Alkyl Halides Preparation and Reactions ORGANIC CHEMISTRY- 1 Alkyl Halides Preparation and Reactions BY Dr. Ghulam Abbas Assistant Professor UNIVERSITY OF NIZWA

RX = Alkyl halide INTRODUCTION Alkyl halides, halogen-substituted alkanes are named systematically as Haloalkanes . They are also known as Organohalides, compounds that contain one or more halogen atoms. Alkyl halides are widespread in nature, and over 5000 organohalides have been found in algae and various other marine organisms. RX = Alkyl halide

Halogens increase in size going down the periodic table, so the lengths of carbon–halogen bonds increase accordingly. In addition, C -X bond strengths decrease going down the periodic table. Such as for CH3F bond length 139 pm and bond strength is 460 kJ/mol while CH3Br bond length is 178 pm and bond strength 294 kJ/mol.

Nomenclature

Alkyl Halides Alkyl halides are organic molecules containing a halogen atom bonded to an sp3 hybridized carbon atom. Alkyl halides are classified as primary (1°), secondary (2°), or tertiary (3°), depending on the number of carbons bonded to the carbon with the halogen atom. The halogen atom in halides is often denoted by the symbol “X”.

There are other types of organic halides There are other types of organic halides. These include vinyl halides, aryl halides, allylic halides and benzylic halides. Vinyl halides have a halogen atom (X) bonded to a C—C double bond (C=C-X). Aryl halides have a halogen atom bonded to a benzene ring. (Ar-X). Allylic halides have X bonded to the carbon atom adjacent to a C—C double bond. (C=C-C-X) Benzylic halides have X bonded to the carbon atom adjacent to a benzene ring (Ar-C-X).

Preparation 1. Halogenation

Preparation Reaction with HX HX is obtained from NaX + conc. H2SO4

Preparation From alcohol 3 3

Preparation From alcohol – cont. ROH + HX  RX + H2O ROH + SOCl2  RCl + SO2 + HCl Pyridine (as solvent) (This product is most easily purified)

Preparation Diazonium coupling From diazonium salt, you can make the following aryl halide:

Physical Properties It has a little higher boiling point than corresponding alkane of comparable molecular mass. This is due to the dipole-dipole attraction between the molecules as they are polar. CH3Cl, CH3Br and C2H5Cl are gases in room temperature while other members are liquids. Chlorobenzene is colourless liquid. All alkyl and aryl halides are insoluble in water due to the inability to form extensive H-bond with water molecules.

Chemical Properties Hydrolysis – cont. Side product : alkene (From dehydrohalogenation)

Chemical Properties Hydrolysis – For phenol – industrial process

Chemical Properties Formation of amine If RX is in excess, further reaction is expected since RNH2 is an even stronger nucleophile.

Chemical Properties Formation of amine (cont.) RX + RNH2  R2NH + HX RX + R2NH  R3N + HX RX + R3N  R4N+ X- Quarternary ammonium salt

Chemical Properties Formation of amine (cont.) Uunder normal condition aryl halide is very difficult to have nucleophilic substitution rx

Chemical Properties Formation of nitrile

Chemical Properties Formation of ether (Williamson’s synthesis) But not: (Why?) RX is usually 1ry alkyl halide should NOT be 2ry and 3ry. (Why?)

Chemical Properties Formation of ester RX + R’COO- Ag+  R’COOR + AgX Hydrolysis reaction (alcohol formation)

Chemical properties Formation of Grignard Reagent excess

Chemical properties Wurtz Reaction Wurtz – Fittig Reaction

Chemical properties Reaction with Grignard reagent alkane What kind of reaction is this ? How do you prepare :

Chemical Properties Reduction

Substitution Reaction The reaction in which one bond is broken and one bond is formed so that one group is substituted for another group. This is known as substantiation. Nucleophilic Substitution Reaction In which one nucleophile is substituted for another nucleophile Electrophilic Substitution Reaction In which one electrophile is substituted for another electrophile

Nucleophilic Substitution Reactions Nucleophilic Substitution (1896 by the German chemist Paul Walden) Halogen compounds are polar compounds. The electron deficient carbon attach to the halogen is susceptible to the attack of an electron rich species (nucleophile) and undergo nucleophilic substitution.

SN2 Reaction SN2 reaction: It represents nucleophilic, bimolecular reaction, (Bimolecular means that two molecules i.e. nucleophile and alkyl halide, take part in the step whose kinetics are measured.) Two species in the rate determine step When Nu─ attacks on a substrate the breaking of old bond and formation of a new bond takes place simultaneously and the reaction proceed through the formation of transition state. Transition state (T.S.) is a slow step and is called rate determing step.

The SN2 Reaction Methyl group is small Sterically accessible compounds react by this mechanism!! Methyl group is small Mechanism - Bimolecular Nucleophilic Substitution [SN2] - Transition state (trigonal bipyramidal)

Chemical Properties - Transition state

Chemical Properties Bimolecular: Molecularity refers to the number of species that are undergoing bond-making and / or bond-breaking process in the rate determining step. Rate = k [alkyl halide]1 [OH-]1 Second order reaction If concentration of any of the two species is doubled the rate of reaction will be doubled and if conc. of both the substrate and nucleophile is doubled the rate of reaction will increases four times.

SN2 Reaction: stereochemistry .. _ : 3 C B r H E t O ( S ) - e n a i o m .. H O C E t Br _ + 3 (R) enantiomer For an SN2 Reaction: Walden Inversion: Inversion of configuration S to R and R to S in SN2 reactions, observed by Paul Walden 1896. Inversion of configuration

SN2 Reaction: substrate structure Reactivity order---- fastest to slowest!

Inversion of configuration Predicting the Stereochemistry of a Nucleophilic Substitution Reaction (Stereo specific reaction) Inversion of configuration

The Substrate: Steric Effects in the SN2 Reaction Hindered and bulky substrate prevent easy approach of the nucleophile, making bond formation difficult. The transition state of a sterically hindered substrate, is higher in energy and forms more slowly than the corresponding transition state for a less hindered substrate.

The Nucleophile Any species, either neutral or negatively charged, can act as a nucleophile as long as it has an unshared pair of electrons; that is, as long as it is a Lewis base. Nucleophilicity” is usually taken as the affinity of a Lewis base for a carbon atom in the SN2 reaction and “basicity” is the affinity of a base for a proton. Thus a nucleophile attacks on carbon (C) while base attacks on proton (H+) in SN2 reactions.

leaving group Since the leaving group is expelled with a negative charge in most SN2 reactions, the best leaving groups are those that best stabilize the negative charge in the transition state. The greater the extent of charge stabilization by the leaving group, the lower the energy of the transition state and the more rapid the reaction.

In a reaction, the exact nucleophilicity of a species depends on the substrate, the solvent, and the reactant concentrations. • Nucleophilicity usually increases going down a column of the periodic table. Thus, H2S is more nucleophilic than H2O, and the halide reactivity order is I2> Br2> Cl2.

Down the periodic table, elements have their valence electrons less tightly held, and consequently more reactive. The nucleophilicity order can change depending on the solvent. • Negatively (─ve) charged nucleophiles are usually more reactive than neutral ones. As a result, SN2 reactions are often carried out under basic conditions rather than neutral or acidic conditions.

The SN1 Mechanism carbocation

SN1 properties Mechanism - Unimolecular Nucleophilic Substitution [SN1] Unimolecular because in rate determining step, only one molecule is involved. Rate = k [alkyl halide]1 [OH-]0 Rate = k [R-Br]1 Thus it follows first order (unimolecular) kinetics.

Chemical Properties intermediate

SN1 Reaction: stereochemistry With chiral R-X compounds, the product will be racemic (50% of each enantiomer). Racemization Racemization is the conversion of one enantiomer in a 50:50 mixture of the two enantiomers (+ and −, or R and S) of a substance. Racemization is normally associated with the loss of optical activity over a period of time since 50:50 mixtures of enantiomers are optically inactive.

SN1 Reaction Racemization

Chemical Properties Stability of carbonium ion:  SN1 SN2

Factors affecting choice of mechanism Structure of alkyl halide 3ry 2ry 1ry CH3 SN1 SN2 Use of 3ry alkyl halide favour SN1 since: Alkyl group is electron-donating which helps to stablilise the carbonium ion, thus lower the EA.

Factors affecting choice of mechanism Use of 3ry alkyl halide favour SN1 since: Alkyl groups hinder the approach of a nucleophile (OR steric crowding at T.S. would destabilise a bimolecular transition state, thus increase the EA.) is less stable than Not favour SN2 Favour SN2

Factors affecting choice of mechanism Solvent Highly polar (ionising) solvent favour SN1 (because forming ion in 1st step) Polar solvent: aqueous, THF Less polar solvent: alcoholic

Chemical Properties Factors affecting choice of mechanism Choice of nucleophile Strong nucleophile in high conc. favour SN2 while weak nucleophile in dilute solution favour SN1. Strong nucleophile Weak nucleophile OH- H2O NH2- NH3 CN- HCN RO- ROH Presence of Ag+ ion favour SN1

Summary of SN reaction - Unimolecular nucleophilic Substitution (SN1) Bimolecular nucleophilic Substitution (SN2) 2 steps: 1 step:

Summary of SN reaction - Unimolecular nucleophilic Substitution (SN1) Bimolecular nucleophilic Substitution (SN2) Rate = k [alkyl halide] Rate = k [alkyl halide] [Nu-] Carbonium ion formed as intermediate (stabilized by inductive effect) No intermediate carbonium ions but only transition states are involved. Usually occur with tertiary alkyl halide Usually occur with primary alkyl halide Energy profile: 2 peaks Energy profile: 1 peak

Summary of SN reaction - Unimolecular nucleophilic Substitution (SN1) Bimolecular nucleophilic Substitution (SN2) Because of the equal chance of attack from both sides of carbonium ions, a racemic mixture of enantiomers obtained, i.e. optically inactive. Configuration of the carbon centre attacked inverted (inversion of configuration). If the original alkyl halide is optically active, optically active product will be obtained. Rate of Rx: PhCH2X > RCH=CHCH2X > 3o > 2o > 1o Rate of Rx: 1o > 2o > 3o

Vinyl and Phenyl Compounds

Chemical Properties Effect of halogen: Since the electronagativity of halogen decreased down the group, C-Cl bond is more polar than the others. Hence, the carbon join to Cl is the most electron deficient, so the carbon in R-Cl in most susceptible to the attack of nucleophile. The bond strength is also important in determining the rate since bond strength decreased rapidly from C-Cl to C-I bond, the reaction rate decreases in the order : R – I > R – Br > R – Cl