Difficulty: Intermediate | Prerequisites: Parts 1 and 2 of these notes, SN1/SN2/E1/E2 mechanisms, oxidation states in organic chemistry
Alcohols undergo dehydration (to alkenes), conversion to alkyl halides, tosylation, and oxidation to carbonyls. The mechanism and reagent choice depend on whether the alcohol is 1°, 2°, or 3°. Protecting groups (TMS ethers) let you shield -OH during reactions that would otherwise destroy it. Thiols are the sulphur analogues of alcohols: more nucleophilic, more acidic, and capable of forming disulphide bridges.
Dehydration
Elimination of water from an alcohol to form an alkene. In simple terms, you pull off H2O and get a double bond.
Zaitsev's rule
The most substituted alkene is the major product in an elimination reaction. Think of it as "the more stable double bond wins."
Tosylate (-OTs)
A sulphonate ester leaving group formed by reacting an alcohol with tosyl chloride (TsCl) in pyridine. In simple terms, you swap -OH for a group that leaves easily in SN2 reactions.
Jones' reagent (CrO3, H2SO4, H2O, acetone)
A strong chromium-based oxidant. Oxidises 1° alcohols all the way to carboxylic acids, and 2° alcohols to ketones.
PCC (pyridinium chlorochromate)
A milder chromium oxidant used in CH2Cl2. Oxidises 1° alcohols to aldehydes (stops there) and 2° alcohols to ketones.
TMS-Cl (trimethylsilyl chloride)
The reagent used (with Et3N) to protect an alcohol as a trimethylsilyl ether (R-O-SiMe3). In simple terms, you cap the -OH so it will not interfere with other reactions.
Thiol (R-SH)
The sulphur analogue of an alcohol. More acidic, more nucleophilic, and lower boiling than the corresponding alcohol.
Disulphide bridge (R-S-S-R)
A covalent bond between two sulphur atoms, formed by oxidation of two thiols. Critical in protein structure (cysteine residues).
Treatment with acid (H3O+) and heat removes H2O to form an alkene.
Follows Zaitsev's rule: the more substituted (more stable) alkene is the major product.
Mechanism is E1 for 3° and most 2° alcohols: protonation of -OH, loss of water to form a carbocation, then deprotonation to give the alkene.
3° alcohols dehydrate easily under mild acid conditions.
1° and 2° alcohols are harder to dehydrate with acid alone. For these, use POCl3 with pyridine, which proceeds by an E2 mechanism: the alcohol oxygen attacks phosphorus to make a good leaving group, then pyridine acts as the base for anti-periplanar elimination.
The goal is to replace -OH with -X (Cl, Br, or I).
3° alcohols: react with HCl, HBr, or HI directly
The mechanism goes through a carbocation (SN1): acid protonates -OH to make water leave, forming a 3° carbocation, then halide attacks.
1° and 2° alcohols: use SOCl2 (for Cl) or PBr3 (for Br)
SOCl2 (thionyl chloride): the alcohol oxygen attacks sulphur, creating a chlorosulphite intermediate with a good leaving group. Chloride then displaces in an SN2 step. Products: RCl + SO2 + Cl-.
PBr3 works similarly to give RBr.
These reagents avoid carbocation formation, which is important for 1° and 2° substrates where rearrangements are a risk.
React R-OH with tosyl chloride (TsCl) in pyridine.
The product is a tosylate ester (R-OTs), where the -OTs group is an excellent leaving group for SN2 reactions.
This is useful because it converts a poor leaving group (-OH) into a good one without changing the carbon skeleton or causing rearrangements.
Oxidation increases the number of C-O bonds (or decreases C-H bonds) at the carbinol carbon. The mechanism for chromium-based oxidants involves forming a chromate ester, then E2 elimination to give the C=O.
3° alcohols: no reaction with standard oxidants. There is no hydrogen on the carbinol carbon to eliminate, so oxidation cannot proceed.
2° alcohols → ketones:
Jones' reagent (CrO3, H2SO4, H2O, acetone): works.
PCC (pyridinium chlorochromate in CH2Cl2): works.
Na2Cr2O7 (H2O, acetic acid, heat): works.
All three give the same product (the ketone) because a ketone cannot be oxidised further under these conditions.
1° alcohols → aldehydes or carboxylic acids:
Jones' reagent oxidises all the way to the carboxylic acid (R-CH2OH → R-COOH). The aqueous acidic conditions allow the intermediate aldehyde to hydrate and be oxidised again.
PCC in CH2Cl2 stops at the aldehyde (R-CH2OH → R-CHO). The anhydrous, non-acidic conditions prevent over-oxidation.
This distinction between Jones' reagent and PCC for 1° alcohols is one of the most commonly tested points in the chapter.
When a molecule has both an -OH group and another reactive site (e.g. a C-Br for Grignard formation), you often need to protect the alcohol so it does not interfere.
Protection: React R-OH with TMS-Cl (trimethylsilyl chloride) and Et3N (triethylamine) to form the silyl ether R-O-SiMe3. The -OH proton is replaced by a -SiMe3 group.
Why it works: Trimethylsilyl ethers are unreactive under basic conditions and are stable to organometallic reagents. C-Si bonds are long and silicon is not very sterically hindered, so the SN2 reaction to form them is fast.
Deprotection: Treat with aqueous acid (H3O+) to cleave the silyl ether and regenerate the free alcohol.
Example workflow: Protect -OH as TMS ether → form Grignard from C-Br → do Grignard chemistry → remove TMS with acid to get -OH back.
Preparation:
React an alkyl halide (R-X) with HS- (sodium hydrosulphide, NaSH) in an SN2 reaction to give R-SH.
Problem: the thiol product (R-SH) is also a good nucleophile, so it can react with another R-X to form a thioether (R-S-R), giving a mixture.
Solution: use thiourea ((NH2)2C=S) as the nucleophile. It reacts with R-X, and subsequent hydrolysis with aqueous base gives R-SH cleanly, plus urea as a byproduct.
Key properties compared to alcohols:
Thiols are more acidic than alcohols (S-H bond is weaker, thiolate RS- is more stable because sulphur is larger and the charge is more dispersed).
Thiols are better nucleophiles than alcohols (sulphur is larger, more polarisable).
Thiols have lower boiling points than the corresponding alcohols (weaker hydrogen bonding because S-H is less polar than O-H).
Disulphide bridges:
Oxidation (e.g. Br2) converts two thiols to a disulphide: 2 R-SH → R-S-S-R.
Reduction (e.g. Zn/H3O+) cleaves the disulphide back to two thiols.
Biologically, disulphide bonds between cysteine residues are essential for stabilising protein tertiary structure.
Real-world connection: The sulphur chemistry of cysteine residues is central to how proteins fold. Insulin, for instance, is held together by disulphide bridges between its two polypeptide chains.
Students often think all alcohols dehydrate the same way. They do not. 3° alcohols dehydrate readily with acid (E1), but 1° and 2° alcohols need POCl3/pyridine (E2) to avoid poor yields and rearrangements.
A frequent error is assuming PCC and Jones' reagent give the same product from a 1° alcohol. PCC stops at the aldehyde; Jones' reagent goes all the way to the carboxylic acid.
Students forget that 3° alcohols cannot be oxidised. There is no C-H on the carbon bearing -OH, so the E2-type elimination step in the oxidation mechanism cannot occur.
Many students think that SOCl2 and HCl are interchangeable for making alkyl chlorides. SOCl2 is used for 1° and 2° alcohols (SN2 pathway), while HCl works well only for 3° alcohols (SN1 through the carbocation).
When making thiols from R-X + NaSH, students overlook the double-addition problem. The product thiol is nucleophilic and can react again to form the thioether.
⚠️ Jones' reagent vs. PCC for 1° alcohols is one of the most heavily tested distinctions in this chapter. Know which stops at the aldehyde and which goes to the acid.
⚠️ Choosing the right reagent to convert an alcohol to an alkyl halide, based on whether the alcohol is 1°, 2°, or 3°, is a standard exam question.
⚠️ Zaitsev's rule in dehydration: be able to predict the major and minor alkene products.
⚠️ Protecting-group strategy (TMS ethers) appears in multi-step synthesis problems. You will be expected to identify when protection is needed and show protect/react/deprotect sequences.
⚠️ Disulphide bridges come up in biochemistry crossover questions. Know the oxidation/reduction relationship between 2 R-SH and R-S-S-R.
True or False: 3° alcohols can be oxidised to ketones using Jones' reagent.
Fill in the blank: PCC oxidises a 1° alcohol to an ______, while Jones' reagent oxidises it to a ______.
True or False: SOCl2 is used to convert 3° alcohols to alkyl chlorides.
Fill in the blank: Dehydration of alcohols follows ______ rule, giving the more substituted alkene as the major product.
True or False: Disulphide bridges are formed by reduction of thiols.
Answers: 1. False (3° alcohols give no reaction, no C-H to eliminate). 2. Aldehyde; carboxylic acid. 3. False (SOCl2 is for 1° and 2°; 3° alcohols use HCl/HBr/HI). 4. Zaitsev's. 5. False (they are formed by oxidation; reduction cleaves them).
Q: What is the major product when 1-methylcyclohexanol is treated with H3O+ and heat?
A: 1-Methylcyclohexene (the more substituted, Zaitsev alkene). Methylenecyclohexane (the less substituted alkene) is the minor product.
Q: You have 1-decanol (a 1° alcohol) and need to make decanal (the aldehyde). Which oxidant do you choose?
A: PCC in CH2Cl2. Jones' reagent would over-oxidise to decanoic acid.
Q: How would you convert cyclohexanol to cyclohexyl chloride?
A: Treat cyclohexanol (a 2° alcohol) with SOCl2. This gives cyclohexyl chloride via an SN2-type mechanism, avoiding carbocation rearrangements.
Q: Why must you protect an -OH group before forming a Grignard reagent on the same molecule?
A: The -OH proton is acidic enough to quench the Grignard (carbanion + R-OH → R-H + alkoxide). Protecting as a TMS ether removes the acidic proton, allowing Grignard formation at the other end of the molecule.
Q: Two equivalents of cysteine (containing -SH) are oxidised with Br2. What forms?
A: A disulphide bridge (cystine), R-S-S-R, plus 2 HBr. This is the same bond that stabilises protein tertiary structure.
Dehydration connects directly to the elimination reactions chapter (E1 and E2 mechanisms, Zaitsev's rule). Conversion to alkyl halides feeds into substitution chemistry (SN1/SN2). Oxidation of alcohols bridges to the carbonyl chemistry chapters on aldehydes, ketones, and carboxylic acids. Protecting-group strategy is a pillar of multi-step synthesis that runs through the entire second half of most organic chemistry courses. Thiol and disulphide chemistry connects to the biochemistry of amino acids and protein folding.
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