Post on 06-Apr-2018
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 1/42
Muhammad Aswad
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 2/42
Introduction
• Carbonyl compounds are everywherein nature
•
The majority of biologically importantmolecules contain carbonyl groups
O
C
NH
OH
H3C
acetaminophen
HO
O
O
CH3
methyl salicylate
C
CH3
O
HO
acetic acid
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 3/42
Kinds of carbonylcompounds
• Many different kinds of carbonyl compounds• Depending on what groups are bounded to the
C=O unit• All contain an acyl bonded to another
residue – The R subtituent of the acyl group may be alkyl,
aryl, alkenyl, alkynyl – The other subtituent to witch the acyl fragment is
bonded may be a Carbon (C), hydrogen (H), Oxygen(O), Halogen (X), Nitrogen (N), Sulfur (S), or theother atom
• Classify into two general categories based onthe kinds of chemistry they undergo – Ketones and aldehydes –
Carboxylic acid and their derivatives
R C
O
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 4/42
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 5/42
Structure of the CarbonylGroup
C O
•Hybridization of the carbonyl carbon is sp2.•Geometry of the carbonyl carbon is trigonal planar
•Attack by nucleophiles will occur with equal easefrom either the top or the bottom of the carbonylgroup.•Hybridization of the oxygen is “nominally” sp2.
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 6/42
Prochiral
The carbonyl carbon is prochiral. That is, thecarbonyl carbon is not the center of chirality, but itbecomes chiral as the reaction proceeds.
C O
R
R'
:Nu
:Nu
C OH
Nu
RR'
C OH
Nu
RR'
These twoproducts areenantiomers.
In general, bothenantiomers areformed in equal
amount.
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 7/42
Ketone and Aldehyde
ketone
aldehyde
2.5
2.5
2.5
2.1
The –R’ and – H in these compoundscan’t act as a leaving groupIn subtitution reaction
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 8/42
Carboxylic acid and theirderivatives
Propionic acid (a carboxylic acid)
2.5
3.5
Methyl propionate (anester)
Propionyl chloride (an acid chloride) Propionamide (an amide)
The –OH, –OR’, –Cl, –NH2, and –OCOR’, in theseCompounds can act as leaving groups in subtitutioreaction
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 9/42
REACTIVITY OF THE C=O GROUPREACTIVITY OF THE C=O GROUP
NUCLEOPHILIC ADDITION
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 10/42
O
C
..:
δ+
δ - O
C
..:: -
+
THE CARBONYL GROUPTHE CARBONYL GROUP
electrophilicat carbon
nucleophilicat oxygen
Nu:
nucleophilesattack here
H+ or E+
electrophilesadd here
GENERALIZED CHEMISTRY
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 11/42
NUCLEOPHILIC ADDITION TO C=ONUCLEOPHILIC ADDITION TO C=O
MECHANISMS
IN ACID AND IN BASE
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 12/42
+ :Nuslow
::
.. : _
O
CC
O
Nu
:..
:
C
O
Nu
+ H2O
:..
C
O
Nu
Hfast
_
..
Nucleophilic Addition to CarbonylNucleophilic Addition to CarbonylBasic or Neutral SolutionBasic or Neutral Solution
analkoxideion
BASIC SOLUTIONGood nucleophilesand strong bases(usually charged)
-
or on adding acid
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 13/42
+:Nu
slow
:..
O
C
H
C
O
Nu
H+
O
C
H:O
C+ H
+fast
+
:..
..
Nucleophilic Addition to CarbonylNucleophilic Addition to Carbonyl
Acid CatalyzedAcid Catalyzed
Acid catalysis speeds the rate of addition of
weak nucleophiles andweak bases (usually uncharged).
more reactive toaddition than the un-protonated precursor
ACIDIC SOLUTION
(+)
pH 5-6stronger acidprotonates thenucleophile
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 14/42
Reaction of the Carbonyl Groupwith Acids
O
C+ H+
O
C
H
Typical behavior
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 15/42
Reaction of the Carbonyl Groupwith Bases
O
C
+
B:
C
O
B
Typical behavior
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 16/42
The carbocation intermediatehas resonance.
O
C
H
O
C
H
The positive charge character on carbon makes this anexcellent site for attack by Lewis bases (nucleophiles).
O h th
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 17/42
Once we have theintermediate, what happens to
it?Case 1: The Addition Product is Stable.
R C R
OH
Nu
The reaction stops here. This happens most oftenwhen the nucleophilic atom is carbon, oxygen, or
sulfur.
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 18/42
Case 2: Addition-Elimination
R C R
OH
Nu
H
C
Nu
R R
+ O
HH
The addition product is unstable with respect toloss of a molecule of water. This is observed mostoften when the nucleophilic atom is nitrogen orphosphorus.
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 19/42
Case 3: Loss of Leaving Group
R C X
O
Nu
R C
Nu
O
+ X
This process is observed when X is a potentialleaving group. In this case we have nucleophilicacyl substitution .
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 20/42
ORGANOMETALLICSORGANOMETALLICS
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 21/42
Reaction with OrganometallicCompounds
+. .
:
. .M g X+
R MgX R C
R
R
O _ H2Oe t h e r
O
CR R
R C OH
R
R
The products of this sequence are always alcohols.
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 22/42
Addition of OrganometallicReagents
+
(R-MgBr)
M
_ +
H2O
H+
R M
+ M(OH)x
: : : :
:
..
..
O
C
R R
R C R
O
R
R C R
OH
R
The products of the addition arealways alcohols.
Crude outline of the
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 23/42
Crude outline of themechanism of organometallic
addition"R:-"
(from R-MgX)
C O
R'
R
R C O
R
R'
H+
R
C
R'
OHR
R, R' = H, alkyl, or aryl
+slow
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 24/42
+
(R-MgBr)
M
_ +
H2O
H+
R M
O
C
R R
R C R
O
R
R C R
O
R
H
+ M(OH)x
: : : :
:
..
..
(R-Li)
Addition of Organometallic ReagentsAddition of Organometallic Reagents
ether
These reagents cannot
exist in acid solution
workupstep
alcohol
:R-
Synthesis of Alcohols
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 25/42
Whatever is attached to the carbonyl group will be
attached to the resulting alcohol carbon.
R M + C O
H
H
R C OH
H
H
formaldehyde primary alcohol
R M + C O
H
R
R C OH
R
H
secondary alcohol
R M + C O
R'
R
R C OH
R
R'
ketones tertiary alcohol
other aldehydes
(M = Li or MgX)
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 26/42
Example
CH3 CH2 C CH2 CH3
O
CH3MgI
ether CH3 CH2 C CH2 CH3
O
CH3
MgI
H2O, H+
CH3 CH2 C CH2 CH3
O
CH3
H
Organometallics react with ketones toyield tertiary alcohols.
Summary of Reactions ofSummary of Reactions of
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 27/42
Summary of Reactions of Summary of Reactions of
Organometallics with CarbonylOrganometallics with Carbonyl
CompoundsCompounds
• Organometallics with ketones yield
tertiary alcohols
• Organometallics with aldehydes yield
secondary alcohols
•Organometallics with formaldehyde yield
primary alcohols.
• Organometallics with carbon dioxide yield
carboxylic acids.
etc.
All reviewto you
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 28/42
HYDRATESHYDRATES
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 29/42
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 30/42
O HO
OH
HH
..
: :
+
+
..
ACID CATALYSISACID CATALYSIS
O H
+
..
:
:NuAcid catalysis enhances the reactivityof the carbonyl group - nucleophilicaddition proceeds more easily. weak nucleophiles
can react
RECALL
Water is a weak nucleophile.
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 31/42
O H
O HH
C
O
OHH
HO
C
O
OH
H
OH
H
H
O HH O
HH
H
....
..
..
.. ..
..
..
..
..
: : : :
:
+
+
+ a hydrate
WATER ADDS TO THE CARBONYL GROUP OFWATER ADDS TO THE CARBONYL GROUP OF
ALDEHYDES AND KETONES TO FORM HYDRATESALDEHYDES AND KETONES TO FORM HYDRATES
for most compounds the equilibrium
favors the starting materials
and you cannot isolate the hydrate
catalyzed by a
trace of acid
In a reaction where all steps arereversible, the steps in the reversereaction are the same as those in
the forward reaction, reversed!
MICROREVERSIBILITY:
..
+
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 32/42
O HO
OH
HH
..
: :
+
+
..
ACID CATALYSISACID CATALYSIS
O H
+
..
:
:NuAcid catalysis enhances the reactivityof the carbonyl group - nucleophilicaddition proceeds more easily. weak nucleophiles
can react
RECALL
Alcohols are weak nucleophiles.
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 33/42
R CR'
O
ROH R C
O
R'
O
H
R
R C
O
R'
O
H
R
ROH R C
O
R'
O
R
R
+
+ H O
H
+
Addition of AlcoholsAddition of Alcohols
addition of one mole
addition of second mole
hemiketal
an aketal
H+
H+
TWO MOLES OF ALCOHOL WILL ADD
The equilibria normally favor the aldehyde or ketone starting
material, but we will show how they can be made.
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 34/42
H2O
hydrate
hemiacetal acetal
R-O-H
H2O
R-O-H
ADDITION OF WATER AND ALCOHOLSADDITION OF WATER AND ALCOHOLS
WATER
ALCOHOLS
C
OOH OR RO OR
C
OOH OH
RO OR OROH+2
no reactionNaOH
H2O
H2O
H+ acetals arestable to basebut not toaqueous acid
Nucleophilic Acyl Subtitution
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 35/42
Nucleophilic Acyl SubtitutionReaction of Carboxylic Acid
and Derivatives
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 36/42
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 37/42
Alpha–Subtitution Reaction•
Subtitution of an α Hydrogen by an Electrophilic (E+
) andinvolves the formation of an intermediate enol or enolate ion
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 38/42
• Since they are negatively charged,enolate ions behave as nucleophilesand undergo many of reactions.
• For example, enolates react withprimary alkyl halides in the SN2
reaction
• The nucleophilic enolate iondisplaces halida ion and a new C–Cbond forms
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 39/42
• The SN2 alkylation reaction between and
enolate ion and alkyl halida is one of themost powerful method available formaking C—C bonds thereby building uplarger molecules for smaller precursors
Carbonyl Condensation
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 40/42
Carbonyl CondensationReactions
•
Take place when two carbonylcompounds react with each other
• For example, when acetaldehyde is
treated with base, two moleculescombine to yield the hydroxyaldehyde product known as aldol (aldehyde + alcohol)
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 41/42
8/2/2019 Synthesis of Drug -1
http://slidepdf.com/reader/full/synthesis-of-drug-1 42/42
References
1. Mc. Murry, J., 2000, OrganicChemistry , Fifth Edition, Brooks/Cole
2. Fessenden, R. J., Fessenden, J. S.,1986, Kimia Organik Jilid I dan II,
Terj. A. H. Pudjaatmaka, PenerbitErlangga