Organic Chemistry · Part 3 of 9

Organometallic Additions & Carbanion C–C Bond Formation

Named Reactions, Part 3 · 11 sections · about 9,401 words · CSIR-NET Chemical Sciences, GATE Chemistry & IIT-JAM

How chemists use a carbon nucleophile carrying a metal (Mg, Li, Cu, Zn, Cr/Ni) to forge new C–C bonds. Two layers on every reagent — a slow, hand-held beginner path and a research-grade advanced/reference path that treats 1,2- vs 1,4-addition through HSAB, chemoselectivity and protecting-group needs, and addition stereochemistry (Cram / Felkin–Anh vs chelation control, with Newman-projection transition-state diagrams) — closing with a “which organometallic do I use?” decision table. Reagents covered: Grignard, organolithium, Gilman cuprate, Corey–House, Barbier, organozinc / Reformatsky & Blaise, and Nozaki–Hiyama–Kishi.

The 11 sections in Part 3

  • 1Grignard reagents (RMgX) Free below
  • 2Organolithium reagents (RLi)
  • 3Gilman reagents / organocuprates (R₂CuLi)
  • 4The Corey–House synthesis (alkane from two halides)
  • 5The Barbier reaction (one-pot organometallic addition)
  • 6Organozinc chemistry: the Reformatsky & Blaise reactions
  • 7The Nozaki–Hiyama–Kishi (NHK) reaction
  • 8Reagent → job at a glance
  • 9The 1,2 vs 1,4 rule (HSAB) — the most-tested idea
  • 10Chemoselectivity & reactivity ladder
  • 11Stereochemistry quick-reference

Grignard reagents (RMgX)

Free extract

Section D.1 of Part 3, reproduced in full from the book — figures and all. No sign-in, no paywall on this section.

R–Mg–Xfrom R–X + Mgadds to C=O, CO₂, epoxides, nitrilesdry ether, inert atmospherestrong base too
Beginner layer

A carbon glued to magnesium is a carbon nucleophile: it attacks carbonyls to build alcohols, attacks CO₂ for acids, opens epoxides, and adds to nitriles for ketones.

In one line: a Grignard reagent R–Mg–X (made by stirring an organic halide with magnesium metal in dry ether) has a strongly nucleophilic carbon that attacks an electrophilic carbon — most famously the carbonyl carbon of an aldehyde or ketone — forming a new C–C bond and, after aqueous work-up, an alcohol.

Umpolung: the carbon's polarity is invertedCXδ+δ−electrophilic Cinsert MgCMgXδ−δ+NUCLEOPHILIC C
In R–X the carbon is electrophilic (δ+). Inserting magnesium into the C–X bond gives R–Mg–X, in which the same carbon is now nucleophilic (δ−, a carbanion equivalent). This polarity reversal is why a Grignard is a carbon nucleophile. Hand-built schematic —
Make the reagent first. An organic halide R–X (X = Cl, Br, I; alkyl, aryl or vinyl) is stirred with magnesium turnings in an anhydrous ether solvent (diethyl ether or THF) under an inert atmosphere. The magnesium inserts into the C–X bond to give R–Mg–X. The ether is essential: its oxygen lone pairs coordinate to Mg and stabilise (solubilise) the reagent. Everything must be dry — water, alcohols, even acidic C–H destroy the reagent instantly.
Formation: bromobenzene + Mg (dry Et₂O) → phenylmagnesium bromide (PhMgBr). RDKit-rendered (the Mg–Br is drawn schematically).
Typical Grignard reagents. RDKit draws them with an explicit C–Mg bond; the real species is more aggregated (Schlenk equilibrium — advanced layer).
Mechanism — Grignard 1,2-addition to a carbonyl (every arrow explained)
Nucleophilic addition to a carbonyl (1,2-addition)COR'R''CMgR1) C attacks C=O2) π → O (alkoxide)Mg⁺ coordinates the carbonyl O (Lewis-acid activation)
The carbanionic carbon of R–MgX adds to the carbonyl carbon while the C=O π electrons shift onto oxygen to give a magnesium alkoxide; aqueous work-up then protonates it to the alcohol. Mg⁺ acts as a Lewis acid, coordinating the carbonyl oxygen and activating it. Hand-built schematic —
  1. Step 0 — make R–MgX. Mg⁰ inserts into R–X by a radical/surface process at the metal, giving R–Mg–X solvated by ether. The carbon is now δ− (nucleophilic).
  2. Step 1 — C–C bond forms. The nucleophilic Grignard carbon attacks the electrophilic carbonyl carbon. Arrow: C–Mg bonding pair (the “carbanion”) → carbonyl C. Simultaneously the C=O π electrons shift onto oxygen. Arrow: C=O π → O. Mg⁺ coordinates that oxygen as a Lewis acid, so the step often looks like a cyclic, six-membered-like delivery.
  3. Step 2 — a magnesium alkoxide. The product of addition is a halomagnesium alkoxide R'R''C(–O–MgX)–R. No proton is available yet (the medium is aprotic and dry), so the alkoxide is stable until work-up.
  4. Step 3 — aqueous work-up. Adding dilute acid (or water/NH₄Cl) protonates the alkoxide oxygen. Arrow: O⁻ lone pair → H⁺. Out comes the alcohol. Counting: formaldehyde → 1° alcohol; any other aldehyde → 2° alcohol; a ketone → 3° alcohol.

The four carbonyl-class outcomes you must memorise

The electrophile class fixes the alcohol class (and CO₂ gives an acid). One extra carbon (the R of RMgX) is added in every case. RDKit-rendered.

PhMgBr + acetone, then H₃O⁺ — give the product Easy

Electrophile: acetone (a ketone) → expect a 3° alcohol.
Nucleophile: PhMgBr delivers a phenyl group to the carbonyl carbon.
New bond: Ph–C(CH₃)₂–O⁻ MgBr⁺, then protonate on work-up.
Product: 2-phenylpropan-2-ol, (CH₃)₂C(Ph)OH. RDKit below.
Ketone + aryl Grignard → tertiary alcohol. RDKit-rendered.

Convert 1-bromobutane into pentanoic acid (add one carbon as CO₂) Medium

Make the Grignard: 1-bromobutane + Mg / dry Et₂O → butylmagnesium bromide (BuMgBr).
React with solid CO₂ (dry ice): the Grignard carbon attacks a CO₂ carbon, giving a carboxylate salt Bu–CO₂⁻ MgBr⁺.
Acidic work-up (H₃O⁺) protonates the carboxylate.
Product: pentanoic acid, CH₃(CH₂)₃CO₂H — one carbon longer than the halide.
Carboxylation: BuMgBr + CO₂ then H₃O⁺ → pentanoic acid. A one-carbon homologation of the alkyl halide. RDKit-rendered.

EtMgBr opens ethylene oxide (epoxide) — predict the product Medium

Epoxides are strained; a Grignard opens them by SN2 at the less hindered carbon.
EtMgBr delivers an ethyl group to one epoxide carbon; the C–O bond there breaks and the oxygen becomes an alkoxide on the adjacent carbon.
Work-up protonates the alkoxide.
Product: butan-1-ol (a “2-carbon-extended” primary alcohol) — the Grignard gains two carbons, and the new OH ends up β to the carbon that came from the Grignard: Et–CH₂–CH₂–OH.
Epoxide opening: EtMgBr + ethylene oxide then H₃O⁺ → butan-1-ol. The Grignard carbon binds the less hindered epoxide carbon (SN2). RDKit-rendered.

PhMgBr + benzonitrile (PhC≡N), then H₃O⁺ — what forms? Hard

A Grignard adds once to a nitrile C≡N, giving a magnesium imine salt (a metalated ketimine), not a full double addition.
The Grignard carbon binds the nitrile carbon; N becomes N–MgX.
Acidic aqueous work-up hydrolyses the imine to a ketone (via the imine → then hydrolysis).
Product: benzophenone, Ph–CO–Ph — a ketone. Nitriles are a classic ketone source with Grignards.
Nitrile route to a ketone: PhMgBr + PhCN, then H₃O⁺ → benzophenone (via a magnesio-imine that hydrolyses). RDKit-rendered.

⚠ Common mistakes & exam traps

  • Water kills Grignards. Any O–H, N–H, S–H or terminal alkyne C–H protonates the reagent (R–MgX + H–A → R–H + XMg–A). A substrate with a free –OH, –NH₂ or –CO₂H needs protection or an extra equivalent of Grignard.
  • Grignards do not tolerate other electrophilic groups in the same molecule — a ketone, ester, nitrile, epoxide or nitro group will react. This is a chemoselectivity problem, not a footnote.
  • Formaldehyde → 1°, other aldehydes → 2°, ketones → 3° alcohol. Mixing these up is the commonest exam error.
  • With an ester, a Grignard adds twice (via a ketone intermediate) to give a 3° alcohol with two identical R groups — not a ketone. To stop at the ketone use a Weinreb amide. A Gilman cuprate does not rescue an ester — cuprates are essentially unreactive toward esters; the cuprate→ketone trick belongs to acid chlorides.
  • The by-product basic magnesium species and the alkoxide are only quenched at work-up; don't draw the free alcohol before adding acid/water.
  • Vinyl and aryl halides need THF (or activation) — they form Grignards more sluggishly than alkyl halides. Aryl/vinyl fluorides essentially don't react.
Advanced / reference layer

Structure (Schlenk equilibrium), the addition transition state, ester → double addition, 1,2 vs 1,4 with enones, chemoselectivity & protecting groups, and stereochemistry (Cram/Felkin–Anh vs chelation).

A Grignard in solution is not the simple monomer R–Mg–X that we draw. It exists in the Schlenk equilibrium, 2 R–MgX ⇌ R₂Mg + MgX₂, with all species solvated by ether and often aggregated. The position of this equilibrium (and the presence of MgX₂) affects reactivity and, for stereochemistry, the availability of a Lewis-acidic Mg to chelate substrate heteroatoms. For product prediction, treating the reagent as delivering “R⁻” is fine; for mechanism and stereochemistry the aggregation matters.

Schlenk equilibrium:   2 R–Mg–X  ⇌  R₂Mg + MgX₂  (all ···OEt₂ solvated, frequently dimeric/aggregated)

Mechanism: polar vs single-electron-transfer (SET) pathways

Formation of the reagent at the magnesium surface involves radicals (R• intermediates), which is why formation can scramble radical-clock substrates. The addition to a carbonyl is usually drawn as a polar, cyclic process with Mg coordinating the carbonyl oxygen, but for easily reduced ketones a competing SET (single-electron-transfer) pathway (ketyl radical anion + R•) operates and can give reduction or pinacol by-products. Hindered ketones with β-hydrogens can also suffer reduction (hydride delivery) or enolisation instead of addition.

Esters and acid derivatives: double addition

With an ester, the first addition gives a tetrahedral alkoxide that collapses by ejecting –OR' to a ketone; that ketone is more electrophilic than the ester, so a second equivalent of Grignard adds immediately, giving after work-up a tertiary alcohol bearing two identical R groups. Acid chlorides behave similarly (but can be stopped at the ketone by a cuprate). To get a ketone cleanly from a Grignard, use a Weinreb amide [–C(=O)N(Me)OMe], whose stable five-membered chelate stops after one addition.

Ester + 2 PhMgBr → triphenylmethanol (a 3° alcohol with two new Ph groups). The intermediate ketone (benzophenone) is consumed by the second addition. RDKit-rendered.
The Weinreb amide's metal-chelated tetrahedral intermediate is stable until work-up, so exactly one R adds — a clean ketone synthesis. RDKit-rendered.

1,2- versus 1,4-addition to α,β-unsaturated carbonyls (HSAB)

With an enone, a nucleophile can add to the carbonyl carbon (1,2, giving an allylic alcohol) or to the β-carbon (1,4 / conjugate, giving a saturated carbonyl after tautomerisation). Hard, highly ionic organometallics — RMgX and especially RLi — are charge-controlled and add predominantly 1,2 to the hard carbonyl carbon. Soft, less ionic cuprates (R₂CuLi) add 1,4. This hard–soft (HSAB) split is the organising principle of the next chapters: to make the allylic alcohol use a Grignard/RLi; to install R at the β-position use a Gilman cuprate. Grignards can be nudged toward 1,4 by catalytic Cu(I) (which converts them, in situ, into cuprate-like species).

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The remaining 10 sections of this part — Organolithium reagents (RLi), Gilman reagents / organocuprates (R₂CuLi), The Corey–House synthesis (alkane from two halides), The Barbier reaction (one-pot organometallic addition) — and all nine parts of Named Reactions are part of ChemVidya Full Access, along with the other books, 55 Study Notes and 6,000+ practice questions.

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