Mcat Organic Chemistry Lecture 3

Front 1

Carbonyl

Back 1

C double bonded to an O

double bond is shorter and stronger than double bond of alkene

Include:
Aldehydes (nucleophilic addition), ketones (nucleophilic addition), carboxylic acids (nucleophilic substitution), amides (nucleophilic substitution) and esters (nucleophilic substitution)

1. planar stereochemistry
2. partial positive charge on C, partial negative charge on O

susceptible to nucleophilic attack because of planar stereochemistry

any attack on carbonyl will form a nucleophile because of partial positive charge on C

partial negative charge on O means it is easily protonated

Front 2

Aldehyde and Ketone

Back 2

more polar, higher boiling points than alkanes and alkenes of similar MW

lower boiling points than corresponding alcohols because cannot H-bond with each other

excellent solvents because can H-bond with other compounds

soluble in water with up to 4 C

act as substrate in nucleophilic addition or Bronsted-Lowry acid by donating one of its alpha-H

Front 3

alpha-C

Back 3

C attached to carbonyl C is in alpha position

Front 4

alpha-H

Back 4

H attached to alpha-C

donated by bronsted-lowry acid

forms an enolate ion (alpha-C anion) that is stabilized by resonance

Front 5

beta-C

Back 5

if a carbonyl as well as alpha-C (beta-dicarbonyl), then enol is more stable due to internal H-bonding and resonance

dicarbonyl increases acidity of alpha-H between carbonyls, making it more acidic than water and alcohol

Front 6

tautomers

Back 6

reaction at equilibrium and not resonance

involves proton shift, from alpha-C to carbonyl O

due to properties of alpha-H and carbonyl

aldehydes and ketones exist as tautomers at room temperature

Front 7

Acetals and ketals

Back 7

reaction between aldehydes or ketones with alcohols

form hemiacetals and hemiketals through nucleophilic addition (alcohol acting as nucleophile)

If another second molar concentration of alcohol is added, acetal and ketal are formed from hemiacetal and hemiketal

Front 8

Aldol condensation

Back 8

demonstrates alpha-H activity and susceptibility of carbonyl C to a nucleophile

occurs when:
1. an aldehyde reacts with another
2. a ketone reacts with another
3. an aldehyde reacts with a ketone

reaction is catalyzed by an acid or base

steps:
1. base abstracts alpha-H leaving an enolate ion
2. enolate ion acts as nucleophile and attacks carbonyl C to form alkoxide ion
3. alkoxide is stronger base than OH- ion, thus removes a H from H2O to complete aldol
4. aldol is unstable and easily dehydrated by heat or base to become an enal, which is stabilized by conjugated double bonds

Front 9

Halogenation of ketones

Back 9

Halogens add to ketones at alpha-C in presence of acid or base

base makes it difficult to prevent halogenation at more than 1 alpha positive

base is consumed by reaction with H2O as by-product

acid acts as true catalyst and is not consumed by reaction

Front 10

Haloform reaction

Back 10

if base is used with methyl ketone, alpha-C will become completely halogenated

trihalo product reacts with base to produce carboxylic acid and haloform

Front 11

haloform

Back 11

1. chloroform, CHCl3
2. bromoform, CHBr3
3. iodoform, CHI3

Front 12

Wittig Reaction

Back 12

converts ketone (or aldehyde) to alkene

phosphorous ylide is used (neutral molecule with negative charged carboanion)

1. ketone undergoes nucleophilic addition from ylide to form betaine
2. betaine is unstable and breaks down to triphenylphosphine oxide and alkene

mixture of cis and trans isomers are formed

Front 13

Carboxylic Acid

Back 13

behaves as acid or as substrate in nucleophilic substitution reaction

stereochemistry makes it susceptible to nucleophiles

OH group is protonated, forming to good leaving group water and substitution results

strong organic acids, conjugate base is stabilized by resonance

electron withdrawing groups on alpha-C help stabilize conjugate base and thus increases acidity of acid

know:
1. formic acid, methanoic acid
2. acetic acid, ethanoic acid
3. benzoic acid

salt of acids are named with suffix "ate" which replaced "ic"

Front 14

Physical properties of Carboxylic acids

Back 14

make strong double H-bonds to form dimers

dimer increases boiling point by doubling MW of molecules leaving liquid phase

melting point is lowered by double bonds of unsaturated carboxylic acids because impede crystal lattice
saturate carboxylic acids, more than 8 C, are solids

4C or less = water soluble
5C or more = less soluble in water
10C or more = insoluble in water

soluble in nonpolar solvents

Front 15

Decarboxylation

Back 15

when carboxylic acid loses CO2

exothermic, high activation energy

lower activation energy when beta-C is carbonyl because of anion stabilization by resonance or stable cyclic intermediate

final products are tautomers

Front 16

Acyl Chlorides

Back 16

derivatives of carboxylic acids contain acyl groups

RC=O

acyl chlorides form from reaction of inorganic acid chlorides (SOCl2, PCl3, PCl5) with carboxylic acids by nucleophilic substitution

bronsted-lowry acids, donate alpha-H

stronger acids than aldehydes

Front 17

Acid Chlorides

Back 17

most reactive of carboxylic acid derivatives because of stability of Cl- leaving group

love nucleophiles

carboxylic acid derivatives (acid chloride, ester, amide, anhydride) hydrolyze to form carboxylic acids

Front 18

Ester

Back 18

form from reaction of carboxylic acids with alcohols through nucleophilic substitution

strong acid catalyzes reaction by protonating OH of carboxylic acid

process called esterification

Front 19

transesterification

Back 19

alcohols react with esters

an alkoxy group (OR) is substituted for another

Front 20

Acetoacetic ester synthesis

Back 20

production of keton from acetoacetic ester due to strong acidic properties of alpha-H

acidity of alpha-H between carbonyls is increased in beta-dicarbonyl compounds

1. base removes alpha-H resulting in enolate ion
2. enolate ion is alkylated by alkyl halide or tosylate, forming alkylacetoacedic ester
3. alkylacetoacedic ester, a beta-keto ester, is decarboxylated by addition of acid, leaving a ketone

Front 21

amides

Back 21

formed when amine (nucleophile) substitutes at carbonyl of carboxylic acid or one of its derivatives

Front 22

reactivity of carboxylic acid derivatives

Back 22

most (weak base, good leaving group) to least (strong base, poor leaving group) reactive:
1. acyl chloride
2. acid anhydride
3. carboxylic acid
4. ester
5. amide

Front 23

Amines

Back 23

derivatives of ammonia (NH3)

primary amine: NH2R
secondary amine: NHR2
tertiary amine: NR3
quaternary amine: NR4+

nitrogen can take 3 (lone pair of electrons) or 4 bonds (positive charge)

ammonia and amines act as weak bases, donating lone pair electrons

electron withdrawing substituents decrease basicity of amines

electron donating substituents increase basicity of amines

bulky substituents decrease basicity

like to donate negative electrons to stabilize carbocation

Front 24

3 considerations with N-containing compounds

Back 24

1. act as lewis base, donating lone pair electrons
2. act as nucleophile, lone pair attacks positive charge
3. N can take on 4th bond (positive charge)

Front 25

Amine basicity

Back 25

highest to lowest, when functional groups are electron donating

1. secondary
2. primary
3. amonia

Front 26

aromatic amine

Back 26

amines attached to benzene ring

much weaker bases than amines nonaromatic amines because electron pair can delocalize around benzene ring

substituents that withdraw electrons from benzene ring will further weaken aromatic amine

Front 27

physical properties of amines

Back 27

H-bond which raises boiling point and increases solubility

optically inactive, both enantiomers exist

higher boiling point than water, but lower boiling point than alcohol

Front 28

imines and enamines

Back 28

form from reaction of amines with aldehydes and ketones losing water

imine and enamines exist as tautomers

Front 29

Condensation with Ketones

Back 29

1. amine acts a nucleophile, attacking electron deficient carbonyl C of ketone
2. ketone undergoes nucleophilic addition
3. acid catalyst protonates ketons to form unstable intermediate
4. intermediate loses water and proton to produce either enamine or imine

if original amine is secondary, has no proton to give, ketone loses alpha-H and results in enamine (2 substituents)

if original amine is primary, gives up H to form imine (1 substituent)

reaction inhibited with too much acid, because amine is protonated and become weak nucleophile

Front 30

Wolff-Kishner Reduction

Back 30

reduces ketone or aldehyde by removing O and replacing it with 2 H

1. hydrazine (nucleophile) attacks ketone in nucleophilic addition, to produce hydrozone
2. hot strong base deprotonates N and produces desired product with N gas and water as by-products

same thing can be accomplished by adding hot acid, however some ketones and aldehydes cannot survive hot acid

Front 31

Hofmann elimination

Back 31

E2 mechanism

elimination of quaternary ammonium hydroxide to form an alkene (least stable)

Front 32

Amine alkylation

Back 32

alkylation of an amine by alkylhalides

nucleophilic substitution

amine acts as nucleophile

can be made into quarternary ammonium salt by repeated alkylations

amine is a poor leaving group

quarternary ammonium salt is good leaving group

Front 33

diazotization of an amine

Back 33

formed from reaction of primary amines with nitrous acid

1. nitrous acid is protonated by strong acid to form nitrosonium ion
2. nitrosonium ion react with primary amine to form N-nitrosoammonium (unstable)
3. N-nitrosoammonium deprotonates to form N-nitrosoamine
4. N-nitrosoamine tautomerizes to diazenol
5. diazenol, in presence of acid, dehydrates to diazonium ion

diazonium ion can be replaced by a variety of other groups

Front 34

Amides

Back 34

weak acid or base

less basic than amines, due to electron withdrawing properties of carbonyl

amines are hydrolyzed by strong acids or bases

amides with H attached to N are able to H-bond with each other

no substituents on N = primary amides

most stable of carboxylic acid derivatives

Front 35

Lactams

Back 35

cyclic amides

highly reactive due to ring strain

nucleophiles easily react with lactams

Front 36

Hofmann degradation (rearrangement)

Back 36

primary amides react with strong basic solution of chlorine or bromine to form primary amines with CO2 as a by-product

1. amine is deprotonated by strong base
2. deprotonated amine picks up halogen atom, leaving a halide ion and producing N-haloamide
3. N-haloamide is deprotonated
4. rearrangement occurs: R gourp of amine migrates to N to form isocyanate
5. isocyanate reacts with H2O to form carbamic acid
6. carbamic acid decarboxylates, giving off CO2 and leaving amine

can produce amines with a primary, secondary, or tertiary alkyl position

Front 37

Phosphoric acids

Back 37

when heated, form phosphoric anhydrides

react with alcohols to form esters