Aldehydes and Ketones

aldehyde

r group and hydrogen attached to carbonyl group

ketone

2 r groups attached to carbonyl group

formaldehyde

• simplest aldehyde

• used as a preservative

acetone

• simplest ketone

• used as solvent

aldehydes in nature

vanillin, cinnamaldehyde, carvone (spearmint), benzaldehyde (almond)

ketones in nature

progesterone, testosterone

aldehyde nomenclature

1) identify and name the parent chain, replace “e” with “al”

• parent chain must contain the carbonyl carbon, even if it seems like there is a longer parent chain

2) identify the name of the substituents (side groups)

3) assign a number to each substituent

• aldehydic carbon is assigned number 1

4) assemble name alphabetically

ketone nomenclature

1) identify and name parent chain, replace “e'“ with “one”

• parent chain must contain the carbonyl carbon, even if it seems like there is a longer parent chain

• carbonyl is given lowest possible number

2) identify the name of the substituents (side groups)

3) assign a number to each substituent

4) assemble name alphabetically

oxidation of secondary alcohols

bonds added to oxygen to get it ketone

• PCC or strong or mild oxidizing agents can be used because the resulting ketone does not undergo further oxidation

ketone preparation

oxidizing of secondary alcohols

oxidation of primary alcohols

• with strong oxidizing agent like sodium bicarbonate → carboxylic acid

• with mild oxidizing agent like PCC → aldehyde

nucleophilic addition reactions

• the carbonyl carbon is electrophilic due to resonance and inductive effects

• carbonyl carbon is attacked by nucleophiles, forming a new sigma bond in exchange for the carbon-oxygen double/pi bond

• becomes tetrahedral center

are aldehydes or ketones generally more reactive towards nucleophiles

aldehydes

steric effects

aldehydes are less sterically hindered than ketones because they have small hydrogen atom whereas ketones have two bulkier alkyl groups which restricts access to the electrophilic center

electronic effects

aldehyde has a larger partial positive charge on the carbonyl carbon and only one electron donating alkyl group wheres a ketone has two electron alkyl groups that stabilize the partial positive charge (donates electrons to the partial positive to make it less reactive)

nucleophilic addition under basic conditions

1) nucleophilic attack

2) proton transfer

nucleophilic attack

carbonyl group is attacked by nucleophile which breaks the pi bond and throws electron on oxygen to give it a negative charge, forming an anionic intermediate

proton transfer

anionic intermediate is protonated upon treatment with a mild proton source such as water and the proton breaks bond to generate hydroxide anion and an alcohol

general idea of nucleophilic addittion

nucleophile attacks and forms a negatively charged intermediate which is protonated upon acidic workup in organic chemistry

nucleophilic addition in physiological conditions

in the cell the pH is about 7.4 (slightly basic) and the blood buffer system will protonate

blood buffer system

carbonate and phosphate, acids and bases, proteins to keep blood pH at around 7

main nucleophiles

oxygen, nitrogen, hydrogen

oxygen nucleophiles

• water is added to carbonyl to form a hydrate

• under basic conditions, -OH is the nucleophile

base catalyzed hydration

1) nucleophilic attack (carbonyl attacked by hydroxide to form anionic intermediate)

2) proton transfer (anionic intermediate is protonated by water to form the hydrate)

acid catalyzed hydration

• carbonyl is protonated, the H₂O is the nucleophile

1) proton transfer (carbonyl is protonated, rendering it more electrophilic)

2) nucleophilic attack (protonated carbonyl group is attacked by water, forming an oxonium intermediate)

3) proton transfer (oxonium intermediate is deprotonated by water to form the hydrate)

alcohols attacking ketones/aldehydes

under catalytic acid conditions, 1 ketone/aldehyde reacts with 2 alcohols to form an acetal

• water comes from the ketone and good leaving groups are the conjugate base of a strong acid

what are good leaving groups

the conjugate base of a strong acid

acetal

• formed by acid catalyzed reaction of alcohols with ketones or aldehydes

• 2 alkoxy groups bonded to central carbon

alkoxy groups

alkyl group bonded to oxygen atom

oxygen nucleophiles acid catalyzed reaction of acetone to acetal

part 1:

1) proton transfer (carbonyl group is protonated, making it more electrophilic)

2) nucleophilic attack (alcohol attacks protonated carbonyl to generate oxonium intermediate)

3) proton transfer (oxonium intermediate is deprotonated to form a hemiacetal)

hemiacetal

part 2:

4) proton transfer (OH group is protonated converting it into a leaving group)

5) loss of a leaving group (water leaves to regnerate carbon-oxygen double bond)

6) nucleophilic attack (second molecule of alcohol attacks carbon-oxygen double bond to generate another oxonium intermediate)

7) proton transfer (oxonium intermediate is deprotonated generating an acetal)

hemiacetal

halfway to acetal

oxonium intermediate

• oxygen with +1 formal charge and three R groups

• electrophilic

polysaccharides

cellulose is a linear polysaccharide of D-glucose units joined by glycosidic bonds

cellulose

• important functional group in cell metabolism

• acetal in biology

• we cannot digest it unless we change steriochemistry on linkages to make it starch

when drawing mechanisms under acidic conditions, what do you start with

proton transfer

when drawing mechanisms under basic conditions what do you start with

nucleophilic attack

catalytic triad

three amino acids found in enzymes

• used in nucleophilic addition to carbonyls

• allows strong acids and bases to exist simultaneously in active site of an enzyme

how is acetal formation an equilibrium process

• for most simple aldehydes, the acetal is favored at the equilibrium

• for most ketones, the acetal is not favored at the equilibrium

what happens if a diol is used in oxygen nucleophiles

both equivalents of alcohol come from the same compound and cyclic acetal is formed

how is acetal formation reversible

adding water

when is hemiactel formed

as an intermediate in the conversion of a ketone/aldehyde to an acetal

why are hemiacetals difficult to isolate

it is unstable, very reactive, and quickly forms product

cyclic hemiacetals

• occurs when a compound contains both the carbonyl and hydroxy group

• can usually be isolated

• OH is 6 atoms away from carbonyl and spontaneously forms a cyclic ring

what does an aldehyde/ketone form when it reacts with a primary amine under acidic conditions

an imine

imine

compound with carbon-nitrogen double bond

process of an imine being formed

primary amine in the presence of a catalytic acid

• water is removed

• carbonyl is replaced with carbon-nitrogen double bond

imines in body

ARE BAD

nitrogen nucleophile reaction mechanism of carbonyl to imine

part 1:

1) nucleophilic attack (amine attacks the carbonyl group)

2) proton transfer (intermediate is protonated to remove the negative charge)

3) proton transfer (deprotonation gives a carbinolamine)

carbinolamine (halfway point)

part 2:

4) proton transfer (OH group is protonated, converting it into an excellent leaving group

5) loss of a leaving group (water leaves and carbon-nitrogen double bond is formed)

6) proton transfer (intermediate is deprotonated to generate an imine)

why is the protonation of the carbonyl not the first step of imine formation mechanism

the ammonium ion is not acidic enough to protonate a negatively charged oxygen, or an alcohol

what is a good leaving group

conjugate base of a strong acid

what is the correct pH for imine formation and why

• around 5 or it is too slow

• so having a pH of 7.4 in cells is good because we do not want this reaction to occur

• lower pH → all the amines are protonated, so none are available to attack the carbonyl

• higher pH → not enough acid to catalyze the reaction effectively

things to keep in mind for mechanisms

• under acidic conditions, reaction species should either be neutral or have a +1 formal charge, should not end up a negative charge

• in the active site of an enzyme, the catalytic triad allows acids and bases to exist simultaneously

hydrolysis

adding water to destroy something

hydrolysis of acetals

reverse of acetal formation

• hydrolyzed with aqueous acid to yield ketone or alcohol and two equivalents of alcohol

• acetals only react with water under acid conditions beca

hydrolysis of acetals mechanism (acetal to ketone)

part 1:

1) proton transfer (carbonyl group is protonated, rendering it more electrophilic)

2) loss of a leaving group (a molecule of alcohol (ROH) is ejected as a leaving group)

3) nucleophilic attack (water functions as a nucleophile and attacks the powerful electrophile)

4) proton transfer (water functions as a base and removes a proton, giving a hemiacetal)

hemiacetal (halfway point)

part 2:

5) proton transfer (hemiacetal is protonated, generating an excellent leaving group)

6) loss of a leaving group (molecule of ROH is ejected as a leaving group)

7) proton transfer (water functions as a base and removes a proton, giving a ketone)

hydrolysis of imines and enamines

reverse of their formation

enamines

• samething as imine, but has a double bond nearby reversed with water

• amine attached to alkene

alpha carbon

carbon closest to carbonyl

properties of alpha carbon-hydrogen bond

• weakly acidic

• dipole (partially negative oxygen, partially positive carbon)

enols

organic compound containing a hydroxyl group directly bonded to alkene carbon

when do ketones and aldehydes exist in equilibrium with an enol

in the presence of an acid or a base

tautomers

2 different isomers at equilibrium that are acid or base catalyzed

what are ketones and aldehydes to each other

enol tautomers of one another

what does the equilibrium generally favor in a ketone/aldehyde and enol reaction

the ketone/aldehyde

bicarbonate base

base that is a component of the blood buffer system

in blood is a ketone/aldehyde and enol reaction acid or base catalyzed

base

exception where enol is favored in the equilibrium

because the enol is stabilized by conjugation and intramolecular H-bonding it is more stable than a typical enol

aldehyde/ketone to enol mechanism under basic conditions

alpha carbon is deprotonated to form a resonance stabilized anion (enolate) and the anionic intermediate is protonated to give the enol

aldehyde/ketone to enol mechanism under acidic conditions

the carbonyl is protonated to form a resonance stabled cation, then the cationic intermediate is deprotonated to give the enol

is the alpha position in an enol nucleophilic

yes

alpha halogenation under acidic conditions

enol is the reactive intermediate

mechanism for alpha halogenation under acidic conditions

part 1: enol formation

1) proton transfer (carbonyl group is protonated to form a resonance stabilized cation)

2) proton transfer (cationic intermediate is deprotonated to give an enol)

part 2: halogenation

3) nucleophilic attack (enol functions as nucleophuile and attacks molecular bromine)

4) proton transfer (proton is removed)

alpha halogenation under basic conditions

enolate is the reactive intermediate

mechanism for alpha halogenation under basic conditions

1) deprotonation (of carbonyl)

2) nucleophilic attack

what typically occurs under basic conditions in alpha halogenation

poly-halogenation

what is poly halogenation

substitution of multiple hydrogen atoms with halogen atoms

in polyhalogenation what happens once the ketone is brominated

it forms an enolate and brominates again at an even faster rate

what are methyl ketones converted to under basic conditions

carboxylic acids using halogen and hydroxide

Haloform Reaction

methyl ketones getting converted to carboxylic acids using halogen and hydroxide under basic conditions

in alpha halogenation after all three alpha protons are replaced, what happens

the CBr₃ acts as a good leaving group and acyl substitution occurs

acyl substitution

nucleophile replaces leaving group attached to carbonyl carbon, converting one carboxylic into another

• tetrahedral intermediate

• resulting carboxylic acid is deprotonated under basic conditions that forces reaction to completion

aldol additions

when an aldehyde is treated with hydroxide (or alkoxide) an equilibrium forms where significant amounts of both enolate and aldehyde are present

what reaction occurs when an enolate attacks the aldehyde

an aldol addition reaction

aldol

aldehyde and alcohol

• OH on beta carbon

aldol addition equilibrium

aldehydes → aldol product is favored

ketones → aldol product is not favored

aldol addition mechanism under basic conditions

1) proton transfer (alpha carbon is deprotonated to form an enolate)

2) nucleophilic attack (enolate serves as a nucleophile and attacks an aldehyde)

3) proton transfer (resulting alkoxide ion is protonated to give the product)

aldol condensations

• loss of water

• occurs when an aldol addition is performed at elevated temps under acid or basic conditions

• a trans alpha-beta unsaturated carbonyl forms

aldol condensation mechanism

part 1: aldol addition

1) proton transfer (the alpha position is deprotonated to form an elonate)

2) nucleophilic attack (enolate serves as nucleophile and attacks an aldehyde)

3) proton transfer (the resulting alkoxide ion is protonated)

part 2: elimination of water

4) proton transfer (alpha carbon is deprotonated to form enolate)

5) loss of a leaving group (hydroxide is ejected to afford the product)