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Synthetic Reagents and their Applications
1. Triphenylphosphine Reagent
2. BOP Reagent
3. Diethyl Azodicarboxylate Reagent
Submitted to:- Presented by:-
Dr.M.Raghu Prasad sir K.PAKEERAIAH
M.pharm., Ph.D. I/II M.Pharmacy,
Professor, H.O.D Regd No: 218401.
Dept. of Pharmaceutical Chemistry
Shri Vishnu College of Pharmacy (Autonomous)
Affiliated to Andhra Univ., Visakhapatnam; Approved by AICTE and PCI, New Delhi, and recognised by APSCHE

TRIPHENYLPHOSPHINE
Structure of Triphenylphosphane
It is a common organophosphorus compound with the molecular formula P(C6H5 )3 - often
abbreviated to PPh3or Ph3P.
Used in the synthesis of organo metal compound.
Properties that guide its usage are its nucleophilicity and reducing character
P

PROPERTIES
PHYSICAL PROPERTIES:
Colorless crystals at room temperature.
Boiling pont:3770C.
Melting point: 800C.
Insoluble in water.
It dissolves in non-polar organic solvents such as benzene and diethyl ether.
CHEMICAL PROPERTIES:
It undergoes slow oxidation in presence of air to give triphenylphosphine oxide Ph3PO.
2 PPh3 + O2 → 2 OPPh3
This impurity can be removed by recrystallisation of PPh3 from either hot ethanol or hot
isopropanol.

PREPARATION
Triphenylphosphine is inexpensive substance.
It can be prepared in the laboratory by treatment of phosphorus trichloride with phenyl
magnesium bromide or phenyl lithium.
The industrial synthesis involves the reaction between phosphorus trichloride, chlorobenzene,
and sodium.
Phosphoroustrichloride Chlorobenzene Sodium Triphenylphosphane
ClP
Cl
Cl
Cl 3 6 Na P

SYNTHETIC APPLICATION OF TRIPHENYLPHOSPHINE
1) MITSUNOBU REACTION
In this reaction PPh3 and diisopropyl azodicarboxylate (DIAD), or diethyl azodicarboxylate
(DEAD) converts an alcohol and a carboxylic acid to an ester. The DIAD is reduced as it serves
as the hydrogen acceptor, and the PPh3 is oxidized to OPPh3.
C R2
R1
CHO
O
R3
P
CH
R2
O
C
R3
O
R1
OH
H
Triphenylphosphane
N
N
O
O
O
O
Diethyl AzodicarboxylateAlcohol Acid Ester

N
N
O
O
O
O PPh3
N
N
O
O
O
O
PPh3
OO
R
H
N
H
N
O
O
O
O
PPh3
OO
R
R O
H
N
H
H
N
O
O
O
O
OO R O
R
PPh3
OO
R
R
O PPh3

2) APPEL REACTION
In this reaction, PPh3 and CX4 (X = Cl, Br) are used to convert alcohols to alkyl halides,
forming OPPh3 as a byproduct.
PPh3 + CBr4 + RCH2OH → OPPh3 + RCH2Br + HCBr3
This reaction commences with nucleophilic attack of PPh3 on CBr4.
Ethanol 1,1,1,1-Tetra 1-Bromoethane 1,1,1-Tri Triphenylphosphine
-bromomethane -bromomethane -oxide
CH3HO
Br
Br
Br
Br
PPh3
CH2Br
Br
Br
Br P O

3) PREPARATION OF WITTIG REAGENT
The Wittig reagent is a popular synthetic reagent for the synthesis of alkene from ketones and
aldehydes. Triphenyl phosphine alkylidienes is known as the wittig reagent.
An example of witting reagent is triphenylphosphinemethylidine or methylidine phosphoranes.
It is prepared by:
P H3C I P CH3
I

Methyl-Triphenyl-Phosphonium Methylene-Triphenyl-Phosphane
P CH3 P CH2 BuH LiBuLi

BENZTRIAZOL-1-YLOXY) TRIS (DIMETHYLAMINO) PHOSPHONIUM
HEXAFLUORO-PHOSPHATE (BOP)
Structure of BOP reagent
commonly used in the synthesis of peptides.
Solubility:
Insoluble in H2O; soluble THF, CH2Cl2 , MeCN, acetone, DMF, NMP, DMSO.
HMPA
N
N
N
O P
N
N
N
CH3
CH3
CH2
CH3
CH3
H3C
PF6

P
N
N
NO
Cl
O
Cl
Phosgene gas
P
N
N
NCl CO2 Cl
NHN
N
HO
Hydroxybenzotriazole
P
N
N
NN
N
N
O Cl
P
N
N
NN
N
N
O PF6
KPF6
 Preparation:

APPLICATIONS
1.Peptide coupling
Peptide bond formation is a nucleophilic substitution reaction of an amino group (nucleophile)
and a carboxyl group via a tetrahedral intermediate.
BOP is a very efficient reagent which allows in situ formation of hydroxybenzotriazolyl esters.
MECHANISM OF COUPLING REACTION WITH BOP
A tertiary amine is required to generate the carboxylate anion of the amino acid, which then
attacks the phosphorus atom of BOP. The resulting intermediate A rearranges to form the
hydroxybenzotriazolyl ester B, which is then attacked by the amine component to form the
amide product D via the stabilized hydrogen-bonded intermediate C

2. Esterification
Treatment of N-protected amino acids with phenol, and BOP in the appropriate solvent (DCM,
MeCN, DMF) affords the corresponding phenyl esters.
H
N C
H
R
C
O
OHprot H
N C
H
R
C
O
OR1prot
R1OH
BOP

3. Lactam Cyclization.
Cyclization of b-amino acids to b-lactams is efficiently effected by treatment with
BOP .The present method appears to be limited to the formation of b-lactams from
Nonsubstituted b-amino acids (R1 = R2 = R3 = R5 = H, R4 = Me)
R2
R1
HO2C
R3
NHR5
R4
R2
R1
R3
R4
NHR5
BOP NEt
MeCN 80o
C,
,

Diethyl Azodicarboxylate
Structure of Diethyl Azodicarboxylate
Diethyl Azodicarboxylate conventionally abbreviated as DEAD is an organic
compound with the structural formula CH3CH2O2CN=NCO2CH2CH3.
The molecule contain central azo functional group “RN=NR” flanked by two
ethyl ester groups.
N
N
O
O
O
O

N
H
H
N
O
O
O
O
Na2 CO3
2 HCl
HNO3 or Cl2
N
N
O
O
O
O
O
O ClH2N NH2
Hydrazine Ethoxycarbonylchloride
Diethylhydrazodicarboxylate
Diehtylazodicarboxylate
Preparation:

Applications
1) MITSUNOBU REACTION
In this reaction PPh3 and diisopropyl azodicarboxylate (DIAD), or diethyl
azodicarboxylate (DEAD) converts an alcohol and a carboxylic acid to an ester.
The DIAD is reduced as it serves as the hydrogen acceptor, and the PPh3 is
oxidized to OPPh3.
C R2
R1
CHO
O
R3
P
CH
R2
O
C
R3
O
R1
OH
H
Triphenylphosphane
N
N
O
O
O
O
Diethyl AzodicarboxylateAlcohol Acid Ester

O
O
O
N
N
O
O
O
O O
O
O
N
C
HN
C
O O
Et Et
O O
2.Michael reaction
The azo group in DEAD is a Michael acceptor. In the presence of a copper(II) catalyst, DEAD
assists conversion of β-keto esters to the corresponding hydrazine derivatives

CH3
DEAD
CH3
N
CO
H2
CH3C NH
C OO O
H2
C CH3
1-Methyl-4-(3-phenyl-allyl)-benzene
 Another application is the use of DEAD as enophile in ene reactions.

REFERENCE:
1. https://en.wikipedia.org/wiki/Diethyl_azodicarboxylate; downloaded on 07/11/2018
2. Kauer, J. C. "Diethyl azodicarboxylate". Organic Syntheses.; Collective Volume, 4, p. 411
3. Reactions and Reagents; O.P. Agarwal: Page no: 847, 866.
4. Advanced Organic Chemistry; IVthedition; Jerry March; Page no: 913,917
5. https://en.wikipedia.org/wiki/BOP_reagent; downloaded on 28/11/2018
6. https://www.google.co.in/search?dcr=0&q=peptide+bo nd+characteristics
7. http://www.sciencedirect.com/science/article/pii/S0040 403900772571

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