Synthesis of Drug -1

8/2/2019 Synthesis of Drug -1

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Muhammad Aswad



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



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





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.



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.



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



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



REACTIVITY OF THE C=O GROUPREACTIVITY OF THE C=O GROUP

NUCLEOPHILIC ADDITION



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



NUCLEOPHILIC ADDITION TO C=ONUCLEOPHILIC ADDITION TO C=O

MECHANISMS

IN ACID AND IN BASE



+ :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



+: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



Reaction of the Carbonyl Groupwith Acids

O

C+ H+

O

C

H

Typical behavior



Reaction of the Carbonyl Groupwith Bases

O

C

+

B:

C

O

B

Typical behavior



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



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.



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.



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 .



ORGANOMETALLICSORGANOMETALLICS



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.



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



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



+

(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



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)



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



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



HYDRATESHYDRATES





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.



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:

..

+



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.



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.



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



Nucleophilic Acyl SubtitutionReaction of Carboxylic Acid

and Derivatives





Alpha–Subtitution Reaction•

Subtitution of an α Hydrogen by an Electrophilic (E+

) andinvolves the formation of an intermediate enol or enolate ion



• 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



• 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



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)





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

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Synthesis of Drug -1