Difficulty: Intermediate | Prerequisites: Carbonyl reactivity study notes, functional group identification, basic understanding of nucleophiles and electrophiles.
This set of topics covers the four pillars of synthetic manipulation in Organic Chemistry II: oxidising alcohols to carbonyls (and beyond), reducing carbonyls back to alcohols (or further), building new carbon-carbon bonds with organometallic reagents, and replacing C=O with C=C using the Wittig reaction. These reactions form the core synthetic toolkit. Nearly every multistep synthesis problem on an exam will draw from at least two of these categories, so knowing which reagent does what, and where it stops, is essential.
Oxidation in organic chemistry means gaining bonds to oxygen (or losing bonds to hydrogen); reduction is the reverse. PCC and Swern stop at the aldehyde; chromic acid pushes through to carboxylic acid. LiAlH4 is the strong reducer; NaBH4 is milder. Grignard and Gilman reagents add carbon nucleophiles to carbonyls, but they differ in selectivity (1,2 vs 1,4 addition, and whether they over-add). The Wittig reaction replaces a C=O with a C=C, driven by formation of the very stable P=O bond.
Organic reduction
An increase in the number of C-H bonds and/or a decrease in the number of C-O (or C-heteroatom) bonds. In simple terms, the molecule gains hydrogen or loses oxygen.
Organic oxidation
The reverse: a decrease in C-H bonds and/or an increase in C-O bonds.
PCC (pyridinium chlorochromate)
A mild, selective oxidant used in anhydrous DCM. Oxidises primary alcohols to aldehydes (stops there) and secondary alcohols to ketones.
Chromic acid (H2CrO4, Jones reagent)
A strong oxidant used in aqueous conditions. Oxidises primary alcohols all the way to carboxylic acids, and secondary alcohols to ketones. Cannot oxidise tertiary alcohols (no alpha-hydrogen).
Swern oxidation
Uses DMSO and oxalyl chloride ((COCl)2). Stops at the aldehyde stage for primary alcohols. Mild and selective.
DMP (Dess-Martin periodinane)
Another mild oxidant that stops at the aldehyde for primary alcohols.
LiAlH4 (lithium aluminium hydride)
A strong hydride reducing agent. Reduces aldehydes, ketones, esters, and carboxylic acids to alcohols. Reduces amides to amines (not alcohols). Must be used in anhydrous ether or THF.
NaBH4 (sodium borohydride)
A weak, selective hydride source. Reduces aldehydes and ketones to alcohols but cannot reduce esters or carboxylic acids. Can be used in protic solvents such as ethanol.
DIBAL-H (diisobutylaluminium hydride)
At low temperatures, reduces an ester to an aldehyde (stops at one addition). At higher temperatures or with excess, can push to the alcohol.
NaBH3CN (sodium cyanoborohydride)
A very weak, selective hydride source. Used in reductive amination. Does not efficiently reduce esters.
NADH
The biological hydride source. Delivers H- to substrates in enzymatic reductions. Think of it as nature's version of NaBH4.
Grignard reagent (RMgX)
An organomagnesium halide. A strong, hard nucleophile that adds a carbanion (R-) to carbonyls via 1,2-addition. Formed from an alkyl or aryl halide + Mg metal in anhydrous ether or THF.
Umpolung
A reversal of polarity. In an alkyl halide, carbon is electrophilic (delta+). When converted to a Grignard, that same carbon becomes nucleophilic (delta-). In simple terms, flipping a carbon from electron-poor to electron-rich.
Gilman reagent (lithium dialkylcuprate, R2CuLi)
A soft nucleophile formed from 2 equivalents of RLi + CuI. Performs 1,4-addition (conjugate addition) to alpha,beta-unsaturated carbonyls. With acid chlorides, it stops at the ketone stage (does not over-add).
Wittig reaction
Converts a carbonyl (C=O) into an alkene (C=C) using a phosphorus ylide. The driving force is formation of the very strong P=O bond in triphenylphosphine oxide.
Phosphorus ylide (Wittig reagent)
Ph3P=CH2 (or substituted variants). The carbon is nucleophilic (bears a formal negative charge); the phosphorus is electrophilic (bears a formal positive charge).
Oxaphosphetane
The four-membered ring intermediate in the Wittig reaction, containing carbon, phosphorus, and oxygen. It collapses to give the alkene and triphenylphosphine oxide.
Mild oxidants (stop at the aldehyde for primary alcohols)
PCC in DCM: anhydrous conditions prevent the aldehyde from hydrating, so no further oxidation occurs. Also converts secondary alcohols to ketones.
Swern oxidation (DMSO, (COCl)2): mild, anhydrous. Same selectivity as PCC.
DMP (Dess-Martin periodinane): mild, anhydrous. Same selectivity.
Strong oxidants (push through to carboxylic acid)
Chromic acid (H2CrO4, Jones reagent): aqueous conditions allow the aldehyde intermediate to form a hydrate, which is then further oxidised to the carboxylic acid. Also oxidises secondary alcohols to ketones.
Why tertiary alcohols cannot be oxidised
The oxidation mechanism requires removal of a hydrogen from the carbon bearing the -OH group (the alpha-hydrogen) to form the C=O pi bond. A tertiary carbon has no hydrogen to lose, so the elimination step is impossible.
LiAlH4 (strong reducer)
Reduces aldehydes and ketones to alcohols.
Reduces esters to primary alcohols (two hydride equivalents delivered).
Reduces carboxylic acids to primary alcohols.
Reduces amides to amines (the oxygen is lost as part of the aluminate complex, so the product retains nitrogen rather than oxygen).
Must use anhydrous ether or THF, followed by aqueous acid workup.
NaBH4 (weak, selective reducer)
Reduces aldehydes to primary alcohols and ketones to secondary alcohols.
Cannot reduce esters, carboxylic acids, or amides.
Can be used in protic solvents (EtOH, MeOH).
DIBAL-H
At low temperature (-78 C): reduces an ester to an aldehyde (delivers only one hydride, stops at the tetrahedral intermediate stage).
At higher temperature or with excess: full reduction to the alcohol.
NaBH3CN
Very weak. Cannot reduce esters. Used primarily for reductive amination (selective reduction of an imine in the presence of a carbonyl).
Catalytic hydrogenation (H2/Pd, H2/Pt)
Reduces C=C double bonds to C-C single bonds (syn-addition of two hydrogens).
Can also reduce C=O to C-OH under certain conditions.
PCC is an oxidant, not a reductant; a common trap in multiple-choice questions.
Biological hydride source
NADH delivers a hydride equivalent (H-) in enzymatic reductions within the cell. It is the biological analogue of NaBH4.
Grignard reagent synthesis
Requires three things: an alkyl or aryl halide (e.g. bromobenzene), magnesium metal (Mg0), and a dry aprotic solvent (anhydrous diethyl ether or THF). Wet ethanol or any protic solvent will immediately quench the reagent by protonating the carbanion.
Why Grignard reagents are incompatible with protic groups
Grignard reagents are extremely strong bases (the conjugate acid of R- has a pKa of roughly 45 to 60). They will deprotonate any acidic proton with a pKa below about 45, including -OH, -NH2, -COOH, and -SH groups. If the substrate contains an amine (-NH2, pKa around 38), the Grignard will deprotonate it instead of adding to the carbonyl. This is a simple acid-base reaction that destroys the reagent.
Umpolung in Grignard formation
In the starting alkyl halide, the carbon bonded to the halogen is electrophilic (delta+). When magnesium inserts into the C-X bond, that same carbon becomes nucleophilic (delta-). This polarity reversal is called umpolung.
Grignard reactions with different substrates
With an aldehyde: gives a secondary alcohol (after acid workup).
With a ketone: gives a tertiary alcohol.
With an ester (2 equivalents of Grignard): gives a tertiary alcohol. The first equivalent adds and expels the alkoxide to give a ketone; the ketone is more reactive than the starting ester and immediately reacts with the second equivalent.
With an acid chloride: the Grignard is too reactive to stop at the ketone. It adds twice, giving a tertiary alcohol.
Gilman reagent (R2CuLi)
Formed from 2 equivalents of an organolithium (RLi) + 1 equivalent of copper(I) iodide (CuI).
With an acid chloride: adds once and stops at the ketone. The cuprate is a softer, less reactive nucleophile, so it does not add to the ketone product.
With an alpha,beta-unsaturated carbonyl: performs 1,4-addition (conjugate addition) to the beta-carbon, rather than 1,2-addition to the carbonyl carbon. Grignard and organolithium reagents are hard nucleophiles that prefer 1,2-addition.
1,2-addition vs 1,4-addition
Hard nucleophiles (Grignard, organolithium): 1,2-addition, attack the carbonyl carbon directly.
Soft nucleophiles (Gilman reagent): 1,4-addition, attack the beta-carbon of a conjugated system. The nucleophile ends up at the beta position, and the enolate is the initial product.
Purpose
Converts a ketone or aldehyde (C=O) into an alkene (C=C). This is one of the few reliable ways to place a double bond exactly where a carbonyl used to be.
Ylide synthesis (step by step)
React triphenylphosphine (Ph3P) with a primary alkyl halide (e.g. CH3Br) via an SN2 reaction to form a phosphonium salt (e.g. methyltriphenylphosphonium bromide).
Deprotonate the phosphonium salt with a strong base (n-BuLi or NaH) to generate the ylide (Ph3P=CH2).
Mechanism
The nucleophilic carbon of the ylide attacks the electrophilic carbonyl carbon.
A betaine intermediate forms (a zwitterionic species).
The betaine cyclises to form the oxaphosphetane, a four-membered ring containing C, P, and O.
The oxaphosphetane undergoes a retro [2+2] cycloaddition, collapsing to give the alkene product and triphenylphosphine oxide (Ph3P=O).
Driving force
The reaction is thermodynamically driven by the formation of the very strong P=O bond in triphenylphosphine oxide. This bond is one of the strongest in organic chemistry, so its formation pulls the equilibrium decisively toward products.
Example: cyclohexanone to methylenecyclohexane
The ylide needed is Ph3P=CH2 (from CH3Br + Ph3P, then deprotonation with n-BuLi). The ylide carbon attacks cyclohexanone, proceeds through the oxaphosphetane, and collapses to give methylenecyclohexane (an exocyclic alkene) plus Ph3P=O.
Identifying electrophilic and nucleophilic atoms in the ylide
In Ph3P=CH2, the carbon bears a formal negative charge (nucleophilic), and the phosphorus bears a formal positive charge (electrophilic). The carbon is the atom that attacks the carbonyl.
Oxidation definition: increase in C-O bonds, decrease in C-H bonds
Reduction definition: increase in C-H bonds, decrease in C-O bonds
Grignard formation: R-X + Mg --> R-MgX (in anhydrous ether/THF)
Gilman formation: 2 RLi + CuI --> R2CuLi + LiI
Wittig overall: R2C=O + Ph3P=CR'2 --> R2C=CR'2 + Ph3P=O
Chromic acid oxidation: primary alcohol --> aldehyde --> carboxylic acid (aqueous)
PCC oxidation: primary alcohol --> aldehyde (anhydrous, stops here)
Students often think NaBH4 can reduce esters. It cannot; it is too weak. Only LiAlH4 (or DIBAL-H for partial reduction) handles esters.
Confusing PCC with chromic acid: PCC stops at the aldehyde; chromic acid goes to the carboxylic acid. The difference is anhydrous vs aqueous conditions.
Assuming LiAlH4 reduces amides to alcohols. Amides are reduced to amines by LiAlH4. The oxygen is lost; the nitrogen is retained.
Thinking Grignard reagents can be used on substrates with -OH or -NH2 groups. The Grignard will deprotonate these groups before it gets a chance to add to the carbonyl.
Mixing up which organometallic does 1,2 vs 1,4 addition. Grignard and organolithium are hard nucleophiles (1,2). Gilman (cuprate) is soft (1,4).
Know which oxidant to choose for a given transformation. "Primary alcohol to aldehyde" = PCC, Swern, or DMP. "Primary alcohol to carboxylic acid" = chromic acid.
Be ready to predict products of LiAlH4 reduction on different functional groups, especially the amide-to-amine exception.
Grignard + ester questions are common: remember the product is a tertiary alcohol because two equivalents add.
Gilman vs Grignard with acid chlorides: Gilman gives a ketone; Grignard gives a tertiary alcohol.
The Wittig mechanism (phosphonium salt, ylide, oxaphosphetane, driving force) is a favourite long-answer topic.
True or False: PCC can oxidise a primary alcohol to a carboxylic acid. (False, it stops at the aldehyde)
Fill in the blank: LiAlH4 reduces an amide to an ______. (amine)
True or False: NaBH4 is a strong enough hydride to reduce esters. (False)
Fill in the blank: The four-membered ring intermediate in the Wittig reaction is called an ______. (oxaphosphetane)
True or False: Gilman reagents prefer 1,2-addition to alpha,beta-unsaturated carbonyls. (False, they prefer 1,4-addition)
Q: Which reagent is most suitable for oxidising a primary alcohol to a carboxylic acid?
A: Chromic acid (H2CrO4, Jones reagent). It operates in aqueous conditions, allowing oxidation past the aldehyde stage.
Q: What is the product of reducing an amide with LiAlH4?
A: An amine. The oxygen is lost as part of the aluminate complex; the nitrogen is retained.
Q: Contrast the reactivity of CH3MgBr and LiCu(CH3)2 with an acid chloride.
A: CH3MgBr (Grignard) is a hard, strong nucleophile. It adds to the acid chloride to form a ketone, but the ketone is more reactive than the acid chloride toward Grignard, so a second equivalent adds, giving a tertiary alcohol. LiCu(CH3)2 (Gilman) is a softer, weaker nucleophile. It replaces the chloride to form the ketone but is not reactive enough to add again, so the reaction stops at the ketone.
Q: Describe how to convert cyclohexanone into methylenecyclohexane via the Wittig reaction.
A: React Ph3P with CH3Br (SN2) to form methyltriphenylphosphonium bromide. Deprotonate with n-BuLi to generate the ylide Ph3P=CH2. Add cyclohexanone. The ylide attacks the ketone, forms an oxaphosphetane, and collapses to give methylenecyclohexane and triphenylphosphine oxide.
Q: What solvent is required for Grignard reactions, and why?
A: Anhydrous diethyl ether or THF. Grignard reagents are extremely strong bases and will react with any protic source (water, alcohols) to form an alkane, destroying the reagent.
Oxidation and reduction connect directly to carbonyl reactivity (the first set of study notes), because reduction adds a nucleophile (H-) to a carbonyl, and oxidation creates a carbonyl from an alcohol. Organometallic reagents connect to acidity and pKa (the third study notes document), because the incompatibility of Grignard reagents with protic functional groups is fundamentally an acid-base issue. The Wittig reaction connects to alkene chemistry and stereochemistry, as the geometry of the product alkene (E vs Z) depends on whether a stabilised or non-stabilised ylide is used.
Oxidation, reduction, PCC, pyridinium chlorochromate, chromic acid, Jones reagent, Jones oxidation, Swern oxidation, Dess-Martin periodinane, DMP, LiAlH4, lithium aluminium hydride, NaBH4, sodium borohydride, DIBAL-H, diisobutylaluminium hydride, NaBH3CN, NADH, biological hydride, catalytic hydrogenation, H2/Pd, H2/Pt, Grignard reagent, RMgBr, organolithium, RLi, Gilman reagent, lithium dialkylcuprate, R2CuLi, CuI, umpolung, polarity reversal, 1,2-addition, 1,4-addition, conjugate addition, hard nucleophile, soft nucleophile, Wittig reaction, phosphorus ylide, phosphonium salt, oxaphosphetane, triphenylphosphine oxide, Ph3P=O, alkene synthesis, CHEM 212, organic chemistry II