than a carbocation T.S.

Stereochemical Requirements of E2 Reactions

• Anti periplanar geometry (anti coplanar) which is staggering is essential for based induced E2.
• E2 Elimination of cis- and trans- 1-chloro-2- methylcyclohexane takes place at different rates and gives different products.

Factors Affecting E1 and E2 Reaction Rates

• Base strength, E2 requires strong base; E1 is not important
• Nature of polar solvent: E1- Needs polar protic solvent; E2- Needs polar aprotic solvent
• Structure of alkyl portion of alkyl halides.

Nucleophilic Substitution Versus Elimination Reactions

• Sterically unhindered, strong bases (NaOH, NaOCH3) can act as nucleophiles.
• Sterically hindered bases (sodium t-butoxide) are generally poor nucleophiles.

Formation of Organometallic Compounds

• Alkyl, vinyl, and aryl halides react with Group I (Lithium) or Group II (Magnesium) metals to form organometallic compounds.
• The formation involves conversion of an electrophilic carbon into a nucleophilic carbon.
• Reaction with Mg with ether gives grignard reagents

Preparation of Organolithium Compounds

• In the presence of Hexane, CH3CH2CH2Br (1-Bromopropane) reacts with 2Li to yield CH3CH2CH2-Li (n-Propyl lithium) + LiBr
• In the presence of Hexane, Chlorobenzene reacts with 2Li to yield Phenyllithium + LiCl

Grignard Reagents Preparation

• Bromocyclohexane with Mg yields Cyclohexyl magnesium bromide when (C2H5)2O is present
• Vinylmagnesium bromide is the result of the reaction between and H2C=C-Br + Mg when THF is present H

Organometallics Compounds Naming

• Names usually begin from the name of alkyl or aryl group followed by the name of metal.

Organo metallic Reactants

• Organometallics are useful reactants in the synthesis of alcohols, ketones, and carboxylic acids.