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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

Lecturer Notes_Dr. Sumanta Mondal_M. Pharm (Pharmaceutical Chemistry) _GITAM University Page | 1 E-mail: [email protected]; [email protected]

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/cm

3(solid)

Solubility

Decomposes in water

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



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.



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:

Related functional groups compounds

R-N=N=N (azide),

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 Odor: musty

Density: 1.4 (air=1) Boiling point: - 230 C (−9

0 F; 250 K) Solubility: hydrolysis in water

Molecular shape: linear C=N=N Dipole moment: polar

Preparation of Diazomethane - Diazomethane is prepared by hydrolysis of an ethereal solution of an N methyl nitrosamide with aqueous base.



Diazomethane has two common uses.

1. Conversion of carboxylic acids to methyl esters

2. Conversion of alkenes to cyclopropanes



Osmium tetroxide - Osmium tetroxide [also osmium (VIII) oxide] is the chemical compound with the formula OsO4.

Description:

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

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/cm

3

Solubility

5.70 g/100 mL (100C) and 6.23 g/100 mL (25

0C) in water

375 g/100 mL (CCl4) soluble in most organic solvents, ammonium

hydroxide, phosphorus oxychloride



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:

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

IUPAC name: Triphenylphosphane

Chemical formula: C18H15P; Molar mass: 262.29 g/mol

Appearance: white solid; Melting point: 800C; Density: 1.1 g/cm

3

Solubility: Insoluble in water; Soluble in organic solvent

Dipole moment: 1.4 - 1.44 D; Molecular shape: Pyramidal



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:

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).

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/cm

3

Solubility: 14.7 g/L (250C) in water; insoluble in CCl4



Diazopropane Description:

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.

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.



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:

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:

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



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 n-

butyllithium: [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.



Titanium Chloride Description:

Titanium tetrachloride Titanium(III) chloride Titanium(II) chloride

Chemical formula 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

Odor penetrating acid odor penetrating acid odor penetrating acid odor

Density 1.726 g/cm3 2.64 g/cm

3 3.13 g/cm

3

Melting point - 24.10 C 425

0C 1,035

0 C

Boiling point 136.40 C 960

0 C 1,500

0 C

Solubility in water Very Soluble Very Soluble Very Soluble

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.



Dicyclohexylcarbodiimide (DCC) - N,N'-Dicyclohexylcarbodiimide (DCC) is a zero length coupling reagent. DCC has both biochemical and synthetic

applications.

Description:

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.

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/cm

3

Solubility: insoluble in water; insoluble in CCl4

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