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Umpolung — reversed carbonyl polarity

Corey-Seebach reaction (dithiane umpolung)

How the Corey-Seebach reaction (dithiane umpolung) works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.

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In short. A 3-step mechanism. Typical reagents: 1) HS(CH₂)₃SH, BF₃·OEt₂ 2) n-BuLi, THF 3) R′–X 4) HgCl₂/H₂O (or NCS, AgNO₃). Conditions: Deprotonation –30 °C to 0 °C; alkylation –78 °C → 25 °C. Bonds formed: C–S (dithiane); C–C (alkylation); C=O (unmasking); bonds broken: C=O (aldehyde); C–H (C2); C–S (hydrolysis). Stereochemistry: None at carbanion; electrophile attack at planar/axial C2. Rate and selectivity: Deprotonation (pKa ≈ 31) fast with n-BuLi; SN2 alkylation rate-limiting.

At a glance

Reagents1) HS(CH₂)₃SH, BF₃·OEt₂ 2) n-BuLi, THF 3) R′–X 4) HgCl₂/H₂O (or NCS, AgNO₃)
Solvent / conditionsDeprotonation –30 °C to 0 °C; alkylation –78 °C → 25 °C
Bonds formedC–S (dithiane); C–C (alkylation); C=O (unmasking)
Bonds brokenC=O (aldehyde); C–H (C2); C–S (hydrolysis)
StereochemistryNone at carbanion; electrophile attack at planar/axial C2
Rate / selectivityDeprotonation (pKa ≈ 31) fast with n-BuLi; SN2 alkylation rate-limiting

Step 1: Aldehyde → 1,3-dithiane

+BF₃·OEt₂−H₂OROSHSHRSS1 · ALDEHYDE → 1,3-DITHIANEaldehydeSUBSTRATE1,3-propanedithiolC₃H₈S₂NUCLEOPHILE2-R-1,3-dithianeINTERMEDIATEThe thioacetal masks the carbonyl; stable to base and nucleophiles.

An aldehyde condenses with 1,3-propanedithiol to form a 1,3-dithiane — masking the carbonyl as a thioacetal, a stable protecting group under basic conditions.

Step 2: n-BuLi removes the C2–H

++RHSSRSS2 · N-BULI REMOVES THE C2–Hn-butyl anion (n-BuLi)C₄H₉⁻BASE2-R-1,3-dithianeACID2-lithio-1,3-dithianeANIONbutaneC₄H₁₀BYPRODUCTtwo S atoms stabilizethe carbanionSulfur polarizability and long C–S bonds stabilize the anion (pKa ≈ 31).

Strong base (n-BuLi) deprotonates the dithiane's central carbon; the two adjacent sulfurs stabilize the resulting carbanion far better than oxygen would, making this position surprisingly acidic despite looking like an ordinary C–H.

Step 3: Acyl anion equivalent alkylates; unmask

++HgCl₂, H₂OhydrolysisRSSBrRSSBrRSSRO3 · ACYL ANION EQUIVALENT ALKYLATES; UNMASKdithiane anion (acyl anion equiv.)NUCLEOPHILEmethyl bromideELECTROPHILE2,2-disubstituted dithianeINTERMEDIATEbromideBYPRODUCT2,2-disubstituted dithianeSUBSTRATEketonePRODUCTUmpolung: the former carbonyl carbon is now nucleophilic.

This carbanion is now a nucleophilic acyl anion equivalent — it reacts with electrophiles (like alkyl halides) exactly opposite to how the original carbonyl carbon would have behaved. This deliberate reversal of a carbon's natural reactivity is called umpolung, and hydrolysis afterward reveals the new carbonyl.

Abbreviations and terms

R
R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
X
Halogen / leaving group. Cl, Br or I (sometimes any leaving group).
THF
Tetrahydrofuran. Cyclic ether solvent; its oxygen lone pairs solvate Li⁺/Mg²⁺ so organometallics stay dissolved and reactive.
n-BuLi
n-Butyllithium. Very strong base/nucleophile (pKa of butane ≈ 50); deprotonates alkynes and does lithium–halogen exchange.
NCS
N-Chlorosuccinimide. Electrophilic chlorine source.
BF3
Boron trifluoride. Lewis acid (usually as the Et₂O complex).
SN2
Bimolecular nucleophilic substitution. One concerted step with backside attack and inversion; rate = k[RX][Nu].
pKa
Acid-dissociation constant (–log). Lower pKa = stronger acid; used to judge which proton a base removes.

How it compares with related reactions

Corey-Seebach reaction (dithiane umpolung)Clemmensen reductionKnoevenagel condensation
Reagents1) HS(CH₂)₃SH, BF₃·OEt₂ 2) n-BuLi, THF 3) R′–X 4) HgCl₂/H₂O (or NCS, AgNO₃)Zn(Hg), conc. HClDimethyl malonate, aldehyde, cat. piperidine (weak amine)
ConditionsDeprotonation –30 °C to 0 °C; alkylation –78 °C → 25 °CReflux, heterogeneous (metal surface)EtOH or toluene, reflux (−H₂O)
StereochemistryNone at carbanion; electrophile attack at planar/axial C2Not stereocontrolled; mechanism debatedUsually E (thermodynamic)
Rate / selectivityDeprotonation (pKa ≈ 31) fast with n-BuLi; SN2 alkylation rate-limitingWorks best for aryl ketones; avoid acid-sensitive groupsDehydration rapid after aldol addition; Doebner variant decarboxylates

Test yourself

Try to answer each question before opening it.

Which reagents and conditions are typical for the Corey-Seebach reaction (dithiane umpolung)?

1) HS(CH₂)₃SH, BF₃·OEt₂ 2) n-BuLi, THF 3) R′–X 4) HgCl₂/H₂O (or NCS, AgNO₃). Conditions: Deprotonation –30 °C to 0 °C; alkylation –78 °C → 25 °C.

Which bonds are formed and which are broken?

Formed: C–S (dithiane); C–C (alkylation); C=O (unmasking). Broken: C=O (aldehyde); C–H (C2); C–S (hydrolysis).

What is the stereochemical outcome?

None at carbanion; electrophile attack at planar/axial C2

What controls the rate or the selectivity?

Deprotonation (pKa ≈ 31) fast with n-BuLi; SN2 alkylation rate-limiting

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