CHEM210 Lecture : Radical Halogenation, Alkyl Halide Reactivity, and SN2 Substitution

Radical Stability and Selectivity in Alkane Halogenation

• Radical intermediate stability is dictated by carbon substitution:
  • Primary ($1^\circ$) carbon: Attached to only one other carbon atom; yields a primary radical.
  • Secondary ($2^\circ$) carbon: Attached to two other carbon atoms; yields a secondary radical.
  • Tertiary ($3^\circ$) carbon: Attached to three other carbon atoms; yields a tertiary radical.
  • Relative stability hierarchy: Tertiary ($3^\circ$) radical $>$ Secondary ($2^\circ$) radical $>$ Primary ($1^\circ$) radical.
• The major organic product of a free-radical reaction is dictated by the relative stability of the reactive intermediate formed during the rate-determining step:
  • The reaction pathway proceeding through the lowest-energy (most stable) radical intermediate has the lowest activation barrier and forms at the fastest kinetic rate.
  • The major product is not favored because the final product molecule itself is necessarily more stable, but because it originates from the most stable reactive intermediate.
• Physical properties and formation kinetics:
  • Differences in boiling point between constitutional isomers do not govern product distribution.
  • Boiling points are only relevant for physical separation techniques following product formation, or in reactions where product volatility (gas formation) drives an equilibrium.
  • In kinetic reaction coordinate diagrams, the energy level of the highest-energy transition state leading to the intermediate controls the rate of intermediate and product formation.
• Hydrogen classification and isomer differentiation:
  • To determine potential radical substitution sites, all distinct hydrogen environments in an alkane must be cataloged.
  • Equivalent hydrogens: Hydrogens bonded to carbons in chemically identical environments share the same reactivity and rate.
  • Constitutional differences: Even if two distinct types of hydrogens are both primary (e.g., position $a$ versus position $d$), reacting at one versus the other yields distinct constitutional isomers with different IUPAC names, even though their initial rates of hydrogen abstraction may be nearly identical.
• Radical bromination product distribution:
  • Bromination is extraordinarily regioselective compared to other halogenations.
  • In many bromination reactions, the product derived from the most stable radical is the only product formed, or accounts for $>99\%$ of the total product mixture with minor isomers appearing at roughly $1\%$ or less in literature.
  • Less selective reactions may yield product distributions such as $60/40\%$, but bromination predominantly yields a single major organic product.

Regioselectivity and Resonance Stabilization of Allylic and Benzylic Radicals

• Hybridization constraints on radical formation:
  • Radical intermediate formation occurs exclusively at $sp^3$-hybridized carbon centers under standard radical halogenation conditions.
  • Radical formation on an $sp^2$-hybridized carbon requires an extremely high activation energy; vinyl radicals are prohibitively high in energy and do not form under these conditions.
• Classification of specialized carbon positions:
  • Allylic position: An $sp^3$-hybridized carbon directly bonded to an alkene ($C=C$) double bond.
  • Benzylic position: An $sp^3$-hybridized carbon directly attached to an aromatic benzene ring.
• Radical stability comparisons involving resonance:
  • An allylic radical is significantly more stable than a typical tertiary ($3^\circ$) alkyl radical.
  • A benzylic radical is likewise stabilized by resonance delocalization across the aromatic $π$ system.
  • Expanded radical stability hierarchy: Benzylic $\approx$ Allylic $>$ Tertiary ($3^\circ$) $>$ Secondary ($2^\circ$) $>$ Primary ($1^\circ$) $>$ $sp^2$ (vinylic/aryl).
  • In an alkene substrate possessing both secondary allylic positions and unactivated tertiary alkyl positions, radical abstraction occurs preferentially at the secondary allylic position due to resonance stabilization.
• Drawing resonance structures for radicals:
  • Radical electron movement must be depicted using single-barbed ("fishhook") curved arrows, representing the transfer of a single electron.
  • The resonance delocalization of an allylic radical requires three distinct single-barbed arrows:
  • Arrow 1: Originates from the unpaired radical electron and moves into the adjacent carbon-carbon single bond.
  • Arrow 2: Originates from the alkene $\pi$ bond and moves into the adjacent carbon-carbon single bond to pair with the electron from Arrow 1, creating a new $\pi$ bond.
  • Arrow 3: Originates from the alkene $\pi$ bond and moves onto the terminal carbon atom, depositing a lone unpaired electron.
• Stereochemical considerations in radical products:
  • Stereochemistry (wedges and dashes) is omitted when the radical substitution does not generate a chiral carbon center (stereocenter).

The Synthetic Organic Toolbox: Functionalization of Alkanes

• The utility of radical halogenation in organic synthesis:
  • Unfunctionalized alkanes are chemically inert and possess no functional groups that can undergo nucleophilic attack or elimination.
  • Regioselective radical bromination serves as the primary gateway reaction in the synthetic "toolbox" to functionalize an alkane.
  • Converting an alkane into an alkyl bromide ($R-Br$) allows subsequent transformation into alkenes, alcohols, ethers, amines, and other functional groups.
• Halogen selectivity comparison:
  • Bromine ($Br_2$): Highly regioselective; abstracts almost exclusively at the most substituted or resonance-stabilized $sp^3$ carbon position.
  • Chlorine ($Cl_2$): Highly reactive and non-selective; abstracts hydrogens across primary, secondary, and tertiary positions, yielding complex mixtures of constitutional isomers.
  • Fluorine ($F_2$): Extremely exothermic, violent, and non-selective.
  • Iodine ($I_2$): Endothermic, unfavorable, and unreactive under standard synthetic conditions.

Physical and Electronic Properties of Alkyl Halides

• Electrostatic potential maps:
  • Red coloration on an electrostatic potential map denotes regions of high electron density.
  • In alkyl halides, the halogen carries negative charge density, with alkyl fluorides showing dense, intense red localized around the fluorine atom due to high electronegativity and small ionic/covalent radius.
• Reactivity versus electronegativity:
  • A common misconception is that alkyl fluorides are the most reactive alkyl halides due to the high electronegativity of fluorine creating a strong dipole.
  • Experimentally, alkyl fluorides are the least reactive, and alkyl iodides are the most reactive.
• Bond length and orbital overlap:
  • The carbon-fluorine ($C-F$) bond is the shortest in the alkyl halide series, measuring approximately $1.4\text{ \AA}$.
  • Carbon and fluorine have similar orbital sizes ($2p$ orbitals), allowing optimal orbital overlap and forming an exceptionally strong bond.
  • Moving down Group 17 from fluorine to iodine, atomic radius increases, causing bond lengths to lengthen substantially and orbital overlap to deteriorate.
  • The carbon-iodine ($C-I$) bond is significantly longer than the $C-F$ bond.
• Bond strength and kinetic reactivity hierarchy:
  • Carbon-halogen bond strength order: $C-F > C-Cl > C-Br > C-I$.
  • Alkyl halide reactivity order: $R-I > R-Br > R-Cl > R-F$.
  • Chemical reactions of alkyl halides involve breaking the carbon-halogen bond; therefore, bond strength, rather than electronegativity differences, governs leaving group ability and substitution reaction rates.
  • The weakest bond ($C-I$) is cleaved most easily, making alkyl iodides the most reactive alkyl halides.

Nucleophilic Substitution: The $S_N2$ Reaction Mechanism and Energetics

• Characteristics of the $S_N2$ pathway:
  • "$S_N2$" stands for Substitution Nucleophilic Bimolecular.
  • Operates via a concerted, one-step mechanism without forming any reactive intermediates.
  • Requires simultaneous bond forming and bond breaking in a single elementary step.
• Mechanistic steps of $S_N2$:
  • A strong nucleophile bearing a lone pair of electrons attacks the electrophilic carbon atom directly attached to the halogen.
  • The nucleophile does not attack the leaving group.
  • Concurrently with nucleophilic attack, the carbon-leaving group ($C-X$) bond cleaves heterolytically, with both electrons from the bond departing onto the halogen leaving group ($X^-$).
• Leaving group ability:
  • Efficient $S_N2$ substitution requires a stable, weakly basic leaving group.
  • Leaving group effectiveness hierarchy: $I^- > Br^- > Cl^-$.
  • Fluoride ($F^-$) is not a good leaving group due to the high strength of the $C-F$ bond.
• Reaction coordinate and energy diagrams for an exothermic $S_N2$ process:
  • Reaction Coordinate (x-axis) versus Free Energy/Enthalpy (y-axis).
  • Exothermic thermodynamics: The enthalpy change is negative ($\Delta H < 0$); products sit at a lower energy level than the initial starting materials.
  • Kinetic pathway: Because the reaction is concerted and has no intermediates, the curve contains no intermediate energy wells (local minima).
  • Transition state: A single high-energy peak represents the transition state, at which the nucleophile-carbon bond is partially formed while the carbon-halogen bond is partially broken.

Stereochemical Principles, Symmetry, and Enantiomeric Resolution

• Chirality and planes of symmetry:
  • An achiral molecule typically possesses an internal plane of symmetry ($\sigma$).
  • A meso compound contains multiple stereocenters (chiral centers) but is achiral overall due to an internal plane of symmetry.
  • When assessing symmetry in acyclic or flexible molecules, conformations must be considered: a staggered conformation may appear asymmetrical until rotated into an eclipsed or symmetric conformation to verify whether an internal mirror plane exists.
• Enantiomeric resolution of racemic mixtures:
  • Enantiomers have identical physical properties (such as boiling point, melting point, and solubility in achiral solvents) and cannot be separated by standard physical methods.
  • Resolving a racemic mixture of a chiral base requires reaction with an enantiomerically pure chiral acid.
  • The interaction between a racemic base ($(R/S)$) and an enantiopure acid ($(R)$) forms a pair of diastereomeric salts ($(R,R)$ and $(S,R)$).
  • Because diastereomers have different physical and chemical properties, they can be separated by fractional crystallization or chromatography.
• Substitution patterns:
  • Positional isomerism in rings distinguishes between $1,2$-substitution patterns (adjacent carbons) and $1,3$-substitution patterns (separated by one carbon).

Questions, Problem Review, and In-Class Dialogue

• Clarification on intermediate stability versus product boiling points:
  • Question: Can lower boiling point be incorporated to explain why one isomer is the major or only product?
  • Response: Boiling point is irrelevant to the reaction kinetics and intermediate stability. Boiling point matters when physically separating products. Unless a product is continuously removed as a gas, boiling point does not affect regiochemical outcome. The rate of product formation is dictated by the highest-energy barrier leading to the intermediate.
• Clarification on stereochemistry representation:
  • Question: Does the bromine need to be drawn in a specific position, such as on the bottom, and why is stereochemistry not shown?
  • Response: The halogen can be drawn anywhere on the carbon as long as the connectivity is correct. Stereochemistry is omitted because the product carbon is not a chiral center.
• Clarification on equivalent primary carbons:
  • Question: What makes position $d$ and position $a$ different carbons if both are primary?
  • Response: They do not differ in their rate of radical formation because both are primary. However, attaching a bromine to carbon $d$ produces a constitutional isomer with a distinct chemical name compared to bromination at carbon $a$.
• Clarification on minor product percentages:
  • Question: Can there be circumstances where a minor product forms alongside the major product, and is determining exact percentages expected?
  • Response: Yes, forming a single product exclusively is uncommon; often minor products form in small amounts (such as $1\%$), while less selective reactions can give ratios like $60/40\%$. Calculating literature percentages is beyond the scope of the course; focus remains on predicting the major organic product.
• Clarification on allylic versus tertiary stability:
  • Question: Why is an allylic radical more stable than a tertiary radical?
  • Response: The allylic radical is stabilized through resonance delocalization across adjacent $sp^2$ orbitals, which lowers the overall energy below that of an unactivated tertiary radical.
• Clarification on benzylic versus allylic terminology:
  • Question: Can a position adjacent to an isolated alkene double bond be called benzylic?
  • Response: No. A benzylic position requires an aromatic benzene ring. A carbon directly attached to an isolated non-aromatic double bond is allylic.
• Clarification on hybridization limitations:
  • Question: Are radical formations restricted solely to $sp^3$ carbons?
  • Response: Yes, because radicals on $sp^2$-hybridized carbons are extremely high in energy and do not form under these conditions.
• Review of alkyl halide properties quick-quiz:
  • Question: Which alkyl halide is the most reactive?
  • Response: Alkyl iodide, because it possesses the weakest carbon-halogen bond.
  • Question: Which alkyl halide has the shortest carbon-halide bond?
  • Response: Alkyl fluoride ($C-F$).
  • Question: Which alkyl halide has the weakest carbon-halide bond?
  • Response: Alkyl iodide ($C-I$).
• Review of symmetry and chiral resolution problems:
  • Question: Does an achiral molecule have no plane of symmetry?
  • Response: Achiral molecules possess a plane of symmetry. Meso compounds have stereocenters but remain achiral because they possess an internal plane of symmetry.
  • Question: How is an internal plane of symmetry identified in staggered conformations?
  • Response: The bonds must be rotated out of the staggered conformation to verify whether the groups align across a mirror plane.
  • Question: What reagent is required to resolve a racemic mixture of bases?
  • Response: A chiral acid is required to produce diastereomeric salts.
• Class administrative matters and exchanges:
  • Confirmation of genetics laboratory schedule: It was verified that genetics laboratory did not meet on that day.
  • Class assignments: Students discussed completing an extra credit assignment due that evening, reviewing quiz answer keys, and taking screenshots of lecture slides.