COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE

Carbonyl and Related Compounds- 1

Paper- C7T

Narajole Raj College Department of Chemistry

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL

COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE

The Reactivity of the Carbonyl Group:

In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a carbonyl group is often referred to as a carbonyl compound.

Because oxygen is more electronegative than carbon, carbonyl compounds often have resonance structures which affect their reactivity. This relative electronegativity draws electron density away from carbon, increasing the bond's polarity, therefore making carbon an electrophile (i.e. slightly positive). Carbon can then be attacked by nucleophiles (e.g. negatively charged ions, like the cyanide ion) or a negatively charged part of another molecule (e.g. the lone pair electrons of nitrogen in the ammonia molecule). During the reaction, the carbon-oxygen double bond is broken, and the carbonyl group may experience addition reactions. This reaction is known as addition- elimination (because a water molecule is often lost) or condensation. The electronegative oxygen also can react with an electrophile; for example a proton in an acidic solution or with Lewis acids to form an oxocarbenium ion. The polarity of oxygen also makes the alpha hydrogens of carbonyl compounds much more acidic (roughly 1030 times more acidic) than typical sp3 C-H bonds, such as those in methane. For example, the pKa values of acetaldehyde and acetone are 16.7 and 19 respectively, while the pKa value of methane is extrapolated to be approximately 50. This is because a carbonyl is in tautomeric resonance with an enol. The deprotonation of the enol with a strong base produces an enolate, which is a powerful nucleophile and can alkylate electrophiles such as other carbonyls. Amides are the most stable of the carbonyl couplings due to their high resonance stabilization between the nitrogen-carbon and carbon-oxygen bonds.

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL

COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE

Addition to Carbonyl Compounds:

The addition step is more important, and it forms a new C–C σ bond at the expense of the C=O π bond. The protonation step makes the overall reaction addition of HCN across the C=O π bond. Why does cyanide, in common with many other nucleophiles, attack the carbonyl group? And why does it attack the carbon atom of the carbonyl group? To answer these questions we need to look in detail at the structure of carbonyl compounds

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL

COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE in general and the orbitals of the C=O group in particular. The carbonyl double bond, like that found in alkenes (whose bonding we discussed in Chapter 4), consists of two parts: one σ bond and one π bond. The σ bond between the two sp2 hybridized atoms—carbon and oxygen—is formed from two sp2 orbitals. The other sp2 orbitals on carbon form the two σ bonds to the substituents while those on oxygen are fi lled by the two lone pairs. The sp2 hybridization means that the carbonyl group has to be planar, and the angle between the substituents is close to 120°. The diagram illustrates all this for the simplest carbonyl compound, formaldehyde (or methanal, CH2O). The π bond then results from overlap of the remaining p orbitals—again, you can see this for formaldehyde in the diagram.

When we introduced the bonding in the carbonyl group in Chapter 4 we explained how polarization in the π bond means it is skewed towards oxygen, because oxygen is more electronegative than carbon. Conversely, the unfilled π* antibonding orbital is skewed in the opposite direction, with a larger coefficient at the carbon atom. This is quite hard to represent with the π bond represented as a single unit, as shown above, but becomes easier to visualize if instead we represent the π and π* orbitals using individual p orbitals on C and O. The diagrams in the margin show the π and π* orbitals represented in this way.

Because there are two types of bonding between C and O, the C=O double bond is rather shorter than a typical C–O single bond, and also over twice as strong—so why is it so reactive? Polarization is the key. The polarized C=O bond gives the carbon atom some degree of positive charge, and this charge attracts negatively charged nucleophiles (like cyanide) and encourages reaction. The polarization of the antibonding π* orbital towards carbon is also important because, when the carbonyl group reacts with a nucleophile, electrons move from the HOMO of the nucleophile (an sp orbital in the case of cyanide) into the LUMO of the electrophile—in other words the π* orbital of the C=O bond. The

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL

COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE greater coeffi cient of the π* orbital at carbon means a better HOMO–LUMO interaction, so this is where the nucleophile attacks. As our nucleophile—which we are representing here as ‘Nu−’—approaches the carbon atom, the electron pair in its HOMO starts to interact with the LUMO (antibonding π*) to form a new σ bond. Filling antibonding orbitals breaks bonds and, as the electrons enter the antibonding π* of the carbonyl group, the π bond is broken, leaving only the C–O σ bond intact. But electrons can’t just vanish, and those that were in the π bond move off on to the electronegative oxygen, which ends up with the negative charge that started on the nucleophile. You can see all this happening in the diagram below.

Notice how the trigonal, planar sp2 hybridized carbon atom of the carbonyl group changes to a tetrahedral, sp3 hybridized state in the product. For each class of nucleophile

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL

COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE you meet in this chapter, we will show you the HOMO–LUMO interaction involved in the addition reaction. These interactions also show you how the orbitals of the starting materials change into the orbitals of the product as they combine. Most importantly here, the lone pair of the nucleophile combines with the π* of the carbonyl group to form a new σ bond in the product.

The Angle of Nucleophilic attack on Aldehydes and Ketones:

Having introduced you to the sequence of events that makes up a nucleophilic attack at C=O (interaction of HOMO with LUMO, formation of new σ bond, breakage of π bond), we should now tell you a little more about the direction from which the nucleophile approaches the carbonyl group. Not only do nucleophiles always attack carbonyl groups at carbon, but they also always approach from a particular angle. You may at fi rst be surprised by this angle, since nucleophiles attack not from a direction perpendicular to the plane of the carbonyl group but at about 107° to the C=O bond—close to the angle at which the new bond will form. This approach route is known as the Bürgi–Dunitz trajectory after the authors of the elegant crystallographic methods that revealed it. You can think of the angle of attack as the result of a compromise between maximum orbital overlap of the HOMO with π* and minimum repulsion of the HOMO by the electron density in the carbonyl π bond. But a better explanation is that π* does not have parallel atomic orbitals as there is a node halfway down the bond so the atomic orbitals are already at an angle. The nucleophile attacks along the axis of the larger orbital in the HOMO.

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL

COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE

Nucleophilic Addition Reactions of Aldehydes and Ketones:

Before we consider in detail the reactivity of aldehydes and ketones, we need to look back and remind ourselves of what the bonding picture looks like in a carbonyl. Carbonyl carbons are sp2 hybridized, with the three sp2 orbitals forming soverlaps with orbitals on the oxygen and on the two carbon or hydrogen atoms. These three bonds adopt trigonal planar geometry. The remaining unhybridized 2p orbital on the central carbonyl carbon is perpendicular to this plane, and forms a ‘side-by-side’ pbond with a 2p orbital on the oxygen.

The carbon-oxygen double bond is polar oxygen is more electronegative than carbon, so electron density is higher on the oxygen side of the bond and lowers on the carbon side.

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL

COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE

Recall that bond polarity can be depicted with a dipole arrow, or by showing the oxygen as holding a partial negative charge and the carbonyl carbon a partial positive charge.

A third way to illustrate the carbon-oxygen dipole is to consider the two main resonance contributors of a carbonyl group: the major form, which is what you typically see drawn in Lewis structures, and a minor but very important contributor in which both electrons in the pbond are localized on the oxygen, giving it a full negative charge. The latter depiction shows the carbon with an empty 2p orbital and a full positive charge. The result of carbonyl bond polarization, however it is depicted, is straightforward to predict. The carbon, because it is electron-poor, is an electrophile: it is a great target for attack by an electron-rich nucleophilic group. Because the oxygen end of the carbonyl double bond bears a partial negative charge, anything that can help to stabilize this charge by accepting some of the electron density will increase the bond’s polarity and make the carbon more electrophilic. Very often a general acid group serves this purpose, donating a proton to the carbonyl oxygen. The same effect can also be achieved if a Lewis acid, such as a magnesium ion, is located near the carbonyl oxygen.

Unlike the situation in a nucleophilic substitution reaction, when a nucleophile attacks an aldehyde or ketone carbon there is no leaving group – the incoming nucleophile simply ‘pushes’ the electrons in the pi bond up to the oxygen. Alternatively, if you start with the minor resonance contributor, you can picture this as an attack by a nucleophile on a carbocation. After the carbonyl is attacked by the nucleophile, the negatively charged oxygen has the capacity to act as a nucleophile. However, most commonly the oxygen acts instead as a base, abstracting a proton from a nearby acid group in the solvent or enzyme active site.

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL

COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE

Nucleophilic Addition of H2O: Hydration

It has been demonstrated that water, in the presence of an acid or a base, adds rapidly to the carbonyl function of aldehydes and ketones establishing a reversible equilibrium with a hydrate (geminal-diol or gem-diol). The word germinal or gem comes from the Latin word for twin, geminus.

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL

COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE

Isolation of gem-diols is difficult because the reaction is reversibly. Removal of the water during a reaction can cause the conversion of a gem-diol back to the corresponding carbonyl.

In most cases the resulting gem-diol is unstable relative to the reactants and cannot be isolated. Exceptions to this rule exist, one being formaldehyde where the weaker pi- component of the carbonyl double bond, relative to other aldehydes or ketones, and the small size of the hydrogen substituents favor addition. Thus, a solution of formaldehyde in water (formalin) is almost exclusively the hydrate, or polymers of the hydrate. The addition of electron donating alkyl groups stabilized the partial positive charge on the carbonyl carbon and decreases the amount of gem-diol product at equilibrium. Because of this ketones tend to form less than 1% of the hydrate at equilibrium. Likewise, the addition of strong electron-withdrawing groups destabilizes the carbonyl and tends to form stable gem-diols. Two examples of this are chloral, and 1,2,3-indantrione. It should be noted that chloral hydrate is a sedative and has been added to alcoholic beverages to make a “Knock-out” drink also called a Mickey Finn. Also, ninhydrin is commonly used by forensic investigators to resolve finger prints.

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL

COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE

The mechanism is catalyzed by the addition of an acid or base. Note! This may speed up the reaction but is has not effect on the equilibriums discussed above. Basic conditions speed up the reaction because hydroxide is a better nucleophilic than water. Acidic conditions speed up the reaction because the protonated carbonyl is more electrophilic.

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL

COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL

COMPILED AND CIRCULATED BY DR. SK MOHAMMAD AZIZ, ASSISTANT PROFESSOR, DEPARTMENT OF CHEMISTRY, NARAJOLE RAJ COLLEGE

References:

1. Clayden, J. Greeves, and N. Warren. “Organic Chemistry” 2. Chemistry, LibreTexts.

CHEMISTRY: SEM-III, PAPER- C7T: CARBOBYL AND RELATED COMPOUNDS, ADDITION TO CARBONYL