Humboldt State University ® Department of Chemistry

Richard A. Paselk

Chem 328

Brief Organic Chemistry

Summer 2004

Lecture Notes: 21 June

© R. Paselk 2004


Return Exam 1: Average = 63.5%, Std. Dev. = 16.8%, Range = 28-84.

Alcohols, Ethers, and Thiols, 3

Reactions of Alcohols, cont.

Oxidation of Alcohols: The most important reactions of alcohols are their oxidation to aldehydes, ketones, and carboxylic acids (carbonyl compounds). This may be viewed as the formal loss of hydrogen: RR'CH-OH Æ RR'C=O + H2. Primary alcohols are oxidized to aldehydes, which in turn may be oxidized to acids, whereas secondary alcohols are oxidized to ketones. Tertiary alcohols are not normally oxidized since it would be necessary to break a C-C bond (C-C bonds are very strong and stable, thus resistant to reaction without destablizing structural relations or high energy).

Primary alcohols may be oxidized to aldehydes by the careful selection of an oxidizing agent. The best reagent for laboratory scale reactions is pyridinium chlorochromate, C5H6NCrO3Cl (PCC), in dichloromethane solvent:

Other oxidizing agents, such as sodium dichromate (Na2Cr2O7) in aqueous acid or chromium trioxide (CrO3), continue the oxidation process to the carboxylic acid product. The intermediate aldehydes are not generally isolated because they are oxidized to acids too rapidly:

Secondary alcohols are readily oxidized to ketones:



Alcohol Synthesis

Let's first review the reactions we've already seen by which alcohols can be synthesized.

Hydration of alkenes: can add a water molecule across a double bond:

Reaction with water and sulfuric acid as catalyst gives the predicted Markovnikov's product.

Hydroxylation: Diols can be synthesized by direct hydroxylation (oxidation) of an alkene with potassium permanganate in basic solution:

Recall that the reaction takes place with syn stereochemistry. But why? A carbocation intermediate would give no stereochemical preference, whereas the apparently similar halogenation gave us a bromonium intermediate with anti stereochemistry. The syn stereochemistry arises due to the formation of a cyclic intermediate:

which is then hydrolyzed to give the syn product.

ASIDE (not covered Su 2004): the best method for ether preparation -Williamson Ether Synthesis

:Alkoxide salts react with alkyl halides to give ethers in the Williamson ether synthesis reaction:


The alkoxides required can in turn be synthesized from alcohol by reaction with sodium or potassium metal.

The Williamson synthesis is an SN2 reaction, so we expect all of the normal SN2 constraints: Primary alkyl halides are most reactive (E2 competes with more hindered substrates). Thus unsymmetrical ethers are best prepared with the less hindered member being the alkyl halide, with the more hindered member being the alkoxide. For example if we use a tertiary alkoxide ion and a methyl halide the SN2 reaction will predominate:

However, if a primary (or any other) alkoxide ion attacks a tertiary halide the reaction is blocked by steric hindrance and thus the E2 elimination is preferred:


Alcohols via the Reduction of Carbonyl Groups

A valuable method for preparing alcohols is by the reduction of compounds containing carbonyl groups by the formal addition of hydrogen to the C=O double bond:

Reduction of Aldehydes and Ketones: Alcohols can readily be produced by the reduction of aldehydes and ketones to give primary and secondary alcohols respectively:

The usual reducing agent used in this reaction is sodium borohydride, NaBH4, chosen for its safely and convenience:

Reduction of Carboxylic Acids and Esters: Carboxylic acids and esters are more highly oxidized and more stable than aldehydes and ketones and thus require a more powerful reducing agent then NaBH4. Instead LiAlH4, which is far more reactive and more dangerous, is used:

Lithium aluminum hydride distinguishes between the carbonyl groups and alkenes, leaving the latter untouched. Note that whereas the reduction of an aldehyde or ketone adds two hydrogens, the reduction of acids and esters takes four hydrogens.


Ether reactions

Ethers are generally quite unreactive, accounting for their widespread use as solvents. They do not react with halogens, nucleophiles or mild acids or bases.

Acidic Cleavage: This is the only generally useful reaction ethers undergo. Aqueous HI is the acid most commonly used, but HBr will also work. The reaction is a typical nucleophilic substitution, taking place via a SN1 or SN2 mechanism.

Primary and secondary alkyl ethers are attacked by iodide ion to give an SN2 mechanism with acid catalysis:

Note that the iodide attacks the less hindered alkyl group, as we would expect.

Protonation of tertiary ethers in acid lead to spontaneous cleavage to give a carbocation intermediate, resulting in either an SN1 or E1 mechanism for cleavage:

Note the similarity to the analogous alcohol reactions - "water" is lost again, except an alkyl group has been substituted for the H of water to give an alcohol leaving group.



As with alkanes, ethers can exist in cyclic forms. These cyclic ethers generally have the same general properties as linear ethers. Common cyclic ethers such as 1,4-Dioxane (six membered ring, C4H8O2) and Tetrahydrofuran (THF, five membered ring, C4H8O) are thus often used as solvents (they are relatively inert). However, three membered ring ethers have special properties and are given a special name: the epoxides or oxiranes.

The epoxides may be synthesized by reaction of an alkene with a peroxyacid such as Peroxyacetic acid (or Peracetic acid = CH3COOOH) or m -Chloroperoxybenzoic acid:

In any case the peroxy acid is reduced to the carboxylic acid in the reaction.

Epoxides are much more reactive than other ethers due to the strain in the small ring (bond angles of 60° instead of the preferred 109° for sp3 hybridization). Thus dilute aqueous mineral acids convert epoxides to 1,2-diols (vicinal glycols). Ethylene glycol (as used in antifreeze) is thus produced from ethylene oxide, which in turn comes from ethylene:

This reaction takes place via an SN2 attack. The mechanism is analogous to alkene bromination with a bromonium ion intermediate:

Note the production of a trans -1,2-diol, in this case trans -1,2-Cyclopentanediol.

Epoxides are of great interest because of their involvement in various toxic mechanisms. Probably most famous example is Benzo[a]pyrene, a polycyclic aromatic hydrocarbon (PAH) found in combustion products. PAH is converted by our detoxification system (an enzyme in the P450 family) into an epoxide. Unfortunately, PAH's tend to intercalate into the base stacking in DNA. The epoxide can then be attacked by the amine group of the adenine ring in DNA, making a permanent modification to the DNA. If the DNA is now replicated a mutation is incorporated, which can lead to further problems, including, occasionally, cancer.


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Last modified 21 June 2004