carbonyls

What defines carbonyl compounds?

Presence of C=O bond

Describe carbonyl structure

Trigonal planar sp2 hybridised C and O

All sigma bonds lie in same plane about 120° apart

C-O pi bond between parallel p orbitals

Which is the bond responsible for carbonyl reactivity?

Pi bond between parallel C and O p orbitals

Draw the basic structure of a carbonyl group

Compare the C=O bond to C=C in alkenes

C=O is shorter, stronger and more polar

in what ways could a carbonyl compound interact with binding sites in the body?

Hydrogen bonding - C=O is HBA (O can accept 2 h bonds)

Dipole-dipole interactions due to dipole moment

Describe in general how reactions occur at the carbonyl carbon

The electron pair moves from C=O to more electronegative O

After nucleophilic attack

Produces a tetrahedral alkoxide ion intermediate

Formation of new bonds increases steric crowding

how and why does a nucleophile approach carbonyl carbon?

From either above or below plane of C=O

C is slightly positive and electrophilic due to polar C=O bond

This attracts nucleophiles

Are aldehydes or ketones more reactive, and why?

Aldehydes more reactive

Less steric crowding so Nu- only has to pass by 1 side chain (vs 2)

How can reactivity of carbonyls be enhanced?

By protraction of carbonyl O to make the conjugate acid

Proton attached to O draws electrons over O making C more positive

The C becomes more electrophilic and is now more susceptible to nucleophilic attack

Define a hydrogen bond

Short range, directional, inter or intramolecular non-bonded interaction

Between H and lone pair on one of N, O or F

Outline how hydrogen bonding occurs between carbonyl compounds and water

Between 2 lone pairs on delta negative O and delta positive of water

H is h bond donor, O on C=O is acceptor

Outline the importance of hydrogen bonding of carbonyl compounds as drugs

Receptor interactions within the body

Cell components largely made up of hydrogen bonds eg, proteins, water

Carbonyls on drug molecules are able to disrupt this and have an effect

Which form of nucleophilic addition is easier to reverse?

Under acidic conditions

Describe what happens during the reversal of nucleophilic addition under basic conditions

Base (OH-) removes proton on -OH group

O- reforms C=O

Carbonyl formation with loss of leaving group (Nu)

How do carboxylic acids behave in water?

Weak acids - proton donors

Transfer a proton to water to give H3O+ and carboxylate anions R-COO-

Describe what happens during the reversal of nucleophilic addition under acidic conditions

Protonation of original Nu species

Loss of leaving group (Nu-H)

-OH group becomes C=O as loses proton

Give the pKa range for aliphatic and aromatic carboxylic acids

3-5

Why do carboxylic acids have greater acidity than alcohols?

Due to resonance stabilisation of the COO- anion

If a drug has a low pKa at what pH and where would its ionisation be greatest?

At alkaline pH

Small intestine

If a group has an electron-donating inductive effect, will this stabilise or destabilise the anion it’s attached to?

Destabilise

Name a reducing agent you could use to reduce aldehydes or ketones

LiAlH4

Describe how aldehydes and ketones react to oxidation

Aldehydes - to carboxylic acids with oxidising agent eg, CrO3 or KMnO4

Ketones - inert towards oxidation

Why will compounds with pKa higher than water (>16) not ionise in water?

As the water will be the stronger acid

H3O+ is stronger so reverse reaction (proton transfer back to the compound trying to ionise) is more stable

Thermodynamically favourable to form the weaker acid

Why are acyl chlorides the most reactive carbonyl derivative?

1. Hybridisation during resonance - better overlap of 2p orbitals of C and O compared to 3p and 2p of Cl and C

2. Cl- is a better leaving group (than -O-R) as it is the weak base of its strong conjugate acid HCl, and is large and electronegative enough

Explain the difference in acidity between fluoroacetic acid (CF3COOH) and acetic acid (CH3COOH)

Fluoro stronger acid (lower pKa)

Electronegativity on F pulls electron density towards CF3 making it easier to lose H+ on -OH group

CH3 is slightly electron releasing so more difficult to lose H+

State the steps of acid catalysed hydrolysis of esters

H+ added to C=O, lone pair nucleophile on water attacks electrophilic carbon, C=O broken (to form C-O-H), e- on O-CH3 attracted to H on nucleophile group, C=O reformed

Alcohol reforms

Lone pair on -OH group reforms C=O bond

Why does nucleophilic substitution not occur when Y group next to C=O is -H or -R (alkyl/aryl group)?

They cannot behave as leaving groups