Organic Reaction Mechanisms-III

Organic Reaction Mechanisms-III Nucleophilic substitution reaction (SN) : Replacement (displacement) of an atom or group by an other atom or group in a molecule is known as substitution reaction. If substitution reaction is brought about by a nucleophile then it is known as nucleophilic substitution reaction. Generally substitution takes place at sp 3 carbon. R– g + Nu– ⎯→ R–Nu + g– Types of nucleophilic substitution reaction : (I) SN1 (II) SN2 (III) SNi Section (A) : Unimolecular nucleophilic substitution reaction (SN1) (a) (b) (1) Nucleophilic substitution which involves two step process First step : Slow step which involves ionisation (to form carbocation) R– g ⎯→ R+ + g – Second step : Fast attack of nucleophile on carbocation results into product. R+ + Nu– ⎯→ R–Nu SN1 Reaction of Alkyl halide Mechanism : Ionisation of alkyl halide ⎯⎯⎯⎯⎯⎯⎯⎯ → Slow step (rds) Characteristics of SN1 reactions : 1. It is unimolecular, two step process. 2. Carbocation intermediate is formed, so rearrangement is possible in SN1 reaction. 3. It is first order reaction. 4. Kinetics of the reaction Rate  [Alkyl halide] Rate of SN1 reaction is independent of concentration and reactivity of nucleophile. 5. Energetics of the SN1 reaction : Intermediate + – TS-1 (R---X) + – TS-2 (R---Nu) Figure : Free energy diagram for the SN1 reaction. 6. Factors affecting the rate of SN1 reaction : (i) The structure of the substrate : The rds of the SN1 reaction is ionization step, a carbocation is formed in this step. This ionisation is strongly endothermic process, rate of S N1 reaction depends strongly on carbocation stability because carbocation is the intermediate of S N1 reaction which determines the energy of activation of the reaction. Reactivity of SN1  stability of carbocation. SN1 reactivity : 3° > 2° > 1° > CH3–X Organic Reaction Mechanisms-III (ii) Concentration and reactivity of the nucleophile : The rate of SN1 reaction is unaffected by the concentration and nature of the nucleophile. Weak and neutral nucleophile favours SN1 reaction. Mostly solvents (protic) itself functions as nucleophiles in SN1 reaction, so SN1 reaction is termed as solvolysis reaction. water → hydrolysis ; C2H5OH → ethanolysis CH3COOH → acetolysis ; NH3 → ammonolysis (iii) Effect of the solvent : (Ionising ability of the solvent) The use of a polar protic solvent will greatly increase the rate of ionisation of an alkyl halide in any S N1 reaction because it solvate cations and anions so effectively and stabilises the transition state leading to the intermediate carbocation and halide ion, thus the energy of activation is lower. R–X (Solvolysis) Solvated ions Table : Dielectric constants () and ionisation rate of t-Butylchloride in few common solvents Solvent Relative rate  H2O 80 8000 CH3OH 33 1000 C2H5OH 24 200 (CH3)2CO 21 1 CH3CO2H 6 – (iv) The nature of the leaving group : In the SN1 reaction the leaving group begins to acquire a negative charge as the transition state is reached` stabilisation of this developing negative charge at the leaving group stabilises the transition state and this lowers the free energy of activation and there by increases the rate of reaction. Leaving ability of halogen is F¯ < Cl¯ < Br¯ < I¯ 7. Stereochemistry of SN1 reactions : In the SN1 mechanism, the carbocation intermediate is sp 2 hybridized and planar, A nucleophile can attack on the carbocation from either face, if reactant is chiral then attack of nucleophile from both faces gives enantiomers as the product, which is called racemisation. Mechanism of racemisation (SN1)  Reagents for alkyl halide are : H2O , RCOOH , ROH & RSH Ex-1. H O+ acetone 2 ⎯⎯⎯⎯⎯⎯ → + HBr (3° alkyl halide hence no SN2 reaction) Organic Reaction Mechanisms-III CH OH/ Ag+ 3 ⎯⎯⎯⎯⎯→ Ex-2. (carbocation rearrangement) H O 2 ⎯⎯⎯ → Ex-3. + (Racemic product) AgNO3 (2) SN1 Reaction of Alcohols (i) Reaction with hydrogen halides A common method is to treat the alcohol with a hydrohalic acid, usually HI or HBr. These acids are used to convert alcohols into the corresponding alkyl halides. (i) In acidic solution, an alcohol is in equilibrium with its protonated form. Protonation converts the hydroxy group from a poor leaving group (OH)  into a good leaving group (H2O). If the alcohol is protonated all the usual substitution and elimination reactions are feasible, depending on the structure (1°, 2°, 3°) of the alcohol. (ii) Halides are anions of strong acids, so they are weak bases. Solutions of HBr and HI contain nucleophilic Br and I ions. (iii) Concentrated hydrobromic acid rapidly converts t-Butyl alcohol to t-Butyl bromide. The strong acid protonates the hydroxyl group, converting it into a good leaving group. The hindered tertiary carbon atom cannot undergo SN2 displacement, but it can ionise to a tertiary carbocation. Attack by bromide ion gives the alkyl bromide. The mechanism is similar to SN1 mechanism. (iv) 1-Butanol reacts with sodium bromide in concentrated sulfuric acid to give 1-Bromobutane by an SN2 displacement. CH3 (CH2 )2 − CH2 OH NaBr, H2SO4 ⎯⎯⎯⎯⎯⎯⎯⎯ → 1 − bu tanol CH3 (CH2 )2 − CH2Br 1 − bromobutane (90%) Protonation converts the hydroxy group to a good leaving group, but ionization to a primary carbocation is unfavourable. The protonated unbranched primary alcohol is well suited for the S N2 displacement. (v) Secondary alcohols also react with HBr to form alkyl bromides usually by the SN1 mechanism. HBr ⎯⎯⎯ → e.g. (vi) HCl (Hydrochloric acid) reacts with alcohols in much the same way that as the hydrobromic acid. (vii) Chloride ion is a weaker nucleophlile than bromide ion because it is smaller and less polarizable. Lewis acid, such as ZnCl2, is sometimes necessary to promote the reaction of HCl with primary and secondary alcohols.  Mechanism : R–OH Reactivity of HX : Reactivity of ROH :  RDS R − OH2 ⎯⎯⎯→ R −H2O HI > HBr > HCl 3° > 2° > 1° R–X Organic Reaction Mechanisms-III e.g. e.g. CH3 CHCH3 | OH Isopropyl alcohol CH3CHCH3 | Br Isopropyl bromide CH3 | CH3 − C − CH2 – OH | CH3 CH3 | CH3 − C − CH2 – CH3 | Br Lucas Reagent (i) A mixture of concentrated hydrochloric acid and anhydrous zinc chloride is called the Lucas reagent. (ii) Whether an alcohol is primary, secondary or tertiary is identified by the Lucas test, which is based upon the difference in reactivity of the three classes of alcohol towards hydrogen halides. (iii) Alcohol (of not more than six carbons in their molecule) are soluble in the Lucas reagent. The corresponding alkyl chlorides are insoluble. (iv) Formation of a chloride from an alcohol is indicated by the cloudiness that appears when the chloride separates from the solution hence, the time required for cloudiness to appear is a measure of the reactivity of the alcohol. (v) A tertiary alcohol reacts immediately with the Lucas reagent, a secondary alcohol reacts within five minutes and a primary alcohol does not react appreciably at room temperature. e.g. CH3 − CH2 − CH − CH2 − CH3 | OH anhy. ZnCl2 /HCl ⎯⎯⎯⎯⎯⎯⎯⎯⎯ → CH3 − CH2 − CH − CH2 − CH3 | Cl 3 − Chloropentane Section (B) : Bimolecular nucleophilic substitution reaction (SN2) Nucleophilic substitution in which incoming group replaces leaving group in one step only. (1) SN2 Reaction of Alkyl halide : Mechanism : ⎯⎯ → + X– (Leaving group) Characteristic of SN2 1. It is bimolecular, one step concerted process 2. It is second order reaction because in the rds both species are involved 3. Kinetics of the reaction  rate  [alkyl halide] [nucleophile] rate = k[alkyl halide] [nucleophile] If the concentration of alkyl halide in the reaction mixture is doubled, the rate of the nucleophilic substitution reaction is double. If the concentration of nucleophile is doubled the rate of reaction is also double. If the concentration of both are doubled then the rate of the reaction quadriples. Organic Reaction Mechanisms-III 4. Energetics of the reaction : Figure : A free energy diagrams for SN2 reaction 5. No intermediates are formed in the SN2 reaction, the reaction proceed through the formation of an unstable arrangment of atoms or groups called transition state. 6. The stereochemistry of SN2 reaction : As we seen earlier, in an SN2 mechanism the nucleophile attacks from the back side, that is from the side directly opposite to the leaving group. This mode of attack causes an inversion of configuration at the carbon atom that is the target of nucleophilic attack. This inversion is also known as Walden inversion. Inversion ⎯⎯⎯⎯⎯ → 7. Factor's affecting the rate of SN2 reaction  Number of factors affect the relative rate of SN2 reaction, the most important factors are (i) Effect of the structure of the substrate  SN2 reactivity CH3 > 1° > 2° >> 3° (unreactive) The important reason behind this order of reactivity is a steric effect. Very large and bulky groups can often hinder the formation of the required transition state and crowding raises the energy of the transition state and slow down the rate of reaction. Table : Relative rate of reaction of alkyl halides by SN2 mechanism. Substituent Compound Relative rate Methyl CH3X 30 1° CH3CH2X 1 2° (CH3)2CHX 0.02 Neopentyl (CH3)3CCH2X 0.00001 3° (CH3)3CX ~0 (ii) Concentration and reactivity of the nucleophile : – As nucleophilicity of nucleophile increases rate of SN2 increases. – Anionic nucleophiles mostly give SN2 reaction – A stronger nucleophile attacks upon -carbon with faster rate than the rate of departing of leaving group. (iii) The effect of the solvent : Polar aprotic solvent have crowded positive centre, so they do not solvate the anion appreciably therefore the rate of SN2 reactions increased when they are carried out in polar aprotic solvent. (iv) The nature of the leaving group  Weaker bases are good leaving groups. A good leaving group always stabilise the transition state and lowers its free energy of activation and there by increases the rate of the reaction. Order of leaving ability of halide ion F¯ < Cl¯ < Br¯ < I¯ Organic Reaction Mechanisms-III Reagents for alkyl halide are : OH¯ , SH¯ , I¯ ,CN¯, NH3 ....... (strong anionic nucleophiles) aq.KOH Ex-1. CH3–Cl ⎯⎯⎯⎯⎯⎯⎯→ CH3–OH + Cl– Ex-2. NaOH+DMF CH3–CH2–CH2–Br ⎯⎯⎯⎯⎯ → CH3–CH2–CH2–OH + Br– (:OH− )strong nucleophile KOH+DMSO ⎯⎯⎯⎯⎯⎯ → Ex-3. (inversion) (2) SN2 Reaction of Alcohol : (i) Reaction with HX : The protonated  unbranched primary alcohol is well suited for the SN2 reaction. Mechanism : (ii)  X R − OH2 ⎯⎯⎯→ R–X + H2O R–OH Reaction with phosphorus trihalides Several phosphorus halides are useful for converting alcohols to alkyl halides. PBr 3, PCl3, & PCl5 work well and are commercially available. Phosphorus halides produce good yields of most primary and secondary alkyl halides, but none works well with tertiary alcohols. The two phosphorus halides used most often are PBr3 and the P4/I2 combination. 3R–OH + PX3 3R–X + H3PO3 Mechanism : Step-1 : Step-2 : RCH2X+ HOPX2 Remarks The mechanism for the reaction involves attack of the alcohol group on the phosphorus atom, displacing a halide ion and forming a protonated alkyl dihalophosphite In second step a halide ion acts as nucleophile to displace HOPX 2, a good leaving group due to the electronegative atoms bonded to the phosphorus. (iii) Reaction with PCl5 R–OH + PCl5 (iv) S N2 R–Cl + HCl + POCl3 Reaction with thionyl chloride in presence of pyridine Thionyl chloride (SOCl2) is often the best reagent for converting an alcohol to an alkyl chloride. The by products (gaseous SO2 and HCl) leave the reaction mixture and ensure that there can be no reverse reaction. O || Pyridine R–OH + Cl − S − Cl ⎯⎯⎯⎯⎯ → R–Cl + SO2 + HCl Heat Organic Reaction Mechanisms-III Mechanism : .. .. ⎯⎯⎯ → R–O .. – S ⎯⎯→ – H+ .. O: + HCl Cl Chlorosulphite ester ⎯⎯ → R – Cl + SO2 In the first step, the nonbonding electrons of the hydroxy oxygen atom attack the electrophilic sulphur atom of thionyl chloride. A chloride ion is expelled a proton and gives test of chloro sulphite ester. Second step is an SN2 mechanism. Ex-1. CH3 CH2CH2CH2CH2OH CH3 CH2CH2CH2CH2Cl n − Pentyl alcohol Ex-2. n − Pentyl chloride CH 3 CH 3 | | PCl 3 CH 3 – CH 2 – CH – CH 2 – OH ⎯⎯⎯ → CH 3 – CH 2 – CH – CH 2 – Cl PCl 5 ⎯⎯⎯ → Ex-3. SOCl 2 ⎯⎯⎯⎯ → Ex-4. Py (3) SNi Reaction : In SNi mechanism an internal nucleophile attacks from the same side of leaving group, means retension of configuration. It is an SNi mechanism, where i means internal ROH + SOCl2 ⎯⎯→ RCl + SO2 + HCl Mechanism : ⎯⎯ → .. .. ⎯⎯⎯ → R–O .. – S – H+ .. O: Cl Chlorosulphite ester ⎯⎯ → R – Cl + SO2 Ex-1. Ex-2. SOCl 2 ⎯⎯⎯⎯ → + HCl Organic Reaction Mechanisms-III Section (C) : Bimolecular aromatic nucleophilic substitution reaction (SN2 Ar) This is the characteristic reaction of arylhalides with ortho or para electron withdrawing substituent. The reaction mechanism can be visualised as : − X (fast) Step −I → + Nu ⎯⎯⎯⎯ ⎯⎯⎯⎯⎯→ Step −II RDS Intermediate ion is stabilized by resonance. EWG   Rate of reaction  Cl F > Reactivity order towards SN2Ar : NO2 NO2 + KCl NO2 Br NO2 NO2 Ex-2. > OH KOH Ex-1. > NO2 NO2 Cl I Br CH3O NO2 – OCH3 NO2 – + Br NO2 Section (D) : Nucleophilic substitution reaction of Ethers & Epoxides (1) SN1 Reaction of Ethers (i) Reaction with HX : Ethers are unreactive towards most bases, but they can react under acidic conditions. A protonated ether can undergo substitution or elimination with the expulsion of an alcohol. Ethers react with conc. HBr and HI because these reagents are sufficiently acidic to protonate the ether, while bromide iodide are good nucleophiles for the substitution. If R or R’ is 3º then mechanism will be SN1 otherwise SN2. Mechanism : ⎯⎯⎯⎯⎯→ – ROH R–O–R`  Ex. HCl → (CH3 )3 C O C(CH3 )3 (CH3)3COC(CH3)3 ⎯⎯⎯ | H ⎯⎯ → (CH3 )3 C + (CH3)3COH ⎯⎯ → (CH3)3CCl X ⎯⎯⎯→ R`–X Organic Reaction Mechanisms-III (ii) Reaction with H2O/H+ : + R–O–R + H R–O–R –ROH + R + H2O R–OH R–OH2 –H+ H CH3 Ex. CH3 H2O/H+ CH3–C–O–CH2–CH3 CH3–C–OH + CH3–CH2–OH CH3 CH3 (2) SN2 Reaction of Ethers (i) Reaction with HX : A protonated ether can undergo substitution reaction. Ether react with conc. HBr and HI because these reagents are sufficiently acidic to protonate the ether. If R or R’ is 3º then mechanism will be S N1 otherwise SN2. Mechanism : ⎯⎯ → + Ex. X −R alkyl halide + HX ⎯⎯⎯ → X – R + X – R  H CH3CH2–O–CH3 ⎯⎯⎯ → excess HBr ⎯⎯⎯⎯⎯⎯⎯ → Ex. Ex. (ii) Reaction with H2O/H+ : R–O–R H+ + H2O + R–OH + R–OH2 –H+ R–OH R–O–R H (Steric crowding R > R) Ex. CH3–CH–O–CH2–CH3 CH3 H+ + CH3–CH–O–CH2–CH3 H2O CH3 H + CH3–CH–OH + CH3–CH2–OH2 CH3 –H+ CH3–CH2–OH (3) Nucleophilic substitution reaction of Epoxide : Epoxides are much more reactive than ether because of angle strain in three membered ring therefore epoxide readily undergo nucleophilic substitution reaction. In basic medium mechanism is SN2. Nucleophile atacks on less hindered carbon. Nu Nu |  | H → R — CH — CH2 Mechanism : R — CH — CH2 ⎯⎯⎯ | |  OH O Organic Reaction Mechanisms-III Ex. CH3–CH–CH2 O RMgX H2O CH3–CH–CH2–CH2–R CH2 OH In acidic medium mechanism is SN1 type. Nucleophile attacks on more substituted carbon. H ⎯⎯⎯ → Mechanism : Ex. H O 2 ⎯⎯⎯ → H Nu | R — CH — CH2 | OH