phr114l9 aldehyde ketone

Organic Pharmacy

Organic chemistry is based on structural theory which separate organic compounds in families.

ALDEHYDESKETONES

Organic PharmacyAldehyde/ketone characteristics:

Aldehydes general formula: RCHOKetones general formula: R1R2CO


Both compounds aldehydes and ketones contain a carbonyl group: C=O

Carbonyl compoundsThis group is largely involved in chemistry of aldehydes and ketones.Chemistry of both groups are closed but influenced by the difference in structure.


Aldehydes contain the carbonyl group an organic group and an hydrogen.Ketones contain the carbonyl and are substituted by two organic groups.

Difference regarding oxidation: easy on aldehydes, difficult on ketones

Nucleophilic addition: aldehydes are more reactive than ketones


C and O are bond by a sigma and a pi bond.Due to the difference in electronegativity, electrons are not equally shared:The C is holding a partial δ+ charge and O is holding a partial δ- charge.

OC

R

R'

δ+ δ-

Organic PharmacyAldehyde nomenclature:

Identify the longest continuous chain of carbons with the acyl or carbonyl carbon as part of the chain.

Number the carbon chain so that the carbonyl (acyl: R-CO~) carbon is always number 1.


Locate and identify alphabetically the branched groups by prefixing the carbon number it is attached to. If more than one of the same type of branched group is involved use prefixes di for 2, tri for three, etc.


After identifying the name, number and location of each branched group, use the alkane name corresponding to the number of carbons in the continuous chain

Drop the "e" and add the characteristic international ending for all aldehydes, "al"

Alkenals involving double bond will require that the double bond is located but the ending will still be "al" (al > ene)


If replacing the aldehyde group with a carboxyl (-COOH) group would yield a carboxylic acid with a trivial name, the aldehyde may be named by replacing the suffix -ic acid or -oic acid in this trivial name by -aldehyde. For example:

HCHO may be called formaldehyde. CH3CHO may be called acetaldehyde. C6H5CHO may be called benzaldehyde.


H C

H

OFormaldehyde

Methanal

CH3 C

H

OAcetaldehyde

Ethanal

C

H

OCH3CH2

PropionaldehydePropanal

CH3CH2CH2C O

H

n-butyraldehyde

Butanal

C O

H

benzaldehyde

CH3CH CHCH2CHC O

H

CH3

2-methyl-4-hexenal

CH3CH2CH2CH2C

H

O

pentanal

valeraldehyde


CH3 C

CH2

CH3

CH

ClCH3

CH C

CH3

O

H

3-chloro - 2,4,4

-trimethylhexanal

C O

H

CH3

CH2CH3

Br

5-bromo- 4

-ethyl -2-methyl benzaldehyde


The aldehyde group is also called the formyl or methanoyl group.

Organic PharmacyAldehyde other possible nomenclature:

Branched-chain aldehydes can be named as derived straight-chain aldehydes, point of attachment indicated by α, δ, γ, δ…The α-C being the C holding the CHO.

α-C corresponds to C2

C C C C CHOαβγδ

Organic PharmacyKetone nomenclature:

The simplest ketone: acetone CH3-CO-CH3

For most other ketones, we name the two groups related by the carbonyl and followed these names by ketone.

If the carbonyl is attached to a benzene, we can name it as phenone.


Identify the parent chain: longest chain containing the carbonyl.

Replace the –e of the corresponding alkane by –one

Indicate the position of the carbonyl and substituent by number and give the lower number to the C=O.


CH3 C

O

CH3

acetone, propanone

C

O

CH3CH3CH2

ethyl methyl ketone

butanone

CH3CH2CH2 C

O

CH3

methyl n-propyl ketone

2-pentanone

CH3CH2 C

O

CH2CH3

diethyl ketone

3-pentanone

C

O

benzophenone

C

O

CH3

acetophenone


Aldehyde or ketone takes priority over an –OH and -ene.A carbonyl as a substituent is an oxo group

H2C CH CH2 C

O

CH2 CH3

5-hexen- 3

-one

CH3 C CH2 C H

OO

3-oxobutanal

Organic PharmacyAldehyde/ketone physical properties:

Polar carbonyl groups makes aldehydes and ketones polar compounds.

Higher boiling points than non-polar compounds with comparable molecular weight.

No intermolecular bonding (H bonding) because the H is related to the C and not to the O: lower boiling points than comparable alcohols.


Lower aldehydes and ketones are appreciably soluble in water (H bonding between solutes and solvant). Maximum solubility is reached at 5C.

Aldehydes and ketones are soluble in usual organic solvents


Formaldehyde is a gas and is handled either as an aqueous solution (formalin), or as one of his solid polymer:paraformaldehyde (-CH2O-)n or trioxane (CH2O)3

CH2OCH2OCH2OCH2OCH2O

H2C

O

CH2

O O

CH2


Keto-enol tautomerism is catalyzed by either acid or base.The interconversion of the two forms involves the movement of a proton and the shifting of bonding electrons; hence, the isomerism qualifies as tautomerism

Organic PharmacyAldehyde/ketone natural occurrence:

Testosterone Vanillin

Cortisone

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Organic Pharmacy

ALDEHYDESKETONES

REACTIONS

Organic PharmacyAldehyde/ketone reactions:

NUCLEOPHILIC ADDITIONS: Nucleophilic addition on the C of the

carbonyl.C=O group provide a site for nucleophilic addition and increase the acidity of the hydrogen on the alpha carbon.

The oxygen is able to accommodate a negative charge.


Usually aldehydes are more reactive to nucleophilic addition than ketones due to both steric and electronic effects.

steric hindrance is less in aldehydes than in ketones; aldehydes (H and R), ketones (R and R’).

Electronically, aldehydes have one R to provide electrons to the partially positive C, ketones have two.


REVERSIBLE addition of:Water

Alcohol (hemiacetal/acetal formation)Ammonia derivativesHydrogen cyanide

IRREVERSIBLE addition of:Organometallic compoundsCannizaro reaction


REDUCTIONCatalytic reductionReduction by complex metal hydridesReduction to hydrocarbons: Clemmensen and Wolff-Kishner reduction

OXIDATIONAldehydes to carboxylic acidsTollen’s reagent for aldehydesHaloform reaction on methyl ketones

Organic PharmacyAldehyde/ketone reactions: addition of water

1. acid as a catalyzer2. formation of an oxygen cation (oxonium

ion) O+3. release of H+ and of the instable

product

Formation of hydrates which are not stable

Organic PharmacyAldehyde/ketone reactions: addition of alcohol

Acetal and hemiacetal formation.

Organic PharmacyAldehyde/ketone reactions: addition of alcohol

Organic PharmacyAldehyde/ketone reactions: addition of ammonia

derivatives

R2C=O + GNH2

GNH–(R2)C–O–H

R2C=NG + H2O

Aldehyde/ketone reactions: addition of ammonia derivatives (1º amines)

Organic Pharmacy

H2N-G could be:

H2N-OH: hydroxylamine oximeH2N-NH2: hydrazine hydrazoneH2N-NHC6H5: phenylhydrazine phenylhydrazoneH2N-NHCONH2: semicarbazide semicarbazone

Aldehyde/ketone reactions: addition of ammonia derivatives (1º amines)

Organic PharmacyAldehyde/ketone reactions: addition of ammonia

derivatives (1º amines)

Organic PharmacyAldehyde/ketone reactions: addition of cyanide

Cyanohydrine formation: addition of hydrogen cyanide HCN

RCH=O + H–C≡N RCH(OH)CN(cyanohydrin)

Organic PharmacyAldehyde/ketone reactions: addition of

organometallic compounds

Formaldehyde primary alcohol

Aldehyde secondary alcohol

Ketone tertiary alcohol

Organic PharmacyAldehyde/ketone reactions: addition of

organometallic compounds

Organic PharmacyAldehyde/ketone reactions: Cannizzaro reaction

Cannizzaro reaction: disproportionation of an aldehyde with no αH in carboxylic acid and alcohol under the influence of a base.


REDUCTION / OXIDATION:Reduction to alcohol by catalytic

hydrogenation or by using reducing agent (LiAlH4, NaBH4) and reduction to hydrocarbons by Clemmensen and Wolff-Kishner reduction.

Oxidation to acids by KMnO4, K2Cr2O7 and Tollen’s reagent for aldehydes and haloform reactions on methyl ketones.


REDUCTION TO ALCOHOLS:

C O C OH

H2 + Ni, Pt or Pd

LiAlH4 or NaBH4

then H+


REDUCTION TO HYDROCARBONS:Clemmensen reduction: amalgamated Zinc in acidic medium

Wolff-Kishner: hydrazine in basic medium


OXIDATION:Aldehydes:

Tollen’s reagentReaction of aldehydes with silver ion to release

acid and and free silver (silver mirror).


OXIDATION: ketones generally do not go easily further oxidation

Haloform reaction of methylketones:

R-CO-CH3 + X2 → RCOO− + CHX3 + 2OH- X2 + OH− → XO− + X− + H+ (X = Cl, Br, I)

R-CO-CH3 + 3 OX- → RCOO− + CHX3 + 2OH-

(1) R-CO-CH3 + 3 OX- → R-CO-CX3 + 3 OH−(2) R-CO-CX3 + OH− → RCOOH + −CX3 (3) RCOOH + −CX3 → RCOO− + CHX3

OH-


REACTION ON THE α-H OF THE α-C:

The carbonyl activate the carbon-hydrogen bond nearby.α hydrogens (H on the αC) can react with base or acid and give the enol form.The unusual acidity of α hydrogens can be explained by both the electron withdrawing ability of the carbonyl group and resonance in the anion that forms.



The anion formed by the loss of an α hydrogen can be stabilized by resonance to form the enol or enolate

(anion form).

keto enolateCarbanion: carbon wich gain e-



Haloform reaction (iodoform test for methyl ketone)Halogenation of ketones: substitution reactionAldol condensation : addition reaction

Organic PharmacyAldehyde/ketone reactions on the α-C: haloform

Haloform (trihalomethane) reaction of methylketones:

R-CO-CH3 + X2 → RCOO− + CHX3 + 2OH-

X2 + OH− → XO− + X− + H+ (X = Cl, Br, I)R-CO-CH3 + 3 OX- → RCOO− + CHX3 + 2OH-

(1) R-CO-CH3 + 3 OX- → R-CO-CX3 + 3 OH−

(2) R-CO-CX3 + OH− → RCOOH + −CX3

(3) RCOOH + −CX3 → RCOO− + CHX3

hypohalite

OH-

Organic PharmacyAldehyde/ketone reactions: halogenation of ketones

Acid or base catalyzed: formation of an α-haloketone.

C C

OH

X2

H+ or OH-C C

XO

+ HX

alpha haloketone


Electrophilic substitution of an alpha hydrogen by bromine (acid catalyzed, intermediate is enol).


Electrophilic substitution of an alpha hydrogen by bromine (base catalyzed, intermediate is enolate).

Organic PharmacyAldehyde/ketone reactions: ALDOL CONDENSATION

Reaction in which an enolate/enol reacts with a carbonyl compound to form a β-hydroxyketone or β-hydroxyaldehyde (Aldol product), followed by dehydration to give a conjugated enone (or alkenal).

Organic PharmacyAldehyde/ketone reactions: ALDOL CONDENSATION

http://en.wikipedia.org/wiki/Image:Typicalaldol2.gif

Organic PharmacyAldehyde/ketone reactions: aldol condensation

ALDOL REACTION:


ALDOL REACTION:

nucleophile


ALDOL REACTION:Addition of the enolate (or

enol=nucleophile) on the carbonyl (or protonated carbonyl).

Important reaction because it can be used to construct new C-C bonds.

Carbonyl compounds without alpha hydrogen can not form enolate/enol form, then they will not undergo aldol reaction.


ALDOL REACTION: the most simple with ethanal (acetaldehyde)


ALDOL REACTION:


CROSSED ALDOL REACTION:An aldol reaction between two different

carbonyl compounds is a crossed aldol reaction.


CONDENSATION ON ALDOL PRODUCTS:A condensation reaction is a reaction in which water or another small molecule (methanol) is formed by reaction between two organic moleculeFormation of a double bond between the alpha and beta carbon.

Organic Pharmacy

ALDEHYDES KETONES

PREPARATION

Organic PharmacyAldehydes preparation:

• Oxidation reactions:oxidation of primary alcohols: aliphatic

aldehydesoxidation of methylbenzene: aromatic

aldehydes

• Reduction reaction:Reduction of acid/acyl chlorides (aliphatic or aromatic)

Organic PharmacyKetones preparation:

• Aliphatic ketones:oxidation of secondary alcohols reaction between an acid/acyl chloride with an organocopper compounds

• Aromatic ketones: Ar-CO-R or Ar-CO-Arreaction between an acid/acyl chloride and an organocopper compoundsFriedel-Crafts acylation (no

rearrangement)


For both aldehydes and ketones preparation, an important material is the acid or acyl chlorid.

Obtained by reaction of an carboxylic acid RCOOH with SOCl2, PCl3 or PCl5.

R CO

Cl

Organic PharmacyAldehydes / ketones preparation:

Primary: RCH2-OH

Alcohol

oxidation

Aldehydes

Secondary: R-CH-OH

Ketones

R’

Organic PharmacyAldehydes / ketones preparation:

+ organocopper compounds

Aldehydes

Ketones

(Ar or R) Acyl chloride

Ketones

+ Ar-H (Friedel-Crafts acylation)

Reduction


Pyridinium chlorochromate PCC is a reddish orange solid reagent used to oxidize primary alcohols to aldehydes and secondary alcohols to ketones.

Organic PharmacyKetones preparation: Friedel-Crafts acylation

Organic Pharmacy

BACK-UP


R-CH2OH

R-COOH R-COCl

Ar-CH3

Ar-COOH Ar-COCl

R-CHO

Ar-CHO

alcohol

Acid/Acyl chlorid

Aromatic acid/acyl chlorid

oxidation

oxidation

reduction

reduction


Oxidation of primary alcohol:

1-butanol butanal (n-butyraldehyde)

Oxidation of aromatic compounds: methylbenzene

Ar-CH3

Pyridinium

chlorochromate

Ar-CHCl2

Ar-CHOAr-CH(OAc)2

Cl2, heat H2O

H2OCrO3

Acetic anhydre


R-CH-R’

RCOOH RCOCl

OHR-C-R’

OR2’-CuLi


Ar-H

Ar-Br Ar-Li Ar2-CuLi

Ar-COOH Ar-COCl

RCOCl / Ar’COCl, AlCl3

RCOCl / Ar’COCl

R2’-CuLi / Ar2CuLi

Ar-C-R’

O

Ar-C-Ar’

O

phr114l9 aldehyde ketone

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