CHM102: Alkyl Halides Lecture Notes

Introduction to Organohalogens and Alkyl Halides

• Definition of Organohalogens: Organic compounds containing halogen atoms bonded to a carbon atom are classified as organohalogens.
• Major Classes of Organohalogens:
  • Alkyl Halides (Haloalkanes): These consist of a halogen atom bonded to one of the $sp^3$ hybrid carbon atoms of an alkyl group.
  • Vinyl Halides: These consist of a halogen atom bonded to one of the $sp^2$ hybrid carbon atoms of an alkene.
  • Aryl Halides: These consist of a halogen atom bonded to one of the $sp^2$ hybrid carbon atoms of an aryl group (aromatic ring).
• Structural and Chemical Properties:
  • The spatial arrangement of groups around the carbon atom in alkyl halides is tetrahedral.
  • Bond Polarization: Because halogens are more electronegative than carbon, the carbon-halogen ($C-X$) bond is polarized. The carbon atom carries a partial positive charge ($\delta+$) and the halogen carries a partial negative charge ($\delta-$).
  • Group Trends: Moving down the group in the periodic table, the carbon-halogen bond length increases while the bond strength decreases.
• Applications:
  • Alkyl halides serve as solvents for relatively non-polar compounds.
  • They are critical starting materials for the synthesis of various other organic compounds.

Classification of Alkyl Halides

• General Structure: Alkyl halides are formed by replacing one hydrogen atom of an alkane with a halogen atom (e.g., $CH_3Cl$ or $CH_3CH_2CH_2I$).
• Degrees of Substitution: Alkyl halides are classified based on the substitution level of the carbon atom directly attached to the halogen:
  • Primary (1°) Alkyl Halide: The carbon atom bearing the halogen is bonded to no more than one other carbon atom (e.g., $CH_3CH_2Br$).
  • Secondary (2°) Alkyl Halide: The carbon bearing the halogen is attached to two other carbon atoms (e.g., $CH_3CHClCH_3$).
  • Tertiary (3°) Alkyl Halide: The carbon bearing the halogen is attached to three other carbon atoms (e.g., $(CH_3)_3CBr$).

Nomenclature of Alkyl Halides

• General Representation: Alkyl halides are represented as $RX$.
• General Formula: For a monohalide, the formula is $C_nH_{2n+1}X$, where $R$ is the alkyl group.
• Common Names: Frequently used for simple molecules:
  • $CH_3I$ — Methyl iodide
  • $CH_3CH_2Cl$ — Ethyl chloride
  • $CH_3CH_2CH_2Br$ — Propyl bromide
• IUPAC Nomenclature Rules:
  • Identify the parent alkane chain.
  • The halogen group is treated as a substituent (e.g., fluoro-, chloro-, bromo-, iodo-).
  • The halogen prefix precedes the name of the alkane parent.
  • Numbering: If the parent chain has both a halo and an alkyl substituent, number the chain from the end nearest the first substituent found, regardless of whether it is a halogen or an alkyl group.
• IUPAC Examples:
  • $CH_3CHBrCH_3$ — 2-bromopropane
  • $CH_3CH(Cl)CH(CH_3)CH_2CH_3$ — 2-chloro-3-methylpentane

Preparation of Alkyl Halides

1. From Alcohols

• Alcohols react with hydrogen halides, phosphorus tribromide, or thionyl chloride to produce alkyl halides.
• Hydrogen Halides (HX): The reactivity order is $HI > HBr > HCl$. Note that $HF$ is generally unreactive.
  • Example: $CH_3CH_2CH_2CH_2OH + HBr \rightarrow CH_3CH_2CH_2CH_2Br + H_2O$ (Note: reagents like $NaBr$ and $H_2SO_4$ can be used to generate $HBr$ in situ).
• Phosphorus Tribromide ($PBr_3$):
  • Example: $3CH_3CH_2OH + PBr_3 \rightarrow 3CH_3CH_2Br + H_3PO_3$
• Thionyl Chloride ($SOCl_2$):
  • Example: $Cyclohexanol + SOCl_2 \rightarrow Chlorocyclohexane + SO_2 + HCl$

2. Halogenation of Alkanes

• Alkanes react with fluorine, chlorine, or bromine via substitution (halogenation) to produce a mixture of haloalkanes and hydrogen halide. Alkanes generally do not react with iodine.
• Mechanism: One or more hydrogen atoms are replaced by halogen atoms, often requiring heat ($\Delta$) or light ($hv$).
  • Example: $2,2-dimethylpropane + Cl_2 \xrightarrow{heat/light} 1-chloro-2,2-dimethylpropane + HCl$
• "Useful" Chlorination Reactions: These produce only a single major product because all hydrogen atoms in the starting material are chemically identical:
  • $CH_4 + Cl_2 (1 \, equiv) \xrightarrow{hv} CH_3Cl + HCl$
  • $CH_3-CH_3 + Cl_2 (1 \, equiv) \xrightarrow{hv} CH_3-CH_2Cl + HCl$
  • $C(CH_3)_4 + Cl_2 (1 \, equiv) \xrightarrow{hv} (CH_3)_3CCH_2Cl + HCl$
  • $Cyclohexane + Cl_2 (1 \, equiv) \xrightarrow{hv} Chlorocyclohexane + HCl$

3. Addition of Hydrogen Halides to Alkenes

• Hydrogen halides ($HX$) add across the double bonds of alkenes.
• Conditions: Carried out by dissolving $HX$ in solvents like acetic acid ($CH_3COOH$) or dichloromethane ($CH_2Cl_2$), or by bubbling gaseous $HX$ through the alkene liquid.
• Regioselectivity:
  • Markovnikov Rule: In unsymmetrical alkenes, the hydrogen attaches to the carbon with more hydrogens, and the halogen attaches to the carbon with more alkyl substituents.
  • Anti-Markovnikov Addition: If peroxides are introduced specifically with $HBr$, the addition follows an anti-Markovnikov path.

Physical Properties of Alkyl Halides

• Solubility: They generally have low solubility in water but are miscible with other organic liquids.
• Common Solvents: Dichloromethane ($CH_2Cl_2$, methylene chloride), trichloromethane ($CHCl_3$, chloroform), and tetrachloromethane ($CCl_4$, carbon tetrachloride) are standard solvents for non-polar compounds.
• Toxicity: Many chloroalkanes exhibit cumulative toxicity and are carcinogenic; they should be handled in a fume hood.
• States of Matter at Room Temperature:
  • Iodomethane ($CH_3I$): The only monohalomethane that is liquid at room temperature.
  • Ethane derivatives: Bromoethane and iodoethane are liquids; chloroethane is a gas.
  • Higher Alkyl Halides: Chloro-, bromo-, and iodoalkanes with higher molecular weights are liquids.
• Boiling Points: They tend to have boiling points near those of alkanes with similar molecular weights.

Nucleophilic Substitution Reactions

• General Concept: A nucleophile ($Nu:$) — an organic or inorganic species with an unshared electron pair — reacts with the substrate (alkyl halide). The nucleophile replaces the halogen, which departs as a halide ion (the leaving group).
• Mechanism Transition: The carbon-halogen bond undergoes heterolysis. The unshared pair of the nucleophile forms a new bond with the carbon.
• General Equation: $Nu: + R-X \rightarrow R-Nu + :X^-$
• Examples of Nucleophiles and Products:
  • $RX + :OH^- \rightarrow R-OH + X^-$ (Alcohol)
  • $RX + NH_3 \rightarrow R-NH_2 + HX$ (Amine)
  • $RX + :OR^- \rightarrow R-OR + :X^-$ (Ether)
  • $RX + :I^- \rightarrow R-I + X^-$ (Alkyl iodide)
  • Other nucleophiles include $CN^-$, $RC \equiv C^-$, $N_3^-$, $SH^-$, and $RCOO^-$.

A. Unimolecular Mechanism ($S_N1$)

• Kinetics: This is a first-order reaction. The rate depends only on the concentration of the alkyl halide: $\text{rate} = k[RX]$.
• Rate-Determining Step (RDS): The slow step is the heterolytic cleavage of the $C-X$ bond to form a carbocation intermediate.
• Steps:
  1. Slow Step: $R-X \rightarrow R^+ + X^-$ (Formation of carbocation).
  2. Fast Step: $R^+ + :Nu \rightarrow R-Nu$.
• Reactivity Order: The stability of the carbocation governs reactivity: $3^℃ > 2^℃ > 1^℃ > CH_3X$.
• Solvation: The resulting ions are solvated and stabilized by polar solvents like water.

B. Bimolecular Mechanism ($S_N2$)

• Kinetics: This is a second-order reaction overall. The rate depends on both the alkyl halide and the nucleophile: $\text{rate} = k[RX][Nu^-]$.
• Mechanism: It occurs in a single step via a transition state where the bond to the nucleophile is partially forming while the bond to the leaving group is partially breaking.
• Stereochemistry: Often leads to an "inversion of configuration."
• Reactivity Order: This is governed by steric hindrance: $CH_3X > 1^℃ > 2^℃ > 3^℃$. Alkyl groups around the central carbon obstruct the incoming nucleophile.

Elimination Reactions

• Definition: Fragments of a molecule are removed from adjacent atoms to introduce a multiple bond ($C=C$). This often competes with substitution.
• Dehydrohalogenation: The removal of $HX$ from adjacent atoms of an alkyl halide to produce an alkene. It is also called 1,2-elimination or $\beta$-elimination.
• Reagents: Requires a strong base (e.g., $KOH$ in ethanol, $NaOEt$ in ethanol, $KOBut$, or $NaOH$).
• General Reaction: $\text{Base} + H-C_\beta-C_\alpha-X \rightarrow C=C + \text{Base}-H + X^-$.

A. Unimolecular Mechanism ($E1$)

• Kinetics: First-order reaction ($\text{rate} = k[RX]$).
• Mechanism:
  1. Slow Step: Dissociation of the alkyl halide to form a carbocation (identical to the $S_N1$ first step).
  2. Fast Step: A base abstracts a proton from the $\beta$-carbon, and the electrons flow to form the double bond.
• Competition with $S_N1$: Since both share the same intermediate, they usually occur together in protic solvents with poor nucleophiles.
• Favorable Conditions: Substrates that form stable carbocations, weak bases, and polar solvents. Increasing temperature favors $E1$ over $S_N1$.

B. Bimolecular Mechanism ($E2$)

• Kinetics: Second-order reaction ($\text{rate} = k[RX][Base]$).
• Mechanism: A concerted single-step process. In the transition state, the double bond is partially formed while the bond to the $\beta$-hydrogen and the bond to the halogen are partially broken.
• Example: $CH_3CHBrCH_3 + C_2H_5O^- \xrightarrow{EtOH} H_2C=CHCH_3 + C_2H_5OH + Br^-$.

Grignard Reagents and Synthetic Applications

• Definition: Organomagnesium compounds with the general formula $RMgX$ (where $X = Cl, Br, I$).
• Polarity Inversion (Umpolung): While alkyl halides are electrophilic ($C^{\delta+}$), Grignard reagents are nucleophilic ($C^{\delta-}$).
• Preparation: Reacting an alkyl, vinyl, or aryl halide with magnesium turnings in a dry ether or tetrahydrofuran (THF) solvent.
  • $RX + Mg \xrightarrow{\text{dry ether}} RMgX$
  • Discovered by Victor Grignard (Nobel Prize in Chemistry, 1912).
• Synthetic Applications:
  • Alkane Formation: Grignard reagents act as very strong bases and abstract protons from water ($H_2O$), alcohols, or terminal alkynes.
    • $RMgX + H_2O \rightarrow R-H + Mg(OH)X$
  • Reaction with Alkyl Halides: $RMgX + R'X \rightarrow R-R' + MgX_2$.
  • Alcohol Formation (Reaction with Carbonyls):
    • Formaldehyde (Methanal): Yields primary (1°) alcohols ($RMgX + HCHO \rightarrow RCH_2OH$).
    • Higher Aldehydes (e.g., Ethanal): Yields secondary (2°) alcohols ($RMgX + CH_3CHO \rightarrow RCH(OH)CH_3$).
    • Ketones: Yields tertiary (3°) alcohols.
    • Esters: Yields tertiary (3°) alcohols (requires 2 equivalents of $RMgX$).
    • Epoxides: Yields alcohols via ring opening.
  • Ketone Formation: Formed by reacting Grignard reagents with acid chlorides ($R'COCl$).
  • Carboxylic Acid Formation: Reaction with carbon(IV) oxide ($CO_2$) followed by hydrolysis yields carboxylic acids ($RCOOH$).

Questions & Discussion

Reaction Completion Exercises:

• Prompt 1: Predict the outcome of $RCl + Mg$ in ether.
  • Response: $RMgCl$ (Grignard reagent).
• Prompt 2: How to synthesize $RCH_2OH$ from $RCH_2Cl$ using Grignard chemistry?
  • Response: Convert $RCH_2Cl$ to a Grignard reagent ($RCH_2MgCl$) and allow it to react with oxygen or other oxidative processes; or alternatively, start with $RMgCl$ and react with formaldehyde ($HCHO$).