As alcohols are easily synthesized and easily transformed into other compounds, they serve as important intermediates in organic synthesis.
Chemical reactions in alcohols occur mainly at the functional group, but some involve hydrogen atoms attached to the OH-bearing carbon atom or to an adjacent carbon atom. These reactions include oxidation, substitution reactions, protection of alcohols, and preparation of mesylates and tosylates.
Oxidation Reactions
Primary and secondary alcohols are readily oxidized. We saw earlier how methanol and ethanol are oxidized by liver enzymes to form aldehydes. Because a variety of oxidizing agents can bring about oxidation, we can indicate an oxidizing agent without specifying a particular one by writing an equation with the symbol [O] above the arrow. For example, we write the oxidation of ethanol—a primary alcohol—to form acetaldehyde—an aldehyde—as follows:
Secondary alcohols are oxidized to ketones. The oxidation of isopropyl alcohol by potassium dichromate (K2Cr2O7) gives acetone, the simplest ketone:
Unlike aldehydes, ketones are relatively resistant to further oxidation, so no special precautions are required to isolate them as they form.
Alcohol oxidation is important in living organisms. Enzyme-controlled oxidation reactions provide the energy cells need to do useful work. One step in the metabolism of carbohydrates involves the oxidation of the secondary alcohol group in isocitric acid to a ketone group:
Tertiary alcohols (R3COH) are resistant to oxidation because the carbon atom that carries the OH group does not have a hydrogen atom attached but is instead bonded to other carbon atoms. The oxidation reactions we have described involve the formation of a carbon-to-oxygen double bond. Thus, the carbon atom bearing the OH group must be able to release one of its attached atoms to form the double bond. The carbon-to-hydrogen bonding is easily broken under oxidative conditions, but carbon-to-carbon bonds are not. Therefore tertiary alcohols are not easily oxidized.
Substitution Reactions
In nucleophilic substitution reactions, alcohols are considered the poor leaving groups. For alcohols to undergo nucleophilic substitution, the -OH group is usually protenated by a strong acid catalyst to turn it into a good leaving group. Then, nucleophilic substitution can proceed as follows:
- In SN1 reactions, tertiary alcohols are favored.
- In the SN1 reaction, the big barrier is carbocation stability. Since the first step of the SN1 reaction is loss of a leaving group to give a carbocation, the rate of the reaction will be proportional to the stability of the carbocation.
- Carbocation stability increases with resonance as well as increasing substitution of the carbon: tertiary > secondary >> primary (slowest).
- In SN2 reactions, primary alcohols are favored.
- In the SN2 reaction, the big barrier is steric hindrance. Since the SN2 proceeds through a backside attack, the reaction will only proceed if the empty orbital is accessible. The more groups that are present around the vicinity of the leaving group, the slower the reaction will be.
- That’s why the rate of reaction proceeds from primary (fastest) > secondary >> tertiary (slowest). This principle holds for for amines as well.
Protection of Alcohols
The easiest way to protect alcohol is with a silyl group (such as TMS or trimethylsilyl chloride), converting the alcohol from (-OH) to (-O-TMS). Alcohols protected with these can be protected using fluorine (F–).
Tosylates and mesylates are widely used in the protection of alcohols. The conversion to a sulfonate prevents the alcohol from acting as an acid or nucleophile, or from undergoing other undesirable reactions. It allows the desired reaction to occur at another functional group without risking side reactions with the alcohol functionality. Following the reaction, the sulfonate can be converted back to an alcohol.
Preparation of Mesylates and Tosylates
Alcohols can be converted to a type of ester called a sulfonate to become better leaving groups. The formation of sulfonates like tosylates and mesylates is a nucleophilic substitution where alcohol acts as a nucleophile. Due to the many bonds sulfur can make with its empty d orbitals, any negative charge is well-distributed. Due to the distribution charge, sulfonate ions are weak bases and excellent leaving groups. Unlike alcohols, sulfonates do not require protonation to act as leaving groups, they are useful for substitution reactions in pH neutral solvents.
Practice Questions
Khan Academy
MCAT Official Prep (AAMC)
Chemistry Question Pack Question 34
Chemistry Question Pack Question 36
Section Bank C/P Section Question 13
Sample Test C/P Section Question 45
Practice Exam 1 C/P Section Passage 2 Question 6
Practice Exam 1 C/P Section Passage 2 Question 9
Practice Exam 4 C/P Section Question 10
Practice Exam 4 C/P Section Passage 6 Question 31
Practice Exam 4 C/P Section Passage 6 Question 32
Practice Exam 4 B/B Section Passage 1 Question 2
Key Points
• Primary alcohols are oxidized to form aldehydes.
• Secondary alcohols are oxidized to form ketones.
• Tertiary alcohols are not readily oxidized.
• General reactivity of alcohols decreases as the number of substituents on an alcohol group increases; an exception is made for SN1 reactions
• In nucleophilic substitution reactions, alcohols are poor leaving groups and require protenation by an acid catalyst. In SN1 reactions, tertiary alcohols are favored. In SN2 reactions, primary alcohols are favored.
• Silyl groups can be used to protect alcohols, and fluorine can be used to deprotect.
• Tosylates and mesylates are widely used in the protection of alcohols. The conversion to a sulfonate prevents the alcohol from acting as an acid or nucleophile, or from undergoing other undesirable reactions
• Alcohols can also be converted into a sulfonate to become better leaving groups. It allows the desired reaction to occur at another functional group without risking side reactions with the alcohol functionality.
Key Terms
Primary alcohol: Alcohol with hydroxyl group connected to a primary carbon, also written as (-CH2OH)
Secondary alcohol: Alcohol with hydroxyl group connected to secondary carbon, also written as (-CHROH)
Tertiary alcohol: Alcohol with hydroxyl group connected to a tertiary carbon, also written as (-CHR2OH)
“R” Group: Seen when defining the above carbons; used as an abbreviation for any group where carbon is attached to the rest of the molecule.
Aldehyde: An organic compound containing the group —CHO, formed by the oxidation of alcohols.
Ketone: An organic compound containing a carbonyl group =C=O bonded to two hydrocarbon groups, made by oxidizing secondary alcohols.
Silyl ethers: A group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group.
Leaving group: An atom (or a group of atoms) that is displaced as stable species taking with it the bonding electrons.
Sulfanate: A salt or ester of a sulfonic acid.
Tosylate: An ester containing a tosyl group.
Mesylate: Any salt or ester of methanesulfonic acid
Nucleophilic substitution: A fundamental class of reactions in which a leaving group is replaced by an electron-rich compound.
Nucleophile: A molecule or substance that has a tendency to donate electrons or react at electron-poor sites such as protons.