Appel Reaction

Alcohol Reactions: Appel Reaction using CX4 and PPh3

Alcohol Reactions: Appel Halogenation (PPh₃ with CCl₄ or CBr₄)

Introduction

The Appel reaction turns an alcohol (R–OH) into the corresponding alkyl chloride or bromide (R–Cl or R–Br) using triphenylphosphine (PPh₃) and a tetrahalomethane (CCl₄ or CBr₄). The process runs under mild, essentially neutral conditions. PPh₃ first activates the tetrahalomethane, generating a halide donor and an electrophilic phosphorus center. The alcohol is converted into an alkoxyphosphonium intermediate, and halide then performs a backside SN2 displacement at carbon with single inversion. Triphenylphosphine oxide (Ph₃P=O) and haloform (CHCl₃ or CHBr₃) form as thermodynamic sinks that help drive the reaction.

Primary and many secondary alcohols react cleanly; tertiary substrates often eliminate instead of substituting. Compared to direct HX additions, the Appel reaction avoids carbocation rearrangements and operates without strong acid.

Quick Summary

Reagents/conditions: PPh₃ (1.1–1.5 equiv) with CCl₄ (→ chloride) or CBr₄ (→ bromide) in dry CH₂Cl₂, THF, or toluene at 0–25 °C.
Outcome: R–X (X = Cl or Br) with single inversion at the reacting stereocenter; byproducts are Ph₃P=O and CHX₃.
Mechanism class: Polar, closed-shell; activation at phosphorus followed by halide SN2 at carbon.
Scope: Primary excellent; secondary good (CBr₄ preferred); tertiary favor SN1 substitution with some elimination competition.
Selectivity: CBr₄ is faster/softer (better for hindered 2°); CCl₄ gives chlorides but can promote E2.
Limitations: Neopentyl and phenolic substrates react poorly; haloform/halide toxicity demands careful handling.

Reagent set: PPh3 with CBr4 under dry CH2Cl2, 0-25 degC — Bromide path — softer halide donor, faster for hindered or secondary alcohols.

Reagent set: PPh3 with CCl4 under dry CH2Cl2, 0-25 degC — Chloride path — delivers alkyl chlorides; monitor for competitive elimination.

Mechanism (five steps)

Step 1 – Activation: PPh₃ attacks CBr₄/CCl₄ to give a halomethylphosphonium salt plus X⁻.
Step 2 – Proton transfer: CX₃⁻ behaves as a base, removing the hydroxyl proton and generating an alkoxide.
Step 3 – Alkoxyphosphonium assembly: The alkoxide attacks PPh₃⁺, forging the [R–O–PPh₃]⁺ intermediate.
Step 4 – Substitution: Primary/secondary alcohols undergo SN2; tertiary substrates ionize first and react by SN1.
Step 5 – Products: Alkyl halide + Ph₃P=O + CHX₃ with the expected stereochemical outcome (inversion for SN2, racemization for SN1).

Step 1 — PPh₃ activates CX₄ and releases halide

Triphenylphosphine attacking the tetrahalomethane carbon while a halide departs. — PPh₃ attacks the electrophilic carbon of CBr₄/CCl₄, ejecting X⁻ and forming a halomethylphosphonium species that primes the sequence.

Step 2 — Trihalomethyl base removes the alcohol proton

Trihalomethyl carbanion abstracting the hydroxyl proton as the O–H bond breaks. — CX₃⁻ (generated in Step 1) behaves as a weak base, deprotonating the alcohol to give haloform (CHX₃) and a reactive alkoxide.

Step 3 — Alkoxide attacks phosphorus (alkoxyphosphonium)

Alkoxide lone pair forming the P–O bond while halide leaves the phosphonium complex. — The alkoxide attacks the phosphorus center of PPh₃⁺–X, generating the alkoxyphosphonium intermediate that will undergo substitution.

Step 4 — Halide substitution at carbon

Halide performing backside attack as the C–O bond breaks toward oxygen and Ph3P=O forms. — Primary/secondary centers experience backside SN2 attack: X⁻ displaces the alkoxyphosphonium and O–P collapses into Ph₃P=O, giving Walden inversion.

Step 5 — Products and byproducts

Products panel showing alkyl halide, triphenylphosphine oxide, and haloform. — The reaction delivers the alkyl halide alongside Ph₃P=O and haloform (CHX₃); these thermodynamic sinks drive the transformation forward.

SN1 variant — tertiary substrates

Tertiary alcohols ionize after Step 3 to give a carbocation; halide capture then proceeds via SN1, often with partial racemization and some E1 byproducts.

Ionization to a tertiary carbocation

Loss of the oxygen–carbon bond to give a tertiary carbocation and Ph3P=O. — The alkoxyphosphonium collapses: the C–O bond breaks to form a tertiary carbocation while Ph₃P=O departs—setting the stage for SN1 capture.

Halide capture of the carbocation

Halide anion approaching the planar carbocation to form the tertiary alkyl halide. — Halide attack on the planar carbocation furnishes the tertiary alkyl halide; solvent cages and ion pairs control the degree of racemization vs. inversion.

Mechanistic Checklist

Activation happens at phosphorus; draw the alkoxyphosphonium ([R–O–PPh₃]⁺ X⁻) before showing substitution.
The carbon–oxygen bond breaks through an SN2 event → single inversion. No SN1/rearrangements in the standard pathway.
Driving force: formation of strong P=O (Ph₃P=O) and haloform (CHX₃).
Primary ≫ secondary ≫ tertiary for substitution efficiency; tertiary still substitutes via SN1 with notable elimination competition.
Phenols and other aryl–O systems do not undergo Appel halogenation (no SNAr).
Compare alternatives: PBr₃, SOCl₂/pyridine, Mitsunobu all give R–X but with different byproducts/conditions.

Worked Examples

Alcohol class & substrate	Reagents in play	Representative product	Notes
Primary — 1-hexanol	Dry CH₂Cl₂, 0 °C to room temperature.	1-bromohexane	Typically 80–90 % yield once Ph₃P=O is removed by filtration.
Secondary (chiral) — (R)-2-butanol	Room temperature run; bromide path maximizes SN2 speed.	(S)-2-bromobutane	Observed inversion (R → S) is the classic Appel stereochemical probe.
Secondary (hindered) — cyclohexan-1-ol	Chloride variant; chill to suppress E2.	chlorocyclohexane	Collect CHCl₃ cautiously; Ph₃P=O is removed by trituration.
Tertiary — tert-butanol	Even with bromide, watch for E1 side-products while the SN1 capture delivers tert-butyl halide.	tert-butyl bromide	SN1 capture dominates: Appel delivers alkyl halide with racemization; elimination is a competing but secondary path.

Scope & Limitations

Best performers: Primary aliphatic, benzylic, and allylic alcohols (70–95 %).
Secondary: Good, especially with CBr₄; monitor for E2 (CCl₄ is harsher).
Tertiary: SN1 substitution yields alkyl halide with racemization; elimination competes but is not exclusive.
Functional-group tolerance: Neutral conditions tolerate many protecting groups; include a mild base (pyridine, imidazole) if HX buildup is problematic.
Hindered substrates: Neopentyl-like systems react sluggishly—switch to alternative halogenation reagents.

Practical Tips & Pitfalls

Choose CBr₄ for bromides (faster, less E2) and CCl₄ when the chloride is required.
Keep everything dry; add the alcohol last at 0 °C for sensitive substrates.
Typical stoichiometry: 1.2–1.6 equiv PPh₃ and CX₄ per alcohol. Excess ensures full conversion.
Workup: Precipitate/filter Ph₃P=O (hexane trituration or short silica plug). Remove haloform under the hood.
If elimination competes, lower the temperature, shorten the reaction time, or ensure rapid halide capture (slight halide excess).
Polymer-supported PPh₃ simplifies filtration and waste handling.

Exam-Style Summary

PPh₃ with CCl₄ or CBr₄ (Appel conditions) converts R–OH → R–X under neutral conditions. An alkoxyphosphonium intermediate forms, then halide attacks via SN2 to give inversion at carbon. Ph₃P=O and CHX₃ byproducts drive the reaction forward. Primary and secondary alcohols perform well; tertiary substrates usually eliminate.

Related Halogenation Guides

Interactive Toolbox

Mechanism Solver — load the Appel module to toggle CBr₄ (bromide) versus CCl₄ (chloride) and follow the SN2 vs. SN1 divergence.
Reaction Solver — compare predicted outcomes for primary/secondary/tertiary substrates and surface the elimination risk.
IUPAC Namer — validate product names (alkyl bromide/chloride, haloform) without exposing structural encodings.

Study Tools