Upload
nasif-abdur-razzaque
View
259
Download
2
Embed Size (px)
Citation preview
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
Organic PharmacyAldehyde/ketone characteristics:
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.
Organic PharmacyAldehyde/ketone characteristics:
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
Organic PharmacyAldehyde/ketone characteristics:
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.
Organic PharmacyAldehyde nomenclature:
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.
Organic PharmacyAldehyde nomenclature:
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)
Organic PharmacyAldehyde nomenclature:
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.
Organic PharmacyAldehyde nomenclature:
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
Organic PharmacyAldehyde nomenclature:
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
Organic PharmacyAldehyde nomenclature:
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.
Organic PharmacyKetone nomenclature:
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.
Organic PharmacyKetone nomenclature:
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
Organic PharmacyKetone nomenclature:
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.
Organic PharmacyAldehyde/ketone physical properties:
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
Organic PharmacyAldehyde/ketone physical properties:
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
Organic PharmacyAldehyde/ketone physical properties:
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
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.
Organic PharmacyAldehyde/ketone reactions:
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.
Organic PharmacyAldehyde/ketone reactions:
REVERSIBLE addition of:Water
Alcohol (hemiacetal/acetal formation)Ammonia derivativesHydrogen cyanide
IRREVERSIBLE addition of:Organometallic compoundsCannizaro reaction
Organic PharmacyAldehyde/ketone reactions:
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.
Organic PharmacyAldehyde/ketone reactions:
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.
Organic PharmacyAldehyde/ketone reactions:
REDUCTION TO ALCOHOLS:
C O C OH
H2 + Ni, Pt or Pd
LiAlH4 or NaBH4
then H+
Organic PharmacyAldehyde/ketone reactions:
REDUCTION TO HYDROCARBONS:Clemmensen reduction: amalgamated Zinc in acidic medium
Wolff-Kishner: hydrazine in basic medium
Organic PharmacyAldehyde/ketone reactions:
OXIDATION:Aldehydes:
Tollen’s reagentReaction of aldehydes with silver ion to release
acid and and free silver (silver mirror).
Organic PharmacyAldehyde/ketone reactions:
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-
Organic PharmacyAldehyde/ketone reactions:
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.
Organic PharmacyAldehyde/ketone reactions:
REACTION ON THE α-H OF THE α-C:
Organic PharmacyAldehyde/ketone reactions:
REACTION ON THE α-H OF THE α-C:
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-
Organic PharmacyAldehyde/ketone reactions:
REACTION ON THE α-H OF THE α-C:
Organic PharmacyAldehyde/ketone reactions:
REACTION ON THE α-H OF THE α-C:
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
Organic PharmacyAldehyde/ketone reactions: halogenation of ketones
Electrophilic substitution of an alpha hydrogen by bromine (acid catalyzed, intermediate is enol).
Organic PharmacyAldehyde/ketone reactions: halogenation of ketones
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
Organic PharmacyAldehyde/ketone reactions: aldol condensation
ALDOL REACTION:
Organic PharmacyAldehyde/ketone reactions: aldol condensation
ALDOL REACTION:
nucleophile
Organic PharmacyAldehyde/ketone reactions: aldol condensation
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.
Organic PharmacyAldehyde/ketone reactions: aldol condensation
ALDOL REACTION: the most simple with ethanal (acetaldehyde)
Organic PharmacyAldehyde/ketone reactions: aldol condensation
ALDOL REACTION:
Organic PharmacyAldehyde/ketone reactions: aldol condensation
ALDOL REACTION:
Organic PharmacyAldehyde/ketone reactions: aldol condensation
CROSSED ALDOL REACTION:An aldol reaction between two different
carbonyl compounds is a crossed aldol reaction.
Organic PharmacyAldehyde/ketone reactions: aldol condensation
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 PharmacyAldehyde/ketone reactions: aldol condensation
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)
Organic PharmacyAldehydes preparation:
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
Organic PharmacyAldehydes preparation:
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
Organic PharmacyAldehydes preparation:
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
Organic PharmacyAldehydes preparation:
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
Organic PharmacyKetones preparation:
R-CH-R’
RCOOH RCOCl
OHR-C-R’
OR2’-CuLi
Organic PharmacyKetones preparation:
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