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Chapter 12. Alcohols

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1. Nomenclature

2. Physical Properties

3. Reactions

4. Synthesis Methods

1. Nomenclature

⑴ There are IUPAC nomenclature and common names.

⑵ Alcohol (R-O-H) nomenclature

① Determine the longest carbon chain (ring) structure containing the alcohol as the parent structure.

② Number each carbon starting from the carbon closest to the -OH group in the carbon chain.

③ If there are substituents, name them in alphabetical order.

④ In cases of mixtures of alkyl, halo, alkene, and alkyne groups, the priority of functional groups is as follows:

○ -OH > Alkene > Alkyne (if alkene and number are the same) > Halogen

⑤ Common names

○ Example: propyl alcohol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, isobutyl alcohol, neopentyl alcohol

⑶ Polyols (polyalcohols): More than 2 alcohols

① Attach suffixes like -diol, -triol to the end of the main chain’s name.

② Assign lower numbers to provide at least one alcohol with a smaller number, and name them alphabetically.

③ Common names: ethylene glycol (ethane-1,2-diol), glycerol (propane-1,2,3-triol)

2. Physical Properties

⑴ Degree of alcohols

① Definition: The degree of carbon with an attached -OH group.

② Higher degree of alcohol → Lower solubility in water

③ Higher degree of alcohol → Increased intermolecular forces → Decreased melting and boiling points

○ Boiling points: 1-butanol (117 ℃) > 2-methyl-1-propanol (107 ℃) > 2-butanol (98 ℃) > 2-methyl-2-propanol (82 ℃)

○ Melting points: 1-butanol (-90 ℃) > 2-methyl-1-propanol (-108 ℃) > 2-butanol (-115 ℃)

○ Unlike boiling points, melting points are influenced not only by intermolecular forces but also by packing, so the melting point of 2-methyl-2-propanol (25 ℃) is quite high.

⑵ Boiling points of alcohols

① Higher number of carbons leads to stronger intermolecular forces and higher boiling points.

○ Example: methanol (65 ℃) < ethanol (78 ℃) < propan-1-ol (97 ℃)

② Much higher boiling points than alkenes, alkynes, and alkyl halides due to hydrogen bond.

③ 1,3-diols have higher boiling points than 1,2-diols.

○ Reason: 1,2-diols with well-formed intramolecular hydrogen bonding have weaker intermolecular hydrogen bonding.

⑶ Acidity of alcohols

① Acidity in solution: methyl > 1^st > 2^nd > 3^rd

○ Key Memorization: pK_a

○ Methanol (MeOH): 15.5

○ Ethanol (EtOH): 16

○ i-PrOH: 16.5

○ t-BuOH: 18

○ Solvation effect

○ Alcohols with more alkyl groups have weaker solvation effects due to hydrogen bonding.

○ As a result, alkoxide ions, which are the conjugate bases, are less stabilized, leading to lower acidity of alcohols with more alkyl groups.

○ Inductive effect

○ Inductive effects explain acidity in solution, but not in the gas phase.

② Acidity of alcohols in the gas phase: methyl < 1^st < 2^nd < 3^rd

○ No solvation effect in the gas phase.

○ The acidity of tertiary alcohols is the greatest because the alkyl groups have a strong effect on dispersing the negative charge.

○ Generally, the acidity of thiols is greater than that of alcohols due to the polarizability, that is, the size effect.

⑷ Strength of hydrogen bonding in alcohols

① Strength of hydrogen bonding: primary alcohol > secondary alcohol > tertiary alcohol

② Steric hindrance: 1^st < 2^nd < 3^rd

3. Reactions

⑴ Overview

① Central aspect of reactions: Since OH^- is a strong base and a poor leaving group, processes that transform it into a good leaving group occur.

② Type 1: Dehydration reaction (Important to memorize): S_N2 reactions involve 1st or secondary alcohols. Non-S_N2 reactions involve 2^nd or tertiary alcohols.

○ SOCl₂ group: S_N2 reaction

○ HCl group: S_N1 reaction

○ POCl₃ (catalyst: pyridine) group: E2 reaction

○ H₂SO₄ group: E1 reaction

③ Type 2: Alcohol protection and deprotection reactions

④ Type 3: Acid-base reactions

⑤ Type 4: Oxidation reactions

⑥ Type 5: Other reactions: Ether synthesis, ester synthesis, pinacol rearrangement reaction

⑵ 1-1. S_N2 reaction

① Reagents: SOCl₂, PBr₃, PCl₃, PCl₅ + 1^st or secondary alcohols

○ primary alcohols, secondary alcohols: Since X^- is a weak base, S_N2 reaction occurs rather than E2.

○ reactivity: secondary alcohols < primary alcohols

○ tertiary alcohols: S_N1/E1 reactions are very slow, so the reaction is considered not to occur.

○ Reaction of alcohols with SOCl₂ depending on the solvent

○ Pyridine solvent: Inversion of configuration

○ Ether solvent: Retention of configuration

○ Hypothesis 1: If ether acts as a nucleophile, two S_N2 reactions occur, explaining the mechanism.

○ Hypothesis 2: S_Ni (SN internal): Explains that retention occurs due to intramolecular S_N2 reaction.

② SOCl₂ mechanism

○ Converts alcohols into good leaving groups

Figure 1. S_N2 reaction of alcohols in the presence of SOCl₂

Figure 2. S_Ni reaction

○ Features

○ No carbocation

○ No rearrangement

○ Reacts with 1^st and secondary alcohols: Does not react with tertiary alcohols

○ Inversion of configuration

○ 3^rd amines act as bases, generating the nucleophile Cl^- through reaction with HCl, promoting the reaction

○ Le Chatelier’s principle: Pyridine is used in the reaction with SOCl₂ to generate SO₂(g) and promote the forward reaction.

○ Not always limited to S_N2 reactions

○ This mechanism occurs not only with alcohols but also with carboxylic acids.

Figure 3. Reaction generating acyl chlorides from carboxylic acids

③ PBr₃, PCl₃ Mechanism

○ Converts alcohol into a good leaving group

○ In the PBr₃, PCl₃ reaction, pyridine, a weak base, can be used to increase the reaction rate

○ Due to regulations on the excessive use of reagents, pyridine is not used recently

Figure. 4. S_N2 reaction of alcohol in the presence of PX₃

○ Features

○ No carbocation

○ No rearrangement reactions

○ 1 equivalent of PX₃ can react with 3 equivalents of alcohol

○ Reaction proceeds with primary and secondary alcohols: Does not react with tertiary alcohols

○ Inversion of configuration

④ PCl₅ Mechanism

Figure 5. S_N2 reaction of alcohol in the presence of PCl₅

⑶ 1-2. S_N1 reaction

① Reagents: HCl, HBr, HI + secondary or tertiary alcohols

○ HCl reaction is relatively weak, so it is catalyzed by catalysts like ZnCl₂.

○ HF ≪ HCl < HBr < HI

○ primary alcohols: S_N2 reaction. Without waiting for the leaving group (H₃O⁺) to release, X^- carries out a nucleophilic attack.

○ secondary alcohols, tertiary alcohols: S_N1 reaction; HX is a strong acid, readily generating the excellent leaving group -OH₂⁺.

② Mechanism

Figure 6. S_N1 reaction of alcohols in the presence of HX

③ Carbocation: racemization, rearrangement

④ Lucas test: Distinguishes between primary, secondary, and tertiary alcohols using HCl and ZnCl₂.

○ The solution where a reaction occurs becomes turbid.

○ Reaction equation: ROH + HCl → RCl (catalyst: anhydrous ZnCl₂, conditions: room temperature)

○ Primary alcohol: No reaction (S_N2)

○ Secondary alcohol: Reaction after about 5 minutes (S_N2 and S_N1)

○ Tertiary, allylic, or benzylic alcohol: Immediate reaction (S_N1)

⑷ 1-3. E2 reaction

① Reagents: POCl₃ + 2 equiv. pyridine + secondary or tertiary alcohols

○ Tip: E2 reaction is mostly conducted using only POCl₃.

○ primary alcohols

○ secondary alcohols, tertiary alcohols: E2 reaction occurs

② Mechanism

Figure 7. E2 reaction of alcohols in the presence of POCl₃

③ Zaitsev’s rule

Figure 8. E2 reaction of alcohols in the presence of POCl₃

⑸ 1-4. E1 reaction

① Reagents: H₂SO₄, H₃PO₄, TsOH, and other non-halogen acids + secondary or tertiary alcohols + heat

○ primary alcohols: E2 reaction (E1 also possible)

○ secondary alcohols, tertiary alcohols: E1 reaction

② Mechanism

Figure 9. E1 reaction of alcohols in the presence of H₂SO₄, H₃PO₄

③ (Formula) Examination of ring-closure reaction after attaching H+ to O in H+, and if ring-closure reaction does not occur, review Saytzev’s rule after H₂O elimination.

④ Carbocation: Consider rearrangement reaction and racemization.

⑤ When both alkene and -OH group are present in a single molecule, alkene reacts first ( ∵ increased reactivity of alkene)

○ To add, the acid-base reaction of the -OH group occurs most rapidly, but the reverse reaction can occur, forming a minor product.

○ Additionally, when the -OH group participates in the reaction, the process can be slowed down due to the release of the poor leaving group H2O.

⑥ Primary alcohols undergo E2 mechanism under the same conditions ( ∵ due to the unstable nature of primary carbocation)

⑹ 2-1. Alcohol protection reaction

① Overview

○ Also known as a good leaving group reaction

○ Alcohol protection reactions are used in the synthesis of Grignard reagents

○ Basically utilize Ether Synthesis

② Type 1. Sulfonyl ester protecting group: More commonly used as a leaving group derivative of alcohol

○ Tosylation: When TsCl (catalyst: pyridine) reacts with alcohol, -OH group becomes -OTs. Retention of configuration.

○ Reaction: ROH + TsCl + pyridine → ROTs

○ TsCl: para-toluenesulfonyl chloride

○ Mechanism

Figure 10. Alcohol protection reaction using TsCl

○ Mesylation: When MsCl (catalyst: Et₃N) reacts with alcohol, -OH group becomes -OMs. Retention of configuration.

○ Reaction: ROH + MsCl + pyridine → ROMs

○ MsCl: methanesulfonyl chloride

○ Mechanism

Figure 11. Alcohol protection reaction using MsCl

○ Triflylation: When TfCl (catalyst: pyridine) reacts with alcohol, -OH group becomes -OTf. Retention of configuration.

○ Reaction: ROH + TfCl + pyridine → ROTf

○ TfCl: trifluoromethanesulfonyl chloride

○ -OTf is the best leaving group among those encountered in organic chemistry

○ It can even form unstable vinyl cation through S_N1 reaction

○ Common features

○ Retention of configuration: Alcohol performs nucleophilic attacks, so there is no change in self-coordination.

○ Note that there is a difference between retention of configuration and absolute configuration (R, S) preservation.

○ Alcohol performs nucleophilic attacks S_N2 reaction: 1° alcohol with small steric hindrance reacts preferentially

○ Pyridine or Et₃N is used as base.

② Type 2. Silyl ether protecting group: Utilizes silicon compound (silyl ether) with Et₃N as the common catalyst

○ Silicon compound: Represented as R’OSiR₃

○ TMSCl: (CH₃)₃SiCl

○ TBDMSCl: tert-SiMe₂Cl

○ Features

○ Significant steric hindrance, but Si forms longer bonds than C due to its 3rd-period nature

○ Stable at pH 4 ~ 12

○ Imidazole or pyridine generate alkoxide ion, removing byproduct HCl

③ Type 3. t-butyl ether protecting group

○ (Formula) 1. H₂SO₄, 2. CH₂=C(CH₃)₂ (isobutylene)

○ Easily removable as a stable leaving group when treating ether with dilute acid.

⑺ 2-2. Alcohol deprotection reaction

① TBAF (tetrabutylammonium fluoride), or Bu₄NF, can recover alcohol functionality from silyl ethers

○ Si-O bond strength: ~110 kcal/mol

○ Si-F bond strength: ~140 kcal/mol

② Strong acidic conditions can also recover alcohol functionality from silyl ethers

⑻ 3. Acid-Base Reactions

① Alcohols can act as acids with pKa values of 16 ~ 18

② ΔpK_a > 0 for a productive reaction, and ΔpK_a > 7 for unidirectional reaction

③ Reaction example

Figure 12. Example of acid-base reaction

⑼ 4. Oxidation Reactions

① Oxidation stages of alcohols

Figure 13. Oxidation stages of alcohols

② Strong oxidation of primary alcohols: Reaction converting primary alcohols to carboxylic acids

○ Related reagents

○ K₂Cr₂O₇

○ H₂CrO₄

○ CrO₃

○ KMnO₄

○ Reasons why KMnO₄ is not frequently used in alcohol oxidation

○ Chromium-based oxidants selectively oxidize alcohols without affecting internal alkenes or alkynes, unlike KMnO₄

○ KMnO₄ reacts with not only alcohol but also alkenes and alkynes

○ Jones reagent: Combination of CrO₃, i.e., CrO₃ + H₂SO₄ + H₂O

○ Performs strong oxidation of primary alcohols

○ Can also achieve mild oxidation under gentle conditions

③ Mild oxidation of primary alcohols: Reaction converting primary alcohols to aldehydes

○ Related reagents

○ PCC (pyridinium chlorochromate): Anhydrous conditions

○ DMP (Dess-Martin periodinane)

○ HOCl

○ NaOCl / CH3COOH / 0 ℃

○ Swern oxidation reagent

○ Collins reagent

○ Magtrieve oxidant (CrO₂)

○ TEMPO

○ Ag₂CO₃

○ (Formula) 1° alcohol + NaOCl + RCOOH (e.g., acetic acid) + 0 ℃ → aldehyde

○ NaClO (sodium hypochlorite, bleach) + RCOOH → HClO

○ Mechanism 1: R-CH₂-OH + HClO → R-CH₂-OH₂⁺ + OCl^-

○ Mechanism 2: R-CH₂-OH₂⁺ + OCl^- → RCH₂OCl + H₂O (S_N2 reaction)

○ Mechanism 3: RCH₂OCl + :B^- → RCHO + HB + Cl^- (E2 reaction)

○ (Formula) 1° alcohol + TsCl → R-OTs, R-OTs + DMSO → R-OSMe₂, R-OSMe₂ + NaHCO₃ → RCHO

○ Used for aldehyde synthesis

④ Oxidation of secondary alcohols

○ Related reagents

○ K₂Cr₂O₇

○ Na₂Cr₂O₇

○ H₂CrO₄

○ CrO₃

○ KMnO₄

○ PCC

○ Dess-Martin periodinane

○ DMSO / oxalyl chloride

○ Mechanism of CrO₃ oxidation of secondary alcohols

Figure 14. Mechanism of CrO₃ oxidation of secondary alcohols

○ Mechanism of HOCl oxidation

Figure 15. Mechanism of HOCl oxidation

○ Oxidation reaction of NaOCl: Secondary alcohol + NaOCl + RCOOH (e.g. acetic acid) + 0 ℃ → Ketone

○ Oxidation reaction of cyclohexyl alcohol: Using H₂CrO₄ as the reference,

○ When -OH group is in the axial direction, the oxidation reaction is faster.

○ Reason 1: Since the -OH group is axial, the hydrogen is in the equatorial position, making it easier for the base to approach to remove the hydrogen in the equatorial position.

○ Reason 2: When chromic acid ester is oriented axially, the reactant becomes more unstable, resulting in lower activation energy for activation.

⑤ Oxidation reaction of tertiary alcohols: Generally, oxidation reactions do not occur.

○ Exception: Clemmensen Reduction

⑥ Selective oxidizing agents for allylic and benzyl alcohols: MnO₂

○ Usually, ordinary alcohols are not oxidized.

⑦ Oxidative cleavage reaction of diols

○ Reagent: HIO₄

○ (Formula) After breaking the carbon-carbon bond in the presence of a diol, connect -OH groups to each fragment, forming ketones or aldehyde groups.

Figure. 16. Mechanism of oxidative cleavage reaction of diols

○ Mechanism

○ Common: Involves a pentagonal transition state.

○ Case 1: Metaperiodic acid conditions

○ Case 2: Orthoperiodic acid conditions

⑽ 5-1. Ether synthesis

① Symmetric ether synthesis

○ Summary: Elimination reaction is dominant at high temperatures, while addition reaction is dominant at low temperatures. It can be explained by entropy change and ΔG = ΔH - TΔS.

○ (not desirable) H₂SO₄, 180℃: R-CH₂OH + H₂SO₄ → R=CH₂. E1 Elimination of alcohols

○ (desirable) H₂SO₄, 140℃: R-CH₂OH + H₂SO₄ → R-CH₂-O-CH₂-R

○ Drawback: Symmetric ether synthesis results in various ethers (i.e., ROR, R’OR, R’OR’), making it inappropriate.

○ As an exception, when a tertiary alcohol is used, successful synthesis of unsymmetric ethers can be achieved ( ∵ S_N1 reaction)

② Williamson Ether Synthesis: Unsymmetric ether synthesis

○ Step 1. ROH + NaH → RO^-Na⁺ + H₂

○ Step 2. RO^- + R’I → ROR’ + I^- (S_N2): The configuration of R’ is inverted.

○ Limitation: If R’X is not a methyl halide or a 1st-degree halide, elimination reaction dominates and is inappropriate.

③ Alkoxy mercuration-demercuration

○ The same reaction with oxymercuration-demercuration of alkenes

○ Reagents: 1. Hg(O₂CCF₃)₂, HOCH(CH₃)₂, 2. NaBH₄, HO^-

○ Useful when Williamson Ether Synthesis is not applicable

⑾ 5-2. Ester synthesis

① Ester synthesis through reaction of acyl chlorides, acid anhydrides and alcohols

② Ester synthesis via reaction of carboxylic acids and acid catalysts (Fischer esterification)

⑿ 5-3. Pinacol rearrangement reaction

① Pinacol rearrangement: Consideration of intramolecular S_N2 reaction leading to stereo inversion

Figure. 17. Mechanism of Pinacol Rearrangement

② Semi-pinacol rearrangement reaction

○ Type 1: Consideration of intramolecular S_N2 reaction leading to stereo inversion

Figure. 18. Semi-pinacol Rearrangement Type 1

○ Type 2: Formation of a carbocation leads to a racemic mixture

Figure. 19. Semi-pinacol Rearrangement Type 2

○ Type 3: Consideration of intramolecular S_N2 reaction leading to stereo inversion

Figure. 20. Semi-pinacol Rearrangement Type 3

4. Synthesis Methods

⑴ Nucleophilic Substitution Reaction of Alkyl Halides

⑵ Alkenes, Alkynes

① Acid-Catalyzed Hydration of Alkenes

② Oxymercuration-Demercuration of Alkenes

③ Hydroboration and Oxidation of Alkenes

④ 1,2-Dihydroxylation of Alkenes

⑤ Hydrogenation of Alkynes: Forms enol upon hydration, which becomes a ketone through tautomerization; therefore, alcohols are not formed.

⑶ Acetal and Hemiacetal Formation of Ketones

⑷ Oxidation-Reduction Reactions

① NaBH₄: Mild reducing agent

○ Cannot reduce carboxylic acids to alcohols

○ Reduces aldehydes to primary alcohols

○ Reduces ketones to secondary alcohols

○ Prolonged reaction can reduce alcohols to H

② LiAlH₄: Strong reducing agent

○ Reduces carboxylic acids to primary alcohols

○ Reduces ketones to secondary alcohols

○ Prolonged reaction can reduce alcohols to H

○ LiAlH₄ used as a reagent is much stronger than NaBH₄ as a reducing agent

③ (Formula) NaBH₄ and LiAlH₄ are considered sources of H^- for reduction

Figure 21. Example of alcohol generation using LiAlH₄

○ H₂O can be replaced by another acid as a source of H⁺

○ Carboxylic acid interpretation: -COOH temporarily becomes -C⁺O^-OH, and when H^- attaches to C⁺, it becomes -CHO^-OH, which then becomes -CHO.

○ Aldehyde interpretation: -CHO temporarily becomes -C⁺O^-OH, and when H^- attaches to C⁺, it becomes -CH₂O^-.

○ Ketone interpretation: -CO^- temporarily becomes -C⁺O^--, and when H^- attaches to C⁺, it becomes -CHO^--.

○ Alcohol: Alcohols can also be reduced; -COH becomes -C⁺, and when H^- attaches to C⁺, it becomes -CH.

⑸ Carbon-Carbon Coupling Reactions (Organometallic Reagent Reactions)

① Grignard reagent: RMgX

○ (Formula) RMgX: Mg becomes δ⁺ and R has a strong negative charge. Seek electrophilic carbons and connect them to R.

Figure 22. Example of ester reaction with Grignard reagent

○ Grignard reagents do not react with carboxylic acids

Figure 23. Grignard Reagent and Carboxylic Acids

② Alkyl lithium reagent: RLi

○ (Formula) RLi: Li becomes δ⁺ and R has a strong negative charge. Seek electrophilic carbons and connect them to R.

③ Gilman reagent: R₂CuLi

○ (Formula) R₂CuLi: CuLi becomes δ⁺ and R has a strong negative charge. Seek electrophilic carbons and connect them to R.

Input: 2019.01.11 15:11

Edited: 2022.02.01 21:57