Electrophilic Carbonyls

What does electrophile mean?

A chemical species (atom, ion, or molecule) that is electron-deficient

What does electrophilic carbonyl mean?

Electrophilic carbonyl: the partially positive carbon in a C=O group that is susceptible to nucleophilic attack due to bond polarisation.

How is carbonyl made to be electrophilic?

• Oxygen is much more electronegative than carbon

• It pulls electron density toward itself

• This polarises the C=O bond

So:

• Oxygen becomes δ⁻ (partially negative)

• Carbon becomes δ⁺ (partially positive)

That δ⁺ carbon is the electrophilic carbonyl carbon.

• Electrophile = electron-loving

• The carbonyl carbon accepts an electron pair

• Nucleophiles (e.g. OH⁻, NH₃, CN⁻) attack the carbonyl carbon

What is a leaving group?

A leaving group is an atom or group of atoms that can detach from a molecule by taking a pair of electrons with it during a reaction.

What makes a good leaving group?

• Stable on its own after leaving

• Usually weakly basic

• Often able to stabilise negative charge

What does “carbonyl without a leaving group” mean?

It means a carbonyl compound where nothing attached to the carbonyl carbon can easily leave.

• Aldehydes and ketones are carbonyls without a leaving group

• H or alkyl groups cannot act as leaving groups (H^- and R^- would be extremely unstable)

Carbonyls WITHOUT leaving groups:

Aldehyde

Ketone

What does ketone + water form?

Water adds across the carbonyl (C=O) bond to create a form a hydrate

Is ketone + water a nucleophilic addition or substitution reaction?

Nucleophilic addition

Ketones/Aldehydes reaction with H₂O Mechanism:

• H₂O is a weak nucleophile, so it attacks the electrophilic carbonyl carbon

• It forms a tetrahedral intermediate

• Proton transfer takes place. Proton transfers from the +vely charged OH₂⁺ group to the negatively charged O^- , neutralising charges, stabilising the molecule

• Because there is no leaving group, the intermediate cannot collapse by expelling a group, so the reaction stops at addition, not substitution

This reaction is all in equilibrium

Which is the major and minor product?

The equilibrium is heavily based to the left

Formaldehyde

Formaldehyde + H₂O

Which is the major and minor product?

There is no inductive effect here (because H is neither electron withdrawing or donating), so formaldehyde is very reactive due to its carbonyl C being very electrophilic and the water attacks it, and so the equilibrium lies to the right.

Cyclic ketone + H₂O

Which is the major and minor product?

This is due to sterics

• The 3C ring is a triangle shape. The angle in a 3C ring is 60°. There is very high ring strain therefore in the cyclic ketone, as the sp² angle is 120°.

• In the product, the sp³ angle is now 109° which is closer to 60°, so there is reduced ring strain. The molecule wants to be in the hydrated form because it is “happier”

When considering why a reaction occurs, what 2 points do you have to consider?

• Steric argument

• Electronic argument

Carbonyl + Alcohol Reaction Mechanism → Draw it out

• The H in R-OH (alcohol) protonates the O in C=O

• This makes the C=O C more electrophilic, so is very δ+

• Therefore the lone pair of electrons on the O in R-OH (alcohol) moves via curly arrow to the electrophilic C.

• Making a bond, leads to bond breaking in C=O

If R¹ = Alkyl, what is this known as?

Hemi ketal

Hemi ketal derives from a…

ketone

If R¹ is H, what is this molecule known as?

Hemi acetal

Hemi acetal derives from an…

aldehyde

Ketone + Alcohol

How is a cyclic hemi acetal formed?

It forms when an alcohol group within the same molecule reacts with its aldehyde group.

(A cyclic hemi ketal can form from the same molecule reacting with its ketone group)

What are chair conformations?

• Six-membered rings are not flat

• They adopt a chair shape to minimise strain

• Substituents can be:

  • Axial (straight up or down)

  • Equatorial (around the “equator” of the ring)

For β-D-glucose, almost all OH groups are equatorial. What does this mean

• Minimal 1,3-diaxial interactions

• Minimal steric hindrance

• Very stable

What does ring flipping do?

• Converts axial → equatorial

• Converts equatorial → axial

• Does not change:

  • Connectivity

  • Stereochemistry (up/down remains the same)

Ring flipping β-D-glucose causes all equatorial OH groups to become axial. What does this mean?

• All previously equatorial OH groups become axial

• Many 1,3-diaxial steric clashes

• Much higher energy

• Therefore minor conformation

What is an anomeric carbon?

The carbonyl carbon of glucose before ring formation

What happens to the anomeric carbon after cyclisation?

It becomes the new stereogenic centre, and has an -OH and an -OR (ring oxygen) attached

What does the anomeric carbon define?

Whether it is an α or β anomer

α/β anomer

These are not ring flips. They differ in configuration at the anomeric carbon (C1) only

α-anomer

The hydroxyl (-OH) group on the anomeric carbon (C1) is on the opposite side (trans) of the ring from the CH₂OH group (on C5)

β-anomer

A beta (β) anomer is a specific stereoisomer of a cyclic sugar where the hydroxyl (-OH) group on the anomeric carbon (C1 in aldoses) points to the same side (cis) as the CH₂OH group attached to the highest-numbered carbon (like C5 in glucose) in the ring

Are α/β anomer epimers?

Yes

Iminium

Imine

• Imine is the N analogue of a carbonyl group.

• This means that an imine is structurally and chemically analogous to a carbonyl, but with N replacing O

Electrophilic carbonyls reacting with amine

Condensation reaction

Biosynthesis of Amino Acids

• An (here: pyruvic acid)

• Is converted into an α-amino acid (here: alanine)

• Using vitamin B₆ cofactors:

  • Pyridoxamine (PMP)

  • Pyridoxal (PLP)

Pyruvic acid Vs Pyruvate

• Pyridoxamine donates an NH2 group, acting as an amine donor

• Pyruvic acid is an α-keto acid. This carbon skeleton will become alanine.

• The amine from pyridoxamine reacts with the carbonyl carbon of pyruvate

• Water is eliminated (−H₂O)

• An imine (C=N) is formed

The two imine drawings represent:

• Electron rearrangement

• Proton shifts

• Stabilisation by the PLP/PMP system

• Water adds back in

• The imine is hydrolysed

This splits the intermediate into:

• Alanine (now has –NH₂)

• Pyridoxal (PLP) (now without the amine)

So:

• PMP → PLP

• Pyruvate → Alanine

Electrophilic carbonyls reacting with a secondary amine

What is enamine?

If carbonyls have a leaving group, what does the mechanism look like?

• Nucleophile attacks the carbonyl C

• A tetrahedral intermediate forms

• The nucleophile substitutes the LG

Acyl chloride → Ester

Carboxylic acid → Ester

• Requires an acid catalyst since carboxylic acid is not very reactive on its own. This is because the carbonyl carbon in the COOH is not very electrophilic (the -OH donates electron density by resonance, making for a poor LG)

• The acid catalyst protonates the carbonyl O and increases the δ⁺ on the carbonyl carbon, making it more electrophilic

• Now that the carbonyl carbon is activated:

  • The alcohol HO–R′ attacks the carbonyl carbon

  • Forms a tetrahedral intermediate

  You now have:

  • Two –OH groups

  • One –OR′ group

  • One of the oxygens is protonated

• 4. Proton transfer (key rearrangement step)

• At this stage:

  • There is a bad leaving group (–OH)

  • We need to convert it into a good leaving group

• So a proton transfer occurs:

  • A proton moves from one oxygen to another

  • Converts –OH into –OH₂⁺

• This step:

  • Does not change connectivity

  • Just rearranges protons

  • Makes the next step possible

• 5. Loss of water (leaving group step)

  Now:

  • H₂O is a good leaving group

  • Water leaves

  • The tetrahedral intermediate collapses

  • C=O reforms

  This gives a protonated ester.

  6. Deprotonation (regeneration of catalyst)

  Finally:

  • A base (often water or alcohol) removes the proton

  • Neutral ester is formed

  • Acid catalyst is regenerated

Acyl chloride → Amide

Ester → Carboxylic acid + Alcohol

• Using Acid hydrolysis (H₂O)

Ester → Carboxylic acid + Alcohol

• Using Base/Alkaline hydrolysis (OH^-)

Amide → Carboxylic acid + Ammonium salt

• Using Acid hydrolysis

Amide → Carboxylate salt + Ammonia/amine

• Using Base/Alkaline hydrolysis (OH^-)