Nucleophilic Addition – Carbonyl Compounds

by Adam Le Gresley, PhD

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    00:01 containing the double bond. Right. Okay. So, how do carbonyl compounds react? What I have shown here on the board is an idealised ketone where we have two different alkyl or aryl groups shown as R and R’ attached to a carbonyl, that’s the carbon double bond to the oxygen. Now, I said to you that nucleophilic addition is the typical reaction and indeed, the typical reagent or reactant in this particular case is usually of the form NuH or HNu where, for example, the nucelophile could indeed be, let’s say, water or indeed, it could be cyanide. Therefore, for example, we could react hydrogen cyanide. Bear that all in mind, we’ve got a nucleophile here which is idealised. We’ve called it Nu-. What happens in this case is that the nucleophile attacks the carbonyl at the delta positive carbon, opens up the double bond between the carbon and the oxygen and places a formal negative charge on the oxygen. This is then capped by the counterride, which in this case of NuH would be H+ and this generates here our nucleophile directly added on to R carbon-oxygen double bond, as you can see here. Now, the actual name of the group that’s formed as a consequence depends very much on the substituent of the nucleophile itself.

    01:27 First step, as I said, nucleophilic attack on the carbonyl. Second step, protonation of the resulting anion and that’s all you really need to know for the nucleophilic addition to carbonyl compounds. Bear in mind one important geometric factor.

    01:43 We said before that carbonyl compounds start off as trigonal, trigonal planar. This is by virtue of the fact that the carbon and, indeed, the oxygen are sp2-hybridised. By the time the reaction has finished, however, both the intermediate and the final compound are tetrahedral; tetrahedral, in a not too dissimilar fashion, to the molecule methane, for example. So, what else? Reduction to an alcohol.

    02:11 So, here we have another idealised ketone in a sort of similar fashion to when we were talking about alcohols. Whereas it’s possible to oxidise an alcohol up to a ketone, it’s also possible, when desirable, to reduce a ketone down to an alcohol. In this particular case, I’ve shown only a ketone. This is reduced down to, in this particular case, a secondary or, in this case, primary alcohol where R or R’ can either be hydrogen or indeed, it can be alkyl. So, we’ve made no distinction in this case.

    02:46 Lithium aluminium hydride is quite flammable and reacts violently with water and so, should actually be treated with a fair amount of caution. However, it will reduce most ketones and indeed, it reduces mostly any of the carbonyl containing compounds. The things which are slightly more reactive such as aldehydes, sodium borohydride is a useful way of achieving this. So, let me have a look and let me show you a particular example of a nucleophilic addition reaction and this is the addition of cyanide over a carbon-oxygen double bond. In this particular case, what we see is a formation of a cyanohydrin compound. This is where we’ve got the nucleophilic attack of the cyanide on the carbonyl carbon to give and then kept by the H+ form from it in effectively one step. Once you’ve done that, what you can then do is hydrolyse that nitrile group which is then formed with acid and water to give you a carboxylic acid, but look at what we’ve actually done. What we’ve effectively done is we’ve added a carbon unit to something which is already has a carbon unit on it, the carbonyl carbon. So, what this allows us to do is effectively extend the chain, in this case, the aliphatic chain and to incorporate a carboxylic acid group at the end of it. This itself can always be reduced down and a number of other reactions can be done with this, but this is an important synthetic step is that we can progressively add to successive number of carbons in this fashion.

    04:26 Okay. Addition of water. Remember what I said is that the nature of the compounds that are formed, that is to say, their names and nomenclature depend very much on the nucleophile which is added. In this particular scenario, water reacts with acetone to give something called a gem diol, gem diol being short for geminal diol. If we go back to nomenclature, right back at the very beginning and we were talking about germinal; geminal meaning that we actually have two substituents on the same carbon.

    04:59 So, therefore, this is two OH groups or two old groups, therefore, diol groups attached to the same carbon and therefore, this is a geminal diol.

    05:08 Note that it is also tetrahedral in structure and indeed this forms very quickly and so, for example, in aldehydes, like for example, formaldehyde, the geminal diol is formed pretty much on contact with water and is the origins of formalin which is a 40 percent solution used to preserve specimens. Now, there’s something else that can happen.

    05:32 Bear in mind what I said. We’ve got water which consists of the nucleophile OH- and also has the H+ needed to cap the oxygen or the O- that’s formed in the first step of nucleophilic addition. Hemiacetal formation is the result of the reaction of a carbonyl compound with an alcohol and this is also a very important reaction from a biological perspective as well, as we’ll see a little later on when we start looking at sugars.

    06:02 Let’s have a look again at the structure of the alcohol which is shown at the bottom of the board. We’ve shown an aliphatic or aromatic group as R’, also showed that we’ve got oxygen lone pairs. And remember what we said, anything which contains electrons like that, which is rich in electrons, can act as a nucleophile.

    06:20 And what happens in this particular case, is that the lone pairs on the oxygen attack the delta positive of the carbonyl carbon. The freed H+ from the alcohol then caps the O- that’s formed as part of the nucleophilic addition. As you can see here, what we’ve now done is substitute it or add it over R’O onto the carbonyl carbon. And whenever you see this structure where you have a alkyl, oxygen, carbon and then an OH group, irrespective of what circumstance, it is usually considered a hemiacetal.... hemiacetal.

    About the Lecture

    The lecture Nucleophilic Addition – Carbonyl Compounds by Adam Le Gresley, PhD is from the course Organic Chemistry.

    Included Quiz Questions

    1. …the electrophilic carbonyl carbon of ketone combines with the nucleophilic carbon of Grignard reagent.
    2. …the nucleophilic carbonyl carbon of ketone combines with the electrophilic carbon of Grignard reagent.
    3. …of unstable molecular structure of 2-butanone.
    4. …of unstable molecular structure of propyl magnesium iodide.
    5. ...of the catalytic effect of magnesium.
    1. A reaction between Grignard reagent and formaldehyde uniquely yields a mixture of both secondary and tertiary alcohols.
    2. The nucleophilic addition of carbonyl group is two step process involving attack of the incoming nucleophile on carbonyl group at electrophilic carbon followed by protonation of the resulting anion at negatively charged oxygen.
    3. During nucleophilic addition reaction, the sp2 hybridization configuration of electrophilic carbon changes to sp3, hence both the intermediate alkoxide ion and final product exhibit tetrahedral geometry.
    4. The polar reagents like LiAlH4 or NaBH4 reduce the carbonyl group to convert unsaturated aldehyde or ketone to alcohols.
    5. The nucleophilic addition of aldehydes gives secondary alcohols, whereas that of ketones produce tertiary alcohols.
    1. The addition of HCN to a carbonyl group gives rise to tertiary alcohols.
    2. CN- acts a nucleophile due to the presence of an active lone pair of electrons.
    3. The nucleophilic addition reaction of HCN with aldehydes or ketones give rise to cyanohydrins or hydroxy nitrile.
    4. Butanal + Hydrogen Cyanide → 2-Hydroxybutanenitrile
    5. The production of HCN is carried out in situ by mixing aldehyde or ketone with a solution of sodium cyanide in water with traces of sulfuric acid.
    1. …carboxylic acids with carbon chain extension to the original aldehyde or ketone used during the hydroxy nitrile production.
    2. …tertiary alcohols with carbon chain extension to the original aldehyde or ketone used during the hydroxy nitrile production.
    3. …secondary alcohols with carbon chain extension to the original aldehyde or ketone used during the hydroxy nitrile production.
    4. …primary alcohols with carbon chain extension to the original aldehyde or ketone used during the hydroxy nitrile production.
    5. …esters with carbon chain extension to the original aldehyde or ketone used during the hydroxy nitrile production.
    1. Ketones usually form stable hydrates at room temperature.
    2. Carbonyl group of ketones or aldehydes reacts readily with water establishing a reversible equilibrium with very reactive gem-diol (hydrate) having tetrahedral geometry.
    3. Water addition to the carbonyl group is neutral nucleophile addition process involving two-step acid-base reaction.
    4. The nucleophilic attack of OH- ion on the partially positive carbon of carbonyl group leads to the generation of an oxonium ion.
    5. The O- of oxonium ion gets capped by proton liberated from the water in the second step of water addition reaction of ketones.
    1. Formalin is a strong oxidizing agent.
    2. The fixative used in microscopy and histology is a solution of formaldehyde in water.
    3. Formalin kills bacteria and fungi, hence it is used as a disinfectant and biocidal agent.
    4. An exception to gem-diol existence rule, the formaldehyde tends to form more than 98% of hydrate at equilibrium at 20°C.
    5. Formalin is composed of 37-40% of formaldehyde in water.
    1. …Ketones usually form stable hydrates at room temperature.
    2. …by the nucleophilic addition of alcohols to the carbonyl group of ketones or aldehydes.
    3. …by the electrophilic addition of alcohols to the carbonyl group of ketones.
    4. … by the electrophilic addition of alcohols to the carbonyl group of aldehydes.
    5. …by nucleophilic substitution of alcohols to the carbon of carbonyl group of ketones or aldehydes.
    1. The liner hemiacetals molecules are highly stable than the cyclic molecules.
    2. Hemiacetal formation is a reversible nucleophilic addition reaction between alcohol and ketone or aldehyde.
    3. Hemiacetal formation from ketones takes place in the presence of an acid catalyst as alcohols are weak nucleophiles.
    4. Hemiacetals formed by intramolecular cyclization of the alcohol onto an aldehyde are highly stable.
    5. Many sugars existing in biological systems are cyclic hemiacetals.
    1. …the juxtaposition of reacting functional groups in the same molecule.
    2. ...the high stability of the parent molecule.
    3. … the far away positioning of reactant clusters in the same molecule.
    4. …the ability of parent molecule to act as a catalyst to carry out the self-cyclization process.
    5. …the toxic effect of impurities present in the reaction mixture.

    Author of lecture Nucleophilic Addition – Carbonyl Compounds

     Adam Le Gresley, PhD

    Adam Le Gresley, PhD

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