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ADVANCED ORGANIC CHEMISTRY-I (MPC 102T) UNIT-III: Synthetic Reagents
& Applications
Presentation · May 2018
DOI: 10.13140/RG.2.2.17758.95040
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ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)
UNIT- III: Synthetic Reagents & Applications
 Aluminium isopropoxide
- It is the chemical compound usually described with the formula Al(O-i-Pr)3, where i-Pr is the isopropyl group
[–CH(CH3)2].
 Description:
IUPAC name: Aluminium Isopropoxide
Other names: Triisopropoxyaluminium; Aluminium isopropanolate; Aluminium
sec-propanolate; Aluminium triisopropoxide
Chemical formula: C9H21AlO3
Molar mass: 204.25 g/mol
Appearance: white solid; Melting point: 138–1420C; Density: 1.035 g/cm3(solid)
Decomposes in water
Solubility
Insoluble in isopropanol
Soluble in benzene
 Preparation:
- This compound is commercially available. Industrially, it is prepared by the reaction between isopropyl alcohol
and aluminium metal, or aluminium trichloride:
2Al + 6iPrOH → 2Al(O-i-Pr)3 + 3H2
AlCl3 + 3iPrOH → Al(O-i-Pr)3 + 3HCl
 Applications:
1. Meerwein-Ponndorf-Verley Reduction: In a MPV reduction, ketones and aldehydes are reduced to alcohols
concomitant with the formation of acetone.
2. Reductions with Chiral Aluminum Alkoxides: The reduction of cyclohexyl methyl ketone with catalytic
amounts of Aluminium Isopropoxide and excess chiral alcohol gives (S)-1-cyclohexylethanol
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
Page | 1
ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)
UNIT- III: Synthetic Reagents & Applications
3. Diastereoselective Reductions of Chiral Acetals: Reduction of 4-t-butylcyclohexanone with aluminum
isopropoxide in dichloromethane.
4. Oppenauer Oxidation: Cholestenone is prepared by oxidation of cholesterol in toluene solution with
aluminum isopropoxide as catalyst and cyclohexanone as hydrogen acceptor
5. Hydrolysis of Oximes: Oximes can be converted into parent carbonyl compounds by aluminum isopropoxide
followed by acid hydrolysis. Yields are generally high in the case of ketones, but are lower for regeneration of
aldehydes.
6. Regio- and Chemoselective Ring Opening of Epoxides: Functionalized epoxides are regioselectively
opened using trimethylsilyl azide/aluminum isopropoxide, giving 2-trimethylsiloxy azides by attack on the less
substituted carbon.
7. Preparation of Ethers. Ethers (R-O-R) are prepared from aluminum alkoxides, Al(OR)3, and alkyl halides, R-X.
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
Page | 2
ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)
UNIT- III: Synthetic Reagents & Applications
 Diazomethane
- Diazomethane is the chemical compound CH2N2, discovered by German chemist Sir. Hans von Pechmann in
1894.
- Diazomethane is a yellow, poisonous, potentially explosive compound, which is a gas at room temperature. The
structure of diazomethane is explained using three resonance forms.
 Description:
R-N=N=N (azide),
Related functional groups compounds
R-N=N-R (azo)
IUPAC name: Diazomethane
Other names: Azimethylene, Azomethylene, Diazirine
Chemical formula: CH2N2
Molar mass: 42.04 g/mol
Appearance: Yellow gas
Density: 1.4 (air=1)
Boiling point: - 23 C (−9 F; 250 K)
Molecular shape: linear C=N=N
0
0
Odor: musty
Solubility: hydrolysis in water
Dipole moment: polar
 Preparation of Diazomethane
- Diazomethane is prepared by hydrolysis of an ethereal solution of an N methyl nitrosamide with aqueous base.
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
Page | 3
ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)
UNIT- III: Synthetic Reagents & Applications
 Diazomethane has two common uses.
1. Conversion of carboxylic acids to methyl esters
2. Conversion of alkenes to cyclopropanes
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
Page | 4
ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)
UNIT- III: Synthetic Reagents & Applications
 Osmium tetroxide
- Osmium tetroxide [also osmium (VIII) oxide] is the chemical compound with the formula OsO4.
 Description:
IUPAC name: Osmium tetraoxide
Other names: Tetraoxoosmium; Osmium(VIII) oxide
Chemical formula: OsO4
Molar mass: 254.23 g/mol
Appearance: white volatile solid; Melting point: 40.250C; Density: 4.9 g/cm3
5.70 g/100 mL (100C) and 6.23 g/100 mL (250C) in water
Solubility
375 g/100 mL (CCl4) soluble in most organic solvents, ammonium
hydroxide, phosphorus oxychloride
 Preparation of Osmium tetroxide:
- OsO4 is formed slowly when osmium powder reacts with O2 at ambient temperature. Reaction of bulk solid
requires heating to 4000 C.
 Applications of Osmium tetroxide:
1. Hydroxylation of Alkenes
-
Alkenes add to OsO4 to give diolate species that hydrolyze to cis-diols. The net process is called
dihydroxylation.
2. Coordination chemistry
-
OsO4 is a Lewis acid and a mild oxidant. It reacts with alkaline aqueous solution to give the perosmate anion
OsO4(OH)22−. This species is easily reduced to osmate anion, OsO2(OH)44−.
With tert-BuNH2, the imido derivative is produced: OsO4 + Me3CNH2 → OsO3(NCMe3) + H2O
Similarly, with NH3 one obtains the nitrido complex: OsO4 + NH3 + KOH → K[Os(N)O3] + 2H2O
3. Biological staining
-
OsO4 is a widely used staining agent used in transmission electron microscopy (TEM) to provide contrast to
the image.
4. Polymer staining
5. Osmium ore refining
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
Page | 5
ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)
UNIT- III: Synthetic Reagents & Applications
 Triphenylphosphine
- Triphenylphosphine is a common organophosphorus compound with the formula [P(C6H5)3] often abbreviated
to PPh3 or Ph3P. It is widely used in the synthesis of organic and organometallic compounds.
 Description:
IUPAC name: Triphenylphosphane
Chemical formula: C18H15P; Molar mass: 262.29 g/mol
Appearance: white solid; Melting point: 800C; Density: 1.1 g/cm3
Solubility: Insoluble in water; Soluble in organic solvent
Dipole moment: 1.4 - 1.44 D; Molecular shape: Pyramidal
 Preparation of Triphenylphosphine:
- Triphenylphosphine is a relatively inexpensive substance. It can be prepared in the laboratory by treatment of
phosphorus trichloride with phenylmagnesium bromide or phenyllithium.
- The industrial synthesis involves the reaction between phosphorus trichloride, chlorobenzene, and sodium.
PCl3 + 3PhCl + 6Na → PPh3 + 6NaCl
 Applications of Osmium tetroxide:
1. Reagent in Mitsunobu reactions: In this reaction, a mixture of PPh3 and diisopropyl azodicarboxylate
("DIAD", or its diethyl analogue, 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.
2. Reagent in Appel reactions: 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
3. Reagent in Staudinger reactions: The Staudinger reaction is a chemical reaction of an azide with a
phosphine or phosphite produces an iminophosphorane.
R3P + R'N3 → R3P=NR' + N2
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
Page | 6
ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)
UNIT- III: Synthetic Reagents & Applications
 N-Bromosuccinimide
- N-Bromosuccinimide (NBS) is a chemical reagent used in radical substitution and electrophilic addition
reactions in organic chemistry. NBS can be a convenient source of the bromine radical (Br•).
 Description:
IUPAC name: 1-Bromo-2,5-pyrrolidinedione; Other names: N-bromosuccinimide (NBS)
Chemical formula: C4H4BrNO2; Molar mass: 177.99 g/mol
Appearance: white solid; Melting point: 175 to 1780C; Density: 2.098 g/cm3
Solubility: 14.7 g/L (250C) in water; insoluble in CCl4
 Preparation of N-Bromosuccinimide:
NBS is commercially available. It can also be synthesized in the laboratory. To do so, sodium hydroxide and bromine
are added to an ice water solution of succinimide. The NBS product precipitates and can be collected by filtration.
 Applications of N-Bromosuccinimide:
1. Addition to alkenes: NBS will react with alkenes in aqueous solvents to give bromohydrins
2. Allylic and benzylic bromination: Standard conditions for using NBS in allylic and/or benzylic
bromination involves refluxing a solution of NBS in anhydrous CCl4 with a radical initiator—usually
azobisisobutyronitrile (AIBN) or benzoyl peroxide, irradiation, or both to effect radical initiation. The allylic
and benzylic radical intermediates formed during this reaction are more stable than other carbon radicals and
the major products are allylic and benzylic bromides. This is also called the Wohl–Ziegler reaction.
3. Bromination of carbonyl derivatives: NBS can α-brominate carbonyl derivatives via either a radical
pathway (as above) or via acid-catalysis
4. Hofmann rearrangement: NBS, in the presence of a strong base, such as DBU, reacts with primary amides
to produce a carbamate via the Hofmann rearrangement.
5. Selective oxidation of alcohols: It is uncommon, but possible for NBS to oxidize alcohols. It was found
that one can selectively oxidize secondary alcohols in the presence of primary alcohols using NBS in aqueous
dimethoxyethane (DME).
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
Page | 7
ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)
UNIT- III: Synthetic Reagents & Applications
 Diazopropane
 Description:
IUPAC name: 2-Diazopropane; Chemical formula: C3H6N2 ; Molar mass: 70.11g/mol
Physical Data: The reagent is a gas at room temperature.
Solubility: The reagent is most commonly prepared and used as a solution in ether.
 Preparation:
 Applications Diazopropane:
- Cyclopropanation of Alkenes: 2-Diazopropane is most commonly used to prepare gem-dimethylcyclopropyl
derivatives
- Cyclopropenation of Alkynes: Alkynes can be converted to the corresponding cyclopropene via the pyrazole
with 2-diazopropane.
- Insertion into Vinylic C-H Bonds: A common side reaction which occurs during attempted cyclopropanation of
alkenes with Diazopropane is an overall insertion into a C-H bond of the alkene. This reaction is favoured by
thermal extrusion of N2 and, for this reason, photolysis is the preferred method of decomposing pyrazolines to
cyclopropanes.
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
Page | 8
ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)
UNIT- III: Synthetic Reagents & Applications
 Diethyl azodicarboxylate
- Diethyl azodicarboxylate, conventionally abbreviated as DEAD and sometimes as DEADCAT, is an organic
compound with the structural formula CH3CH2O2CN=NCO2CH2CH3.
- Its molecular structure consists of a central azo functional group, RN=NR, flanked by two ethyl ester groups. This
orange-red liquid is a valuable reagent but also quite dangerous and explodes upon heating.
 Description:
IUPAC name: Diethyl diazenedicarboxylate;
Other names: Diethyl azidoformate, Diazenedicarboxylic acid
Chemical formula: C6H10N2O4 ; Molar mass: 174.16 g/mol
Appearance: Orange to red to orange liquid; Density: 1.11 g/cm3
Boiling point: 104.50 C
 Preparation of Diethyl azodicarboxylate:
- Diethyl azodicarboxylate is often prepared through two-step synthesis starts from hydrazine, first by alkylation
with ethyl chloroformate, followed by treating the resulting diethyl hydrazodicarboxylate with chlorine,
concentrated nitric acid or red fuming nitric acid. The reaction is carried out in an ice bath, and the reagents are
added drop wise so that the temperature does not rise above 200 C.
 Application of Diethyl azodicarboxylate:
1. Mitsunobu reaction
- DEAD is an important reagent in the Mitsunobu reaction where it forms an adduct with phosphines (usually
triphenylphosphine) and assists the synthesis of esters, ethers, amines and thioethers of alcohols.
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
3. DEAD can be used for synthesis of heterocyclic compounds. Thus, pyrazoline derivatives convert by
condensation to α,β-unsaturated ketones:
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
Page | 9
ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)
UNIT- III: Synthetic Reagents & Applications
 Wittig reagent
- The Wittig reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl
phosphonium ylide (often called a Wittig reagent) to give an alkene and triphenylphosphine oxide.
Reaction Mechanism
 Application of Wittig reagents
1. Preparation of Phosphorus Ylides
- Wittig reagents are usually prepared from a phosphonium salt, which is in turn prepared by the quaternization of
triphenylphosphine with an alkyl halide. The alkylphosphonium salt is deprotonated with a strong base such as nbutyllithium: [Ph3P+CH2R]X− + C4H9Li → Ph3P=CHR + LiX + C4H10
2. Structure of the Ylide:
- The Wittig reagent may be described in the phosphorane form (the more familiar representation) or the ylide form.
- The ylide form is a significant contributor, and the carbon atom is nucleophilic.
- The ylid is prepared via a two-step process: An SN2 reaction between triphenyl phosphine and an alkyl halide
followed by treatment with a strong base such as an organolithium reagent.
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
Page | 10
ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)
UNIT- III: Synthetic Reagents & Applications
 Titanium Chloride
 Description:
Titanium tetrachloride
Titanium(III) chloride
Titanium(II) chloride
TiCl4
TiCl3
TiCl2
Molar mass
189.679 g/mol
154.225 g/mol
118.77 g/mol
Appearance
Colourless liquid
red-violet crystals hygroscopic
black hexagonal crystals
penetrating acid odor
penetrating acid odor
penetrating acid odor
Density
1.726 g/cm3
2.64 g/cm3
3.13 g/cm3
Melting point
- 24.10 C
4250C
1,0350 C
136.40 C
9600 C
1,5000 C
Very Soluble
Very Soluble
Very Soluble
Chemical formula
Odor
Boiling point
Solubility in water
Solubility
soluble in ethanol, HCl
soluble in acetone, acetonitrile
soluble in ethanol
Preparation of Titanium tetrachloride
2 FeTiO3 + 7 Cl2 + 6 C → 2 TiCl4 + 2 FeCl3 + 6 CO
Preparation of Titanium(III) chloride
2 TiCl4 + H2 → 2 HCl + 2 TiCl3
Preparation of Titanium(II) chloride
2 TiCl3 → TiCl2 + TiCl4
 Application of Titanium tetrachloride:
1. Production of titanium metal: The world's supply of titanium metal, about 250,000 tons per year, is made
from TiCl4. The conversion takes place by the reduction of the chloride with magnesium metal, and yields titanium
metal and magnesium chloride. This procedure is known as the Kroll process: 2 Mg + TiCl4 → 2 MgCl2 + Ti
(Liquid sodium has also been used instead of magnesium as the reducing agent, as in the Hunter process.)
2. Production of titanium dioxide: Around 90% of the TiCl4 production is used to make the pigment titanium
dioxide (TiO2). The conversion involves hydrolysis of TiCl4, a process that forms hydrogen chloride:
TiCl4(aq) + 2 H2O(l) <=> TiO2(s) + 4 HCl(aq)
In some cases, TiCl4 is oxidised directly with oxygen: TiCl4 + O2 → TiO2 + 2 Cl2
3. Reagent in organic synthesis: TiCl4 finds diverse use in organic synthesis, capitalizing on its Lewis acidity its
oxophilicity, and the electron-transfer properties of its reduced titanium halides. It is used in the Lewis acid
catalysed aldol addition.
4. Redox: Reduction of TiCl4 with aluminium results in one-electron reduction.
5. Complexes with simple ligands: TiCl4 is a Lewis acid as implicated by its tendency to hydrolyze.
 Application of Titanium(III) chloride:
1. TiCl3 is the main Ziegler-Natta catalyst, responsible for most industrial production of polypropylene. The catalytic
activities depend strongly on the polymorph and the method of preparation.
2. TiCl3 is also a reagent in organic synthesis, useful for reductive coupling reactions, often in the presence of added
reducing agents such as zinc. It reduces oximes to imines.
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
Page | 11
ADVANCED ORGANIC CHEMISTRY – I (MPC 102T)
UNIT- III: Synthetic Reagents & Applications
 Dicyclohexylcarbodiimide (DCC)
- N,N'-Dicyclohexylcarbodiimide (DCC) is a zero length coupling reagent. DCC has both biochemical and synthetic
applications.
 Description:
IUPAC name: N,N'-dicyclohexylcarbodiimide; Other names: DCC
Chemical formula: C13H22N2; Molar mass: 206.33 g/mol
Appearance: white crystalline powder; Melting point: 340C; Density: 1.325 g/cm3
Solubility: insoluble in water; insoluble in CCl4
 Preparation:
- DCC has also been prepared from cyclohexyl amine and cyclohexyl isocyanide.
 Application of Dicyclohexylcarbodiimide:
- DCC is mainly used in amikacin, glutathione dehydrants, as well as in synthesis of acid anhydride, aldehyde,
ketone, isocyanate; when it is used as dehydrating condensing agent.
- DCC is a carbodimide used to couple amino acids during peptide synthesis.
- Dicyclohexylcarbodiimide is an imide. Amides/imides react with azo and diazo compounds to generate toxic
gases.
- N,N'-Dicyclohexylcarbodiimide (DCC) is a zero length coupling reagent. DCC has both biochemical and
synthetic applications. This reagent can be used to couple primary amines to carboxylic acid functional groups.
DCC is soluble in many organic solvents, while the DCU by product is generally insoluble and easily removed.
Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University
E-mail: logonchemistry@gmail.com; phytochemistry@rediffmail.com
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