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Chemistry 2131:
Organic Chemistry for the Life Sciences(3)

Reactions of Alcohols

• we saw in detail that the ability to form hydrogens affects both the boiling points and solubilities of alcohols. These extra intermolecular forces of attraction hold pure molecules in the solid and liquid states at higher temperatures, and the increased positive interactions with water increase their solubilites in this solvent.
• another property of alcohols is their ability to act as acids and bases
• in dilute aqueous solutions, alcohols are weakly acidic. This means that they can give up their proton to generate an alkoxide (negatively charged oxygen).
• one of the lone pairs on a water oxygen attacks the proton and the pair of electrons from the O-H bond go onto oxygen.
• methanol and ethanol are approximately as acidic as water, the longer chain alcohols are somewhat less acidic
• in contrast, in the presence of strong acids, the hydroxyl group can become protonated. That is to say, the alcohol is acting as a base.
• a lone pair on the hydroxyl oxygen abstracts a proton from the hydronium ion to give an oxonium ion

2. Nucleophilic Substitution Reactions:

• like alkyl halides, alcohols can undergo nucleophilic substitution reactions
• the easiest of these to envisage are the S_N1 type reactions with secondary and tertiary alcohols reacting with HCl
• this only works appreciably for low molecular weight water soluble alcohols (think about the reaction conditions necessary for S_N1 to occur).
• the first step is a very important one, and is the major difference between this reaction and that of alkyl halides. In this step the hydroxyl group is rapidly and reversibly protonated. A lone pair on the hydroxyl oxygen removes a proton from the hydronium ion to give water and an oxonium ion.
• the second step is the rate limiting step, the water leaves to generate a carbocation intermediate.
• the carbocation is readily attacked by a chloride ion
• why does the protonation occur in the first step? The hydroxide ion (-OH) is a very poor leaving group, water however is quite a good leaving group.
• this reaction can also proceed by S_N2. In this case, the attack by the Cl- ion is concomitant with the loss of the water. The protonation of the hydroxyl group is necessary in this reaction as well.
• an interesting difference between these two mechanisms is that in order for S_N2 to occur, the reaction must be heated for 5 to 6 hours. For the S_N1 reaction, a few minutes at room temperature suffices.
• one common feature is that these reactions are not favourable thermodynamically. This means that the alcohol is favoured over the halide, or that the equilibrium falls to the left of the equation. In order to have this reaction proceed, the halide product must be removed from the reaction mixture. Fortunately, the reaction takes place in aqueous solution, and the products are not water soluble, so they precipitate out. We use Le Chatelier's principle to drive the reaction.

3. Dehydration:

• another reaction characteristic of alcohols is dehydration. This proceeds by beta-elimination just as alkyl halides undergo elimination. The reaction is the loss of water to generate a double bond.
• the dehydration of an alcohol follows Zaitsev's Rule
• let's look at the example of 2-butanol going to 2-butene. This reaction proceeds by E1.
• in the presence of an acid, the hydroxyl group becomes protonated. This is the same first step as before. As usual, this step is rapid and reversible.
• the water group leaves to give a carbocation intermediate.
• the final step is the removal of the beta-proton by water (acting as a base here), the electrons from the C-H bond become the pi bond between the alpha and beta carbon atoms.
• what is the order of reactivity of the alcohols? Tertiary > secondary > primary.
• this reaction is exactly the reverse of the hydration of an alkene. Try it!
• the rate limiting step is the protonation of the alkene, or the removal of the beta-hydrogen.

4. Oxidation States of Oxygen Containing Functional Groups:

• you know from the lab on alcohols, that alcohols can be oxidized to carbonyl and carboxyl groups (if they are primary)
• let's have a look at the oxidation states of a number of groups. Let's start with a terminal carbon of an alkane and an interiour carbon atom.
• remember that to calculate the oxidation number, we look at carbons that change in a reaction. We assign a value of 0 for all C-C bonds (or bonds to atoms of equal electronegativity), a value of -1 for C-H bonds (or bonds to atoms of less electronegativity), and a value of +1 for C-Y bonds, where Y is a more electronegative atom.
• so, a terminal carbon atom in an alkane has an oxidation number or -3, whereas a secondary carbon has an oxidation number of -2. A primary alcohol has an oxidation number of -1 and a secondary alcohol has an oxidation number of 0. So, if you go from an alkane to an alcohol, that is an oxidation. As an aside, what is the change when you go from an alkene to an alkene?
• if we go to an aldehyde from a primary alcohol, we get an oxidation number of +1, and on to a carboxylic acid we go to +3. For a secondary alcohol going to a ketone we go from 0 to +2.
• one thing to note is that these processes proceed in two electron oxidation steps.
• put in another way the order of most oxidized to least oxidized is carboxyl > carbonyl > hydroxyl > alkyl.

5. Biological Oxidation of an Alcohol:

• last year I covered chemical oxidation of alcohols like the one you did in the lab using potassium dichromate. They are complicated and confusing, and occur in conditions not amenable to real life.
• more important, biological oxidations don't occur by the same mechanisms at all. So, we will look at an example of biological oxidation of an alcohol.
• biological oxidations are catalyzed by enzymes not strong acids. The enzyme we will look at is alcohol dehydrogenase. This enzyme is responsible for metabolizing ethanol into ethanal in the bloodstream, to break it down.
• for every oxidation reaction something must be reduced. In this case, the oxidizing agent is the cofactor nicotinamide adenine dinucleotide. The NAD+ becomes reduced by a hydride shift.
• the business end of NAD+ is the number 4 carbon of the nicotinamide ring. In the active site of the enzyme this group lies right beside the alpha carbon and one of the alpha hydrogens of the ethanol molecule.
• one of the resonance structures for the nicotinamide puts a positive charge on this number 4 carbon. A hydride can move from the alpha carbon to the carbocation to give NADH and a terminal carbocation. This intermediate is resonance stabilized by a lone pair on the hydroxyl group (this puts the positive charge on the oxygen.
• finally, water acts as a base to remove the hydroxyl proton and the electrons come down to form a carbonyl group.
• this is dramatically different than what occurs with chemical oxidation. But this occurs at 37 degrees C in a split second and doesn't require harsh conditions.