Premed · Premed · Organic Chemistry 1
Lecture 17: Alcohols: Synthesis and Reactions
Organic Chemistry I
Learning Objectives
By the end of this lecture, students will be able to:
- Classify alcohols as primary, secondary, or tertiary and name them using IUPAC nomenclature
- Describe the physical properties of alcohols and the role of hydrogen bonding
- Summarize the major methods for synthesizing alcohols
- Describe the conversion of alcohols to alkyl halides using HX, SOCl2, and PBr3
- Explain the dehydration of alcohols to form alkenes
- Describe oxidation reactions of alcohols (to aldehydes, ketones, carboxylic acids)
- Explain the conversion of alcohols to tosylates and mesylates
- Describe the reaction of alcohols with organometallic reagents (Grignard reactions)
Lecture Content
I. Structure, Classification, and Nomenclature
Alcohols contain the hydroxyl (-OH) functional group bonded to an sp3-hybridized carbon, with the general formula R-OH. The oxygen atom is sp3 hybridized with two lone pairs, and the bond angle at oxygen is approximately 104.5 degrees, compressed from the ideal tetrahedral angle by lone pair repulsion.
Alcohols are classified by the substitution pattern of the carbon bearing the hydroxyl group. Primary alcohols (RCH2OH) have the OH on a carbon bonded to one other carbon, secondary alcohols (R2CHOH) have it on a carbon bonded to two others, and tertiary alcohols (R3COH) on a carbon bonded to three others. Methanol (CH3OH) stands as a special case.
IUPAC nomenclature replaces the -e ending of the parent alkane with -ol. The chain is chosen as the longest one containing the hydroxyl group, and numbering gives the OH the lowest possible locant. The hydroxyl group takes priority over double bonds, halogens, and alkyl groups for numbering purposes. Examples include 2-propanol, 2-methyl-1-butanol, and cyclohexanol. Common names such as methyl alcohol, ethyl alcohol, isopropyl alcohol, and tert-butyl alcohol remain in everyday use.
II. Physical Properties of Alcohols
The defining physical characteristic of alcohols is their capacity for hydrogen bonding. The O-H group serves as both a hydrogen bond donor and acceptor, allowing alcohols to form hydrogen bonds with themselves and with water. This gives alcohols dramatically higher boiling points than comparable alkanes or ethers: ethanol (MW 46) boils at 78 degrees C, while dimethyl ether (MW 46) boils at -25 degrees C.
Boiling points increase with molecular weight and decrease with branching (less surface area for van der Waals interactions). Small alcohols (C1 through C3) are completely miscible with water, but solubility decreases as the hydrophobic alkyl chain grows. As a rough guideline, alcohols with up to four or five carbons are water-soluble, with the balance between the polar hydroxyl group and the nonpolar alkyl portion determining overall solubility.
Alcohols are weak acids with pKa values of approximately 16-18, comparable to water at 15.7. They can be deprotonated by strong bases such as NaH, NaNH2, sodium metal, and KOtBu to form alkoxide ions (RO-), which are useful as both nucleophiles and bases.
III. Synthesis of Alcohols
Alcohols can be synthesized from alkenes by three methods: acid-catalyzed hydration (Markovnikov product with possible rearrangements), oxymercuration-demercuration (Markovnikov product without rearrangement), and hydroboration-oxidation (anti-Markovnikov product with syn addition). From alkyl halides, SN2 displacement with hydroxide (R-X + NaOH yielding R-OH) works for primary and methyl substrates, though secondary substrates tend to give elimination.
Reduction of carbonyl compounds provides another major route. Aldehydes reduced with NaBH4 or LiAlH4 give primary alcohols, and ketones give secondary alcohols. Carboxylic acids require the more powerful LiAlH4 for reduction to primary alcohols, as NaBH4 is insufficiently reactive. Esters are also reduced to primary alcohols by LiAlH4.
The Grignard reaction is among the most important methods for alcohol synthesis because it simultaneously forms a new C-C bond. Formaldehyde plus a Grignard reagent (RMgX) gives a primary alcohol, an aldehyde plus RMgX gives a secondary alcohol, and a ketone plus RMgX gives a tertiary alcohol.
<image>Panel A: Summary of alcohol synthesis methods from carbonyl compounds. Formaldehyde (HCHO) + RMgX → RCH2OH (1 degree alcohol). Aldehyde (RCHO) + R'MgX → RR'CHOH (2 degree alcohol). Ketone (RCOR') + R''MgX → RR'R''COH (3 degree alcohol). Each reaction shows the intermediate alkoxide and the acid workup step. Panel B: Reduction of carbonyl compounds: aldehyde + NaBH4 → 1 degree alcohol; ketone + NaBH4 → 2 degree alcohol; carboxylic acid + LiAlH4 → 1 degree alcohol. The reagent specificity (NaBH4 vs. LiAlH4) is noted.</image>
IV. Reactions of Alcohols: Conversion to Alkyl Halides
The hydroxyl group is a poor leaving group because hydroxide (HO-) is a strong base, so it must be converted to a better leaving group before substitution or elimination can occur. Three principal methods accomplish this conversion.
Reaction with hydrogen halides (HX) proceeds by first protonating the hydroxyl to convert it to water (a good leaving group), followed by substitution. Tertiary alcohols react by SN1 at room temperature with HCl, HBr, or HI. Primary alcohols require heating and proceed by SN2, with HBr and HI working well but HCl being sluggish. Secondary alcohols follow a borderline mechanism. The SN1 pathway carries a risk of rearrangements. The Lucas test, using ZnCl2/HCl, exploits these rate differences to distinguish primary, secondary, and tertiary alcohols.
Thionyl chloride (SOCl2) converts alcohols to alkyl chlorides under mild conditions by forming a chlorosulfite intermediate that undergoes SN2-like displacement, giving inversion of configuration when pyridine is used as a base. Phosphorus tribromide (PBr3) converts primary and secondary alcohols to alkyl bromides through an SN2 mechanism with inversion, offering milder and more selective conditions than HBr.
V. Reactions of Alcohols: Dehydration
Acid-catalyzed dehydration, reviewed from Lecture 12, converts alcohols to alkenes using H2SO4 or H3PO4 with heat. Zaitsev's rule predicts the more substituted alkene as the major product. The ease of dehydration follows the order tertiary > secondary > primary, and the mechanism is E1 for tertiary and secondary alcohols but E2 for primary. Rearrangements through carbocation intermediates are possible.
An alternative approach using POCl3 in pyridine converts the alcohol to a chlorophosphate ester, which then undergoes E2 elimination. This method operates under milder conditions than H2SO4 and avoids carbocation rearrangements.
VI. Reactions of Alcohols: Oxidation
Oxidation of alcohols increases the number of C-O bonds (or equivalently, decreases the number of C-H bonds at the carbon bearing the hydroxyl). Primary alcohols can be oxidized either partially to aldehydes or fully to carboxylic acids. PCC (pyridinium chlorochromate) in CH2Cl2 stops at the aldehyde stage under anhydrous conditions. The Swern oxidation (DMSO, oxalyl chloride, triethylamine) also stops at the aldehyde without using chromium. Jones reagent (CrO3/H2SO4/H2O) or KMnO4 pushes the oxidation all the way to the carboxylic acid.
Secondary alcohols are oxidized to ketones by PCC, Jones reagent, KMnO4, or Na2Cr2O7/H2SO4. Because ketones lack a hydrogen on the carbonyl carbon, they cannot be further oxidized under these conditions. Tertiary alcohols cannot be oxidized at all because there is no hydrogen on the carbon bearing the OH group; they are resistant to all common oxidizing agents.
In biological systems, NAD+ serves as the oxidizing agent for alcohols. The enzyme alcohol dehydrogenase converts ethanol to acetaldehyde in the liver using NAD+ as a hydride acceptor.
<image>Panel A: Oxidation state ladder for a one-carbon unit showing: methane (most reduced) → methanol → formaldehyde → formic acid → carbon dioxide (most oxidized). Each step shows the oxidizing agent and the change in oxidation state. Panel B: Practical oxidation scheme. Primary alcohol with PCC gives aldehyde (stopping point shown with a box); same primary alcohol with Jones reagent or KMnO4 gives carboxylic acid (arrow bypasses aldehyde). Secondary alcohol with any oxidant gives ketone (shown in a box). Tertiary alcohol with an X through the arrow indicates no reaction. Each reagent is written above its respective arrow.</image>
VII. Conversion to Tosylates and Mesylates
Tosylation and mesylation convert the hydroxyl group into an excellent leaving group without breaking the C-O bond. Treatment of an alcohol with p-toluenesulfonyl chloride (TsCl) and pyridine produces a tosylate (R-OTs), while methanesulfonyl chloride (MsCl) with triethylamine gives a mesylate (R-OMs). These sulfonate leaving groups are comparable to iodide in leaving ability because the departing sulfonate anion is resonance-stabilized and weakly basic.
A critical feature of this two-step strategy is stereochemical control. Because the C-O bond is not broken during the tosylation or mesylation step, the configuration at the stereocenter is retained. A subsequent SN2 reaction on the tosylate or mesylate then proceeds with inversion, so the overall transformation from alcohol to product gives net inversion. Tosylates and mesylates can undergo all the same reactions as alkyl halides, including SN2 with nucleophiles and E2 with bases, effectively making the original alcohol a substrate for substitution and elimination chemistry.
VIII. The Grignard Reaction in Detail
The Grignard reaction stands as one of the most important carbon-carbon bond-forming reactions in organic chemistry. The Grignard reagent (RMgBr) is a powerful nucleophile in which the carbon bears a partial negative charge. When it attacks the electrophilic carbonyl carbon of an aldehyde, ketone, or other carbonyl compound, an alkoxide intermediate forms. Acid workup (H3O+) then protonates this alkoxide to yield the alcohol product.
The scope of the Grignard reaction is broad: with formaldehyde it produces primary alcohols, with aldehydes secondary alcohols, with ketones tertiary alcohols, with carbon dioxide carboxylic acids (after acid workup), and with epoxides alcohols with an extended carbon chain (via SN2 ring opening at the less hindered carbon).
The major limitation is that Grignard reagents react with any acidic proton in the molecule, including O-H, N-H, carboxylic acid O-H, and terminal alkyne C-H bonds. This protonolysis (RMgBr + HA yielding RH + MgBrA) destroys the reagent, so strictly anhydrous conditions are essential, and sensitive functional groups must be protected before the Grignard reaction is attempted.
