Alkyl Halides Preparation and Reactions ORGANIC CHEMISTRY- 1 Alkyl Halides Preparation and Reactions BY Dr. Sulaiman 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

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”.

Alkyl 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

Preparation 2- Reaction with HX HX is obtained from NaX + conc. H2SO4

Preparation 3- 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 4- 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 – For phenol – industrial process

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

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)

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 :

Electronegativity Electronegativity: the ability of an atom in a bond to pull on the electron. (Linus Pauling) When electrons are shared by two atoms a covalent bond is formed. When the atoms are the same they pull on the electrons equally. Example, H-H. When the atoms are different, the atoms pull on the electrons unevenly. Example, HCl

Electronegativities of Some Elements Element Pauling scale F 4.0 Cl 3.0 O 3.5 N 3.0 S 2.5 C 2.5 H 2.1 Na 0.9 Cs 0.7 Most electronegative element is F which is (EN 4.0). Least electronegative stable element is Cs (EN 0.7).

Up to down Electronegativity decreases Left to right Electronegativity increases

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.

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.

The SN1 Mechanism carbocation

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

Factors affecting choice of mechanism Structure of alkyl halide 3ry 2ry 1ry CH3 SN1 SN2 Use of 3ry alkyl halide favour SN1 since:

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

ALKYL HALIDES Predict SN1 and SN2 This is SN1 reaction because the substrate is secondary and benzylic, the nucleophile is weakly basic, and the solvent is protic. (b) This is SN2 reaction because the substrate is primary, the nucleophile is a reasonably good one, and the solvent is polar aprotic.

SNi Mechanism Aliphatic Nucleophilic substitution reaction leading to retention of configuration (Internal Nucleophilic substations). The displacement of -OH by Cl- using thionyl chloride. This substitution proceeds through SNi Mechanism, in which there is retention of configuration. The reaction follows Second order kinetic Rate α [R3C-OH] [SOCl2]

Neighboring group Participation (NGP) (Retention of configuration) In first step of the reaction the neighboring group acts as nucleophile pushing out the leaving group. In the 2nd step external nucleophile pushing out the neighboring group.

Neighboring group Participation (NGP) The first step is the conversion of the OH to the corresponding alkoxide. This ion (alkoxide) act as nucleophile. It attacks the carbon carrying chlorine from the back side. This is an internal SN2 reaction and result in the inversion of configuration. Second SN2 inversion results in retention of configuration. A classic example of NGP is the reaction of a sulfur or nitrogen mustard or (halide) with a nucleophile, the rate of reaction is much higher for the sulfur mustard and a nucleophile than it would be for a primary alkyl chloride without a heteroatom. Cl-CH2-CH2-S-CH2-CH2

Substitution and Elimination Two kinds of reactions can take place when a nucleophile /Lewis base reacts with an alkyl halide. The nucleophile can either substitute for the halide by reaction at carbon or can cause elimination of HX by reaction at a neighboring hydrogen. Elimination reactions are more complex than substitution reactions. Elimination reactions almost always give mixtures of alkene products, and we can usually predict which will be the major product.

Substitution and Elimination

Dehydrohalogenation Elimination That is, dehydrohalogenation reaction when alkyl halide is heated with a strong base using a relative non-polar solvent.

Elimination: Dehydrohalogenation (cont.)   Note that both base and nucleophile are electron rich species, hence both elimination and nucleophilic reaction would occur at the same time unless the reaction conditions are carefully chosen. Normally, elimination reaction occurs at high temperature, alcoholic medium (relatively non-polar) and the alkyl halide is highly branched (e.g. tertiary or secondary).

Elimination Reactions The reactions in which two groups or atoms are removed from molecule are called Elimination reaction. They result in the formation of unsaturated compounds. Elimination reactions involve the loss of elements from the starting material to form a new  bond in the product.

Classification The two leaving group’s may be removed from the two adjacent atom OR from the same carbon or On this bases elimination reaction are classified as, 1-2 OR β-Elimination The reaction in which both the groups are removed from two adjacent atoms is called β-elimination or 1-2 elimination reaction. This results in the formation of double bond. The general β-elimination reaction can be represented as

1-1 or α Elimination The reaction in which elimination of two groups occur from the same carbon. The carbon to which the leaving group is attached is called α carbon. As the elimination only occurs from α carbon. Therefore the reaction is called α elimination and a carbene is formed. carbene

E2 Mechanism In E2 Mechanism both the groups get deposit simultaneously. Thus the rate of the reaction depends on both the concentration of substrate and base.

ORIENTATION IN E2 MECHANISM There are some substrates on which more than one β carbon are available e.g. Let us consider the alkyl halide Here in this case two β carbon are available so if base induced elimination of this molecule is taken in to consideration then two kinds of olefin will be possible so in this case we consider elimination reaction to be in two modes.

Hoffman Elimination The elimination gives olefin carrying less number of alkyl groups. In this case the hydrogen is eliminated from that β carbon that carries maximum number of hydrogen atoms. Zaitsev Elimination (Zaitsev’s rule) The elimination gives olefin carrying greater number of alkyl group. In this case the hydrogen is eliminated from that β carbon that carries minimum number of hydrogen atoms.

(Zaitsev’s rule)

E1 Mechanism It is a two steps process in the first step the substrate ionizes to form carbonium ion by losing the leaving group. In the second step, the carbonium ion loses hydrogen from the β carbon to from the product.

THREE POSSIBAL REACTIONS II) III)

E1cB Mechanism We know that in E1 mechanism X leaves first and then hydrogen, In E2 mechanism X and H Leave simultaneously. There is a 3rd possibility that H leaving 1st and then X. This is called E1cB mechanism.

E1cB Mechanism Therefore in E1cB mechanism H leaves first leading to the formation of carbanion (─ ive charge). The carbanion loss X to form the end products. This reaction is therefore completed in two steps. This mechanism is called cabanion mechanism.