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

Nucleophilic Addition Reactions

• the characteristic reaction of carbonyl containing compounds is nucleophilic addition. This can occur because the carbonyl carbon is rather partially positive, making it susceptible to attack by nucleophiles, and because the carbonyl oxygen can accept a pair of electrons to become an alkoxide.
• there are two very similar mechanisms for the reaction. The difference is the catalysis, acid or base.
• in the base catalyzed reaction, a strong nucleophile, Nu:-, attacks the carbonyl carbon pushing the pi bond electrons up onto the oxygen atom to give an alkoxide. This intermediate is tetrahedral in geometry giving a tetrahedral carbonyl addition intermediate or TCAI.
• the negatively charged oxygen can now strip a proton from something (for example Nu-H)
• in the acid catalyzed mechanism the first step is the protonation of the carbonyl oxygen to give an oxonium. A contributing resonance structure puts the positive charge on the carbonyl carbon. The net effect of protonation is to make the carbonyl carbon even more electron deficient than it was. This makes it more susceptible to attack by nucleophiles
• in this case a weak nucleophile will suffice. As the nucleophile attacks the pi bond electrons are pushed up onto oxygen to give an O-H group
• it is important to remember that most of these reactions are reversible. This should be indicated with two half arrows in opposite directions. The overall result of the reaction depends largely on the position of the equilibrium.
• the shape of the carbonyl group lends itself to increased reactivity. The planar nature of the group means that it can be attacked from either side. In this respect, an aldehyde is more open to attack than a ketone, because one of the substitutents on the carbonyl carbon is a hydrogen atom, thus approach by the nucleophile is less hindered
• since slkyl groups tend to be electron releasing (a kind of inductive effect), the carbonyl carbon of a ketone is less electron deficient than that of an aldehyde making it less reactive.
• these two factors, the steric factor and the electronic factor, make the aldehyde more reactive in general than the ketone.

2. Hydration:

• the simplest example of a nucleophilic addition reaction is the addition of water, called a hydration reaction.
• the reaction can be acid or base catalyzed
• starting with the base catalyzed mechanism, in the presence of a strong base water can be deprotonatedto give the hydroxide ion (HO-). This strong nucleophile can attack the carbonyl carbon, pushing the pi bond electrons up onto the carbonyl oxygen giving a TCAI which is an alkoxide.
• the reaction is resolved when the alkoxide oxygen removes a proton from the protonated base (alkoxides are very strong bases) to give the diol product
• the product is called a geminal diol or gem diol. This means that is has two hydroxyl groups on one carbon.
• this reaction can also be acid catalyzed. In this reaction, the first step is the protonation of the carbonyl oxygen to give the oxonium ion. This susceptible to attack by the weaker nucleophile, water. A lone pair on a water oxygen attacks the carbonyl carbon, pushing the pi electrons up onto the carbonyl oxygen.
• the water (oxonium ion now) is deprotonated by another water in solution, to regenerate the hydronium ion and to give the gem diol product.
• for most ketones equilibrium favours the keto form, but for some aldehydes (including formaldehyde, methanal) the equilibrium strongly favours the gem-diol.

3. Hemi-acetal Formation:

• a very similar reaction to the hydration reaction is hemi-acetal formation, which involves addition of one mole of alcohol to a carbonyl.
• this reaction can be acid or base catalyzed.
• in the base catalyzed mechanism, the alcohol can be deprotonated (remember alcohols are weak acids) to give an alkoxide, which is a very powerful nucleophile.
• the alkoxide oxygen can attack the carbonyl carbon, pushing the pi bond electrons up onto the carbonyl oxygen making it into an alkoxide ion. This is a TCAI.
• the reaction is resolved when the newly formed alkoxide removes a proton from the protonated base to form the product, a hemi-acetal
• in the acid catalyzed reaction, the first step is the protonation of the carbonyl oxygen atom to give an oxonium
• the carbonyl carbon can then be attacked by a lone pair on the alcohol oxygen atom, pushing the pi electrons up onto the carbonyl carbon, to give a new oxonium ion. The proton is then removed from the oxonium ion by water to regenerate the hydronium ion. This gives the hemi-acetal product.
• this reaction is particularly stable if the reaction occurs to form a ring
• glucose is an excellent example of this. The hydroxyl group on the number five carbon (usually) attacks the carbonyl carbon (number 1). The six membered ring formed is called a pyranose ring. This is the favoured form of glucose. More about this soon.

4. Acetal Formation:

• once the hemi-acetal is formed, a second molecule of alcohol can add, with the loss of water (dehydration) to give a full acetal.
• this reaction is acid-catalyzed. In the first step the hydroxyl group becomes protonate from the hydronium ion to give an oxonium ion. This sets up the hydroxyl group as a good leaving group, water.
• in the next step, a lone pair from the alcohol derived oxygen comes down and pushes the water off. This generates a new cationic intermediate (an oxonium resonance stabilized by a carbocation)
• the formerly carbonyl caron is then attacked by another molecules of alcohol (a lone pair from the hydroxyl group attacks), pushing the pi bond electrons back up onto the other oxygen.
• the resulting oxonium is deprotonated by water to regenerate the hydronium ion.
• like other similar reactions, this is reversible
• an important example of an acetal is the glycoside bond that is the bond between to sugar molecules.

5. Imine or Schiff Base Formation:

• another biologically relevant nucleophilic addition reaction is the addition of derivatives of ammonia or amines.
• The product under these circumstances is called an imine or a Schiff's Base. These are characterized by a carbon doubly bonded to a nitrogen atom.
• in an in vitro reaction (without enzyme) these reactions proceed fastest at pH 4 to 5 (no extreme of high or low pH). The moderate acid requirement is necessary to allow protonation of the the hydroxyl intermediate to allow water to leave.
• let's start with the simplest case, the addition of ammonia.
• ammonia normally exists as the ammonium ion, NH₄+. It is in equilibrium with the NH₃ form.
• under acidic conditions, the carbonyl oxygen can be protonated to give the oxonium ion, making the carbonyl carbon even more electron deficient. The carbonyl carbon can be attacked by the lone pair on ammonia to give an intermediate with a hydroxyl group and a new C-N bond. The nitrogen is positively charged.
• this nitrogen can be deprotonated (the proton can be picked up by water) to give nitrogen with a lone pair.
• under these conditions the hydroxyl can be protonated to give an oxonium. This makes the hydroxyl group a good leaving group.
• another lone pair on nitrogen can attack the formerly carbonyl carbon to form a pi bond, pushing the water group off of the molecule
• the product is a Schiff's base.
• this reaction also occurs with primary amines as well. A common and very relevant example is seen in the active sites of many enzymes. Primary amino groups, such as those found on lysine side chains, often form Schiff's bases with the carbonyl group of the substrate. An example of this is the reaction catalyzed by the enzyme acetoacetic acid decarboxylase.
• Schiff's bases are important in enzyme catalysis for three reasons (at least). They maintain the oxidation state of the carbonyl group. They form a covalent bond to the substrate, so that the substrate cannot diffuse away in the middle of the reaction. And they act as electron sinks and sources for further chemistry.