Source: Klein, Organic Chemistry, Chapter 20 (Sections 20.8–20.13)
Tags: thioacetal, desulfurization, Raney nickel, LAH reduction, NaBH4, Grignard reaction, cyanohydrin, HCN, Wittig reaction, phosphorane, ylide, Baeyer-Villiger oxidation, migratory aptitude, lactone, synthesis strategy, retrosynthetic analysis, IR spectroscopy carbonyl, NMR aldehyde, organic chemistry
Difficulty: Intermediate to Advanced Prerequisites: Parts 1–3 of these notes (Sections 20.1–20.7). Grignard reagents (Section 13.6). Hydride reductions (Section 13.4). SN2 restrictions. IR and NMR fundamentals (Chs. 15–16).
This final part of the chapter covers the remaining nucleophile classes (sulfur, hydrogen, carbon) and two important transformations: the Baeyer-Villiger oxidation and the Wittig reaction. It also ties everything together with synthesis strategy and spectroscopic identification. By the end you should be able to predict products for any nucleophile attacking a carbonyl, plan multi-step syntheses involving C-C bond formation and functional group interconversion, and identify aldehydes and ketones from their IR and NMR data.
Thiols form thioacetals (removable with Raney Ni to give alkanes). Hydride agents (LAH, NaBH₄) reduce carbonyls to alcohols. Grignard reagents add carbon chains. Cyanide gives cyanohydrins. The Wittig reaction replaces C=O with C=C. Baeyer-Villiger oxidation inserts an oxygen next to the carbonyl to produce an ester or lactone. Carbonyls show a strong IR signal near 1715 cm⁻¹, aldehydic C-H at 2700–2850 cm⁻¹, ¹H NMR around 10 ppm, and ¹³C NMR near 200 ppm.
Thioacetal
The sulfur analogue of an acetal: two SR groups on the same carbon, formed by treating a carbonyl with two equivalents of a thiol (RSH) under acidic conditions.
In simple terms, it is an acetal with sulfur atoms where the oxygen atoms would be.
Desulfurization
Replacement of C-S bonds with C-H bonds using Raney nickel (a spongy nickel catalyst with adsorbed hydrogen atoms). Converts a thioacetal into a methylene group (CH₂).
Think of it as "swapping out the sulfurs for hydrogens."
Cyanohydrin
A compound bearing both a cyano group (CN) and a hydroxyl group (OH) on the same carbon, formed by adding HCN to a carbonyl.
In simple terms, a CN and an OH sitting on the same carbon.
Wittig reaction
A reaction that converts a ketone or aldehyde into an alkene by treatment with a phosphorus ylide (Wittig reagent). Replaces C=O with C=C.
Think of it as the go-to method for placing a double bond exactly where a carbonyl used to be.
Phosphorane (Wittig reagent / ylide)
A compound with adjacent opposite charges: a negatively charged carbon bonded to a positively charged phosphorus bearing three phenyl groups (Ph₃P⁺-C⁻). The carbanion end attacks the carbonyl.
In simple terms, it is the reagent that delivers the "other half" of the new C=C bond.
Betaine
The neutral intermediate in the Wittig reaction that carries a negative charge on oxygen and a positive charge on phosphorus (non-adjacent opposite charges).
Oxaphosphetane
The four-membered ring intermediate (containing O and P) that forms when the betaine's oxygen attacks phosphorus intramolecularly. It decomposes to give the alkene and triphenylphosphine oxide.
Baeyer-Villiger oxidation
Treatment of a ketone with a peroxy acid (RCO₃H) to insert an oxygen atom adjacent to the carbonyl, converting the ketone into an ester (or a cyclic ketone into a lactone).
Think of it as "wedging an oxygen in next to the C=O."
Migratory aptitude
The relative tendency of different groups to migrate during the Baeyer-Villiger rearrangement step. Order: H > 3° > 2°, Ph > 1° > methyl.
In simple terms, bulkier, more substituted groups migrate faster.
Lactone
A cyclic ester. Formed when a Baeyer-Villiger oxidation is performed on a cyclic ketone.
Thioacetal formation:
Aldehyde or ketone + 2 RSH, [H⁺] → thioacetal + H₂O
Mechanism is directly analogous to acetal formation, with sulfur replacing oxygen
A dithiol (HS-CH₂CH₂-SH) gives a cyclic thioacetal
Desulfurization with Raney nickel:
Thioacetal + Raney Ni → alkane (both C-S bonds replaced by C-H bonds)
Raney Ni is a spongy form of nickel with adsorbed hydrogen atoms; the hydrogens replace the sulfur atoms
Third method for C=O → CH₂:
Thioacetal formation followed by Raney Ni desulfurization is a third route to convert a ketone to an alkane
The other two: Clemmensen reduction (Zn-Hg, HCl) and Wolff-Kishner reduction (NH₂NH₂ then KOH/H₂O/heat)
Reduction of aldehydes and ketones to alcohols:
LAH (LiAlH₄), then H₂O workup → alcohol
NaBH₄ in MeOH → alcohol
Both reagents deliver hydride (H⁻) to the carbonyl carbon
Simplified mechanism (Mechanism 20.9):
Step 1, nucleophilic attack: H⁻ (delivered by LAH or NaBH₄) attacks the carbonyl, forming a tetrahedral intermediate (alkoxide)
Step 2, proton transfer: the alkoxide is protonated to give the alcohol
Key points:
This reaction is not reversible because hydride is too basic to function as a leaving group
One-way arrows (not equilibrium arrows) are used
The full mechanism is more complex (the Li⁺ cation plays a role), but the simplified two-step version is sufficient for most purposes
Grignard reaction:
Aldehyde or ketone + RMgBr, then H₂O → alcohol with a new C-C bond
Ketones give tertiary (or secondary) alcohols; aldehydes give secondary (or primary) alcohols
Mechanism (Mechanism 20.10): nucleophilic attack by the carbanion (from RMgBr), then proton transfer
Not reversible (carbanions are terrible leaving groups)
One-way arrows
Cyanohydrin formation:
Aldehyde or ketone + HCN (catalytic base or KCN/HCN mixture) → cyanohydrin (HO-CR₂-CN)
Mechanism (Mechanism 20.11): cyanide ion (CN⁻) attacks the carbonyl, then the tetrahedral intermediate abstracts a proton from HCN, regenerating CN⁻ (catalytic cycle)
Reversible; equilibrium favours the cyanohydrin for most aldehydes and unhindered ketones
HCN is extremely toxic and volatile (b.p. 26 °C); an alternative preparation uses KCN + HCl
Cyanohydrins are synthetically useful because the CN group can be further transformed:
LAH reduction: CN → CH₂NH₂ (amino group)
Acid hydrolysis (H₃O⁺, heat): CN → COOH (carboxylic acid)
Wittig reaction:
Aldehyde or ketone + phosphorane (Ph₃P=CR₂) → alkene + triphenylphosphine oxide (Ph₃P=O)
Replaces the C=O with a C=C at the same position
Mechanism (Mechanism 20.12):
Nucleophilic attack: the Wittig reagent (carbanion) attacks the carbonyl → betaine
Intramolecular nucleophilic attack: oxygen attacks phosphorus → oxaphosphetane (four-membered ring)
Rearrangement: the oxaphosphetane decomposes to give the alkene and Ph₃P=O
Preparing Wittig reagents:
Treat triphenylphosphine (Ph₃P) with a primary alkyl halide (SN2), then deprotonate with a strong base (BuLi)
SN2 restrictions apply: primary alkyl halides work best; secondary are slower; tertiary do not work
The Wittig reaction is therefore most useful for mono-, di-, or trisubstituted alkenes; tetrasubstituted alkenes are difficult
Choosing the correct Wittig disconnection:
There are always two possible disconnections at the C=C bond (two ways to split it into a carbonyl + Wittig reagent)
Pick the disconnection where the Wittig reagent comes from a less substituted (preferably primary) alkyl halide, since SN2 is faster with less steric hindrance
Ketone + peroxy acid (RCO₃H, e.g. mCPBA) → ester
Cyclic ketone → lactone (cyclic ester)
Mechanism (Mechanism 20.13):
Nucleophilic attack: the peroxy acid attacks the carbonyl
Proton transfer: intramolecular (or two intermolecular steps)
Rearrangement: C=O reforms with simultaneous migration of an alkyl group to oxygen, producing the ester and releasing a carboxylic acid
Migratory aptitude determines which group migrates when the ketone is unsymmetrical:
H > 3° alkyl > 2° alkyl, phenyl > 1° alkyl > methyl
The group with the higher migratory aptitude migrates preferentially
Example: in a ketone with an isopropyl group and a methyl group, the oxygen is inserted on the isopropyl side because the isopropyl group migrates faster
Two key questions for any synthesis problem:
Is there a change in the carbon skeleton?
Is there a change in the functional group?
Functional group interconversion:
This chapter adds the carbonyl to the existing network of interconvertible functional groups (alkenes, alcohols, alkyl halides, etc.)
Be able to fill in the reagents for every transformation in Figure 20.9 of the textbook
C-C bond-forming reactions in this chapter (three total):
Grignard reaction (adds an alkyl group from RMgBr)
Cyanohydrin formation (adds one carbon as CN)
Wittig reaction (forms a C=C bond with a new carbon chain)
C-C bond-breaking reaction in this chapter (one):
Baeyer-Villiger oxidation (inserts O between C-C, effectively breaking the original bond connectivity)
Retrosynthetic thinking:
Work backward from the product to identify which bond was formed and which reaction could form it
Work forward from the starting material to see how to install the necessary functional group
Many synthesis problems have multiple correct answers
IR signals:
Carbonyl C=O stretch: strong absorption around 1715–1720 cm⁻¹
Conjugated carbonyl (e.g. aryl ketone): lower wavenumber, around 1680 cm⁻¹ (resonance weakens the C=O bond)
Ring strain raises the wavenumber: cyclohexanone at 1715, cyclopentanone at 1745, cyclobutanone at 1780 cm⁻¹
Aldehydic C-H stretch: one or two signals between 2700 and 2850 cm⁻¹ (diagnostic for aldehydes)
¹H NMR signals:
The carbonyl group itself has no proton, so no direct signal
Protons adjacent to a carbonyl are shifted downfield by about +1 ppm compared to protons next to a simple alkyl group (roughly 2.2 ppm for CH next to C=O)
Aldehydic protons appear around 9–10 ppm (very distinctive, few other signals appear this far downfield)
¹³C NMR signals:
The carbonyl carbon produces a weak signal near 190–210 ppm
This is well separated from most other carbon signals, making it easy to identify
Thioacetal: R₂C(SR)₂
Cyanohydrin: R₂C(OH)(CN)
Wittig: R₂C=O + Ph₃P=CR'₂ → R₂C=CR'₂ + Ph₃P=O
Baeyer-Villiger: R-CO-R' + RCO₃H → R-CO-O-R' (oxygen inserted next to the carbonyl)
Migratory aptitude order: H > 3° > 2°, Ph > 1° > methyl
IR: C=O at ~1715 cm⁻¹; aldehydic C-H at 2700–2850 cm⁻¹
¹H NMR: aldehydic H at ~10 ppm
¹³C NMR: C=O carbon at ~200 ppm
Amygdalin, found in apricot and cherry pits, is metabolised to mandelonitrile (a cyanohydrin), which decomposes to release HCN and benzaldehyde. Millipedes use this same cyanohydrin-to-HCN conversion as a chemical defence mechanism, storing the cyanohydrin and the enzyme in separate compartments and mixing them when threatened.
The Wittig reaction earned Georg Wittig the 1979 Nobel Prize in Chemistry. It is routinely used in pharmaceutical synthesis to place double bonds with precise positional control.
Students sometimes assume the Wittig reaction can produce tetrasubstituted alkenes easily. It cannot: the SN2 step in Wittig reagent preparation requires a primary (or at most secondary) alkyl halide, which limits the substitution of the product alkene.
A common error is confusing the three C=O → CH₂ methods. Keep them straight: Clemmensen uses Zn-Hg/HCl (acidic), Wolff-Kishner uses NH₂NH₂ then KOH/heat (basic), and thioacetal/Raney Ni is a two-step process through sulfur.
Students often forget the migratory aptitude order during Baeyer-Villiger problems, placing the oxygen on the wrong side. Remember: the more substituted group migrates preferentially (H > 3° > 2°, Ph > 1° > methyl).
In cyanohydrin formation, students sometimes use CN⁻ as if it were consumed. It is catalytic: CN⁻ attacks, then the tetrahedral intermediate takes a proton from HCN, regenerating CN⁻.
⚠️ Three methods for converting C=O → CH₂ (Clemmensen, Wolff-Kishner, thioacetal/Raney Ni): know all three, when to use each (acidic vs. basic vs. neutral conditions), and be able to identify them in synthesis problems.
⚠️ Wittig disconnection problems are common: given a target alkene, identify the two possible carbonyl + Wittig reagent pairs, and select the one requiring the less substituted alkyl halide.
⚠️ Baeyer-Villiger migratory aptitude: H > 3° > 2°, Ph > 1° > methyl. Be able to predict which side of an unsymmetrical ketone receives the inserted oxygen.
⚠️ Cyanohydrin as a synthetic intermediate: know that CN can be reduced to NH₂ (with LAH) or hydrolysed to COOH (with H₃O⁺/heat). These transformations extend the carbon chain by one and introduce useful functional groups.
⚠️ Spectroscopy: a strong IR absorption near 1715 cm⁻¹ is the carbonyl stretch. Aldehydic C-H at 2700–2850 cm⁻¹ distinguishes aldehydes from ketones. A ¹H NMR signal near 10 ppm confirms an aldehyde. A ¹³C signal near 200 ppm confirms a carbonyl carbon.
True or False: Raney nickel converts a thioacetal into a ketone. ___
Fill in the blank: The Wittig reaction converts a C=O into a ________.
True or False: In the Baeyer-Villiger oxidation, the less substituted group migrates preferentially. ___
Fill in the blank: The aldehydic proton appears at approximately ________ ppm in a ¹H NMR spectrum.
True or False: The reduction of a carbonyl with NaBH₄ is reversible. ___
Answers: 1. False (Raney Ni converts a thioacetal into an alkane, replacing both C-S bonds with C-H). 2. C=C (alkene). 3. False (the more substituted group migrates preferentially). 4. ~10 ppm. 5. False (hydride is too basic to function as a leaving group, so the reaction is irreversible).
Q: Propose a two-step method for converting cyclohexanone into cyclohexane using sulfur chemistry.
A: (1) Treat cyclohexanone with 1,2-ethanedithiol (HS-CH₂CH₂-SH) and acid catalyst to form the cyclic thioacetal. (2) Treat the thioacetal with Raney nickel to replace both C-S bonds with C-H bonds, giving cyclohexane.
Q: Identify the reagents needed to prepare the following compound from cyclohexanone via a Wittig reaction: methylenecyclohexane (cyclohexane ring with an exocyclic =CH₂).
A: Treat cyclohexanone with the Wittig reagent Ph₃P=CH₂ (methylenetriphenylphosphorane). The Wittig reagent is prepared from CH₃I + PPh₃ followed by BuLi.
Q: Predict the major product of treating 2-methylcyclohexanone with mCPBA (a peroxy acid).
A: A seven-membered lactone, with the oxygen inserted on the more substituted side of the carbonyl (next to the carbon bearing the methyl group), because the more substituted carbon has a higher migratory aptitude.
Q: A compound with molecular formula C₄H₈O shows a strong IR absorption at 1720 cm⁻¹ and a ¹H NMR signal at 9.8 ppm. What functional group is present?
A: An aldehyde. The IR signal at 1720 cm⁻¹ is the C=O stretch, and the ¹H NMR signal near 10 ppm is the aldehydic proton.
Q: Starting from benzaldehyde, how would you prepare mandelic acid (2-hydroxy-2-phenylacetic acid, PhCH(OH)COOH)?
A: (1) Treat benzaldehyde with KCN/HCN to form the cyanohydrin (PhCH(OH)CN). (2) Hydrolyse the CN group with H₃O⁺ and heat to give the alpha-hydroxy acid (PhCH(OH)COOH).
Hydride reductions (LAH, NaBH₄) connect directly to alcohol chemistry (Ch. 13). Grignard reactions link to organometallic chemistry and will reappear with carboxylic acid derivatives (Ch. 21). The Wittig reaction is a cornerstone of alkene synthesis alongside elimination reactions (Ch. 8). Cyanohydrin chemistry extends into nitrile reactions (Ch. 21). The Baeyer-Villiger oxidation connects carbonyl chemistry to ester chemistry. The spectroscopic signatures covered here are used routinely in structure determination problems throughout the rest of the course.
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