MC-carbonyl Chemistry

the group,its nomenclature its properties,reacivity and its type of reactions

What is a carbonyl compund?

-Something that contains a carbonyl group c=o

eg . aldehydes,ketones,carboxylic acid,esters,

drug containing carbonyls - aspirin,paracetomol

note- all amino acids contain carbonyl group

What are some common names used to describe simple ketones and aldehydes?

-formaldehyde- 2 H

-butyraldehyde - 4 carbon

-benzaldehyde- benzene ring

-acetone- normal 3C

-acetophenone - benzene and 3 C

-benzophenone - 2 benzene rings

What are some common names used to describe carbonyl-containing substituent groups ?

• collectively known as acyl groups 

• formyl- 1 hydrogen and a chain 

• acetyl - no hydrogen and a chain 

• Benzoyl- benzene ring and a chain 

What are some properties of the carbonyl bond?

• in an aldehyde and ketone it is sp2 hybridized 

• The carbon-oxygen double bond consists of an π bond and a σ bond

  • Carbonyl bond in Ketone and aldehyde is polar allowing dipole moment ( the π bond isn’t fully moved so you have slight charges )

• as oxygen is more electronegative than carbon 

Why are aldehydes and ketone HBA but not HBD?

• they can’t donate a proton

• the C-H bond isn’t polarised as the carbon and hydrogen have similar ELECTRONEGATIVITIES - so only temporary induced dipole

• they are HBA as the 2 lone pairs on oxygen is available - this makes them soluble in water

Why are Aldehydes more reactive than ketones ?

In aldehydes 🇦:

• Less steric hindrance

• Only one alkyl chain which stabilizes the positive charge

• less stable as less alkyl groups lower electron releasing effect so = more reactive

In Ketone:

• More steric hindrance

• Two alkyl chains that stabilizes

the positive charge

• more R groups = more Electrons induced through sigma bonds = more stable

Why can carbonyl bonds do nucleophilic and electrophilic reactions ?

• Due to carbonyl bond polarisation, carbonyl group is involved in nucleophilic and electrophilic reactions

• the carbon has a delta + charge ( electrophilic carbon - electron poor) 

• the oxygen has 2 lone pairs and a delta - charge (nucleophilic oxygen - electron rich )

How does the carbonyl group do nucleophilic addition ?

• nucleophile attacks delat = centre ,

• breaking the π bond

• the tetrahedral intermediate - forms as a new bond is formed between the Nu - C

• this is called alkoxide ( eg methoxide etc)

How can carbonyl groups do electrophilic addition ?

• oxygen lone pair attacks electrophile

• the oygen now has a + charge = 3 bonds Formation of oxonium intermediate

• one of the double bonds break and carbon now has a + charge

Note - most addition involves both steps,the order in which these occurs depends on the nature of the reagent and reaction conditions ( The Ph )

What changes when nucleophilic addition happens in basic conditions?

In basic conditions, reaction completed by attack of nucleophile and then abstraction of proton

(electrophile) from solvent:

1. nucleophilic attack = a tetrahedral intermediate 

2. protonation to oxygen thi is called nucleophilic as the most significant change is formation of C-Nu 

What  changes when nucleophilic addition happens in acidic conditions ?

In acidic conditions, conjugate acid forms first – more reactive electrophile – and can react

with less nucleophilic reagent

• Electrophilic addition of a proton to oxygen happens first

1. protonation 

2. nucleophilic attack - tetrahedral intermediate 

3. abstraction of proton 

Example - normal conditions of nucleophilic addition

Why do we have nucleophilic substitution instead of addition ?

• if there is a leaving group = substitution not with methyls or hydrogens

1. nucleophile attack and forming a tetrahedral intermediate

2. loss of leaving group - and reformation of π bond

summary - addition of nucleophile,loss of leaving group

What makes a good leaving group ?

• lower pka of conjugate acid ( what is made if you add a proton to L group)= better leaving group 

• eg weak bases = good l groups 

• strong bases=poor l groups 

What are bad leaving groups ?

• hydrogen or alkyl ( like methyls,ethyls) are poor leaving groups 

• this is because the conjugate base for h2 = h- high pKa = 35

• for rH the conjugate base = R- high pKa = 50 

• so are therefore poor leaving groups 

Give an example of a leaving group ?

• Acyl Halides - really important

• carboxylic acid derivatives - have better leaving groups

• acyl halides - can form esters ,and form amides

What is a ⍶ , ϐ unsaturated carbonyl compound ?

• α-carbon is the carbon directly next to carbonyl

• β-carbon is the carbon next to α-carbon

• C=O and C=C are conjugated

why - the conjugated system is reactive for drug design

What are the properties of ⍺,β-Unsaturated Carbonyl Compounds?

The conjugation changes the electronic properties of the alkene

• In the conjugated system, alkenes are electrophiles

• The carbonyl pulls electron density away through resonance, making the alkene electron-poor and therefore electrophilic.

What is a conjugate addition mechanism ?

1. nucleophilic attack , the double bond breaks and the oxygen double bond breaks , so the oxygen has a negative charge

2. intermediate - enolate -a resonance-stabilized anion formed by removing a proton from the alpha-carbon (the carbon next to a carbonyl group) of an organic compound

3. then there is tautomerism - more stable form a type of structural isomerism where a molecule can exist in two or more interconvertible forms called tautomers, becaus ethe protons move

4. you then have a saturated compound

note- this is favoured at a higher temperature , which nucleophiles like thiols , amines , enolates , cyanide

Example - conjugate addition - hydrogen cyanide 

• Nucleophile attacks the β-carbon (position 1 → 4).

• Intermediate: Enolate → tautomerizes to saturated carbonyl.

watch a video :

What are some common carboxylic acid derivatives ?

What are key carboxylic acid derivatives and their reactivity ?

What are the key steps in esterification - in acidic conditions ?

1. protonation - lone pair attacks a proton ,it forms a bond with oh , oxygen now has a + ve charge because it is forming too many bonds

2. nucleophilic attack, lone pair on the oh on an alcohol attacks the carbon on carbonyl group , the double bond breaks to squash the positive charge on oxygen

3. a tetrahedral intermediate is formed , there is a + ve charge on the oxygen that has just attached to the carbon 

4. there is an equilibrium , the proton is lost to the solvent , then protonation of the oxygen atom from solvent , any oxygen atom can be protonated in the molecule 

5. the lone pair on the oh forms a double bond and the oh2 ( protonated oxygen that has a + ve charge ) leaves 

6. there is still a positive charge on the hydroxyl oxygen so that leaves

7.  you have your ester and H + 

ESTERIFICATION - general equation

Alcohol + Carboxylic acid —→ ester + water

Note - esters are more conveniently prepared with more reactive derivatives such as acyl chlorides or anhydrides

What is transesterification ?

A chemical reaction where an ester and an alcohol swap their alkyl groups, typically in the presence of a catalyst.

Describe what happens in acid- catalysed transesterification ?

1. protonation of the lone pair on the oxygen

2. nucleophilic attack of the etOH on the carbonyl,the oH double bond breaks

3. there is now a + ve charge on the oxygen , the hydrogen is then kicked off- by tautomerism

4. the bond breaks removing the + vely charged oxygen group , and a new bond is formed between the OH the carbon.- a double bond

5. there is now a + vely charged oxygen , with a hydrogen with a double bond

6. the hydrogen - proton leaves forming its ester

What is the mechanism for hydrolysis of esters - acid catalysed ?

1. protonation

2. nucleophilic attack by water , hydrogen is lost

3. the double bond reforms and the alcohol group is kicked out

4. there is a positive charge on double bonded hydroxyl groups , hydrogen leaves

5. the alcohol and proton is regenerated

What is the mechanism for the hydrolysis of esters under basic conditions ?

1. the hydroxyl group attacks the carbonyl , the double bond O breaks

2. the lone pair of electrons refirm the double bond , the single oxygen bond breaks

3. the - vely charged group now attack the hydrogen which then causes the bond to break

4. a carboxylate anion is formed and an alcohol

What is the mechanism for the synthesis of amides ?

Amides are more stable then esters 

1 .an amine  attacks the carbonyl on the acyl halide the double bond breaks 

2. a second amine attacks the hydrogen which then squashes the + ve charge

3. the oxygen then reforms its double bond , kicks out halide , and a salt is formed 

4. amide is formed and halide ion 

note- acid anhydrides can also be used for the synthesis of an amide 

Compare the hydrolysis of amides vs esters leaving groups ?

Amides are hydrolysed under basic or acidic conditions:

• The reaction is significantly slower compared to ester hydrolysis

• The leaving group in case of ester (-OR) is far better leaving group compared to amide (-NHR)

• -NHR is far stronger base (weaker leaving group ) compared to -OR

Note - amides are hard to hydrolyse

Leaving Conjugate Ac PKa group:

-OR ROH 15

-NHR NH2R 35

What is the conjugation in the hydrolysis of amides and esters ?

The lone pair in a p orbital on the N is conjugated with the π bond of the carbonyl

amides are more stubborn - it has a hard leaving group nh2

due to it being a poor leaving group as PKA = 35 , strong base

The NH2 is conjugated with the π bond of the carbonyl

What is the mechanism for the hydrolysis of amides - acidic conditions ?

What is the mechanism for the hydrolysis of amides under basic conditions ?