Alkyl Halides R-X (X = F, Cl, Br, I) Classification of alkyl halides according to the class of the carbon that the halogen is attached to. RCH2-X R2CH-X R3C-X 1o 2o 3o

Nomenclature: common names: “alkyl halide” (fluoride, chloride, bromide, iodide) IUPAC names: use rules for alkanes halogen = halo (fluoro, chloro, bromo, iodo) Cl CH3CH2CH2CH2-Br CH3CHCH3 n-butyl bromide isopropyl chloride 1-bromobutane 2-chloropropane 1o 2o

CH3 CH3 CH3CHCH2CHCH3 CH3CCH3 Br I 2-bromo-4-methylpentane tert-butyl iodide 2-iodo-2-methylpropane 2o 3o CH3 Cl-CHCH2CH3 sec-butyl chloride 2-chlorobutane 2o

Physical properties: polar + no hydrogen bonding => moderate boiling/melting points water insoluble Uses: pesticides, refrigerants (freons), solvents, synthetic intermediates. CH3Br CClF3 CCl4

Synthesis of alkyl halides: 1. From alcohols a) HX b) PX3 Halogenation of certain hydrocarbons 3. (later) 4. (later) 5. Halide exchange for iodide

From alcohols. #1 synthesis! With HX R-OH + HX  R-X + H2O i) HX = HCl, HBr, HI ii) may be acid catalyzed (H+) iii) ROH: 3o > 2o > CH3 > 1o iv) rearrangements are possible except with most 1o ROH

CH3CH2CH2CH2-OH + NaBr, H2SO4, heat  CH3CH2CH2CH2-Br n-butyl alcohol (HBr) n-butyl bromide 1-butanol 1-bromobutane CH3 CH3 CH3CCH3 + HCl  CH3CCH3 OH Cl tert-butyl alcohol tert-butyl chloride 2-methyl-2-propanol 2-chloro-2-methylpropane CH3-OH + HI, H+,heat  CH3-I methyl alcohol methyl iodide methanol iodomethane

CH3CHCH2-OH + PBr3  CH3CHCH2-Br …from alcohols: b) PX3 i) PX3 = PCl3, PBr3, P + I2 ii) ROH: CH3 > 1o > 2o iii) no rearragements CH3CH2-OH + P, I2  CH3CH2-I ethyl alcohol ethyl iodide ethanol iodoethane CH3 CH3 CH3CHCH2-OH + PBr3  CH3CHCH2-Br isobutyl alcohol isobutyl bromide 2-methyl-1-propanol 1-bromo-2-methylpropane

Halogenation of certain hydrocarbons. R-H + X2, Δ or hν  R-X + HX (requires Δ or hν; Cl2 > Br2 (I2 NR); 3o>2o>1o) yields mixtures!  In syntheses, limited to those hydrocarbons that yield only one monohalogenated product. CH3 CH3 CH3CCH3 + Cl2, heat  CH3CCH2-Cl CH3 CH3 neopentane neopentyl chloride 2,2-dimethylpropane 1-chloro-2,2-dimethylpropane

Halide exchange for iodide. R-X + NaI, acetone  R-I + NaX  i) R-X = R-Cl or R-Br ii) NaI is soluble in acetone, NaCl/NaBr are insoluble. CH3CH2CH2-Br + NaI, acetone  CH3CH2CH2-I n-propyl bromide n-propyl idodide 1-bromopropane 1-idodopropane

ROH HX PX3 NaI acetone RX X2, Δ or hν RH

Outline a possible laboratory synthesis for each of the following alkyl halides using a different synthesis for each compound: 1-bromobutane neopentyl chloride n-propyl iodide tert-butyl bromide

CH3CH2CH2CH2-OH + PBr3  CH3CH2CH2CH2-Br CH3CCH3 + Cl2, heat  CH3CCH2-Cl CH3CH2CH2-Br + NaI, acetone  CH3CH2CH2-I CH3 CH3 CH3C-OH + HBr  CH3C-Br

R-H R-X NR  Acids Bases Active Metals Oxidants Reductants Halogens

Reactions of alkyl halides: Nucleophilic substitution Best with 1o or CH3!!!!!! R-X + :Z-  R-Z + :X- 2. (later) Preparation of Grignard Reagent R-X + Mg  RMgX Reduction R-X + Mg  RMgX + H2O  R-H R-X + Sn, HCl  R-H

nucleophilic substitution R-W + :Z-  R-Z + :W- substrate nucleophile substitution leaving product group good nucleophile  strong base good leaving group  weak base

R-X + :OH-  ROH + :X- alcohol R-X + H2O  ROH + HX alcohol R-X + :OR´-  R-O-R´ + :X- ether R-X + -:CCR´  R-CCR´ + :X- alkyne R-X + :I-  R-I + :X- iodide R-X + :CN-  R-CN + :X- nitrile R-X + :NH3  R-NH2 + HX primary amine R-X + :NH2R´  R-NHR´ + HX secondary amine R-X + :SH-  R-SH + :X- thiol R-X + :SR´  R-SR´ + :X- thioether Etc. Best when R-X is CH3 or 1o!

CH3CH2CH2-Br + KOH  CH3CH2CH2-OH + KBr CH3CH2CH2-Br + HOH  CH3CH2CH2-OH + HBr CH3CH2CH2-Br + NaCN  CH3CH2CH2-CN + NaBr CH3CH2CH2-Br + NaOCH3  CH3CH2CH2-OCH3 + NaBr CH3CH2CH2-Br + NH3  CH3CH2CH2-NH2 + HBr CH3CH2CH2-Br + NaI, acetone  CH3CH2CH2-I + NaBr

Mechanism for nucleophilic substitution: “substitution, nucleophilic, bimolecular” “curved arrow formalism” uses arrows to show the movement of pairs of electrons in a mechanism.

Kinetics – study of the effect of changes in concentration on rates of reactions. CH3—Br + NaOH  CH3—OH + NaBr rate = k [ CH3-Br ] [ OH- ] Tells us that both CH3-Br and OH- are involved in the rate determining step of the mechanism. “bimolecular”

Relative rates of R—X R-I > R-Br > R-Cl “element effect”  C—X bond is broken in the rate determining step of the mechanism.

SN2 stereochemistry CH3 CH3 H Br + NaOH  HO H (SN2 conditions) (S)-(-)-2-bromooctane (R)-(+)-2-octanol 100% optical purity SN2 proceeds with 100% inversion of configuration! (“backside attack” by the nucleophile)

SN2 100% backside attack by the nucleophile Evidence: stereochemistry = 100% inversion of configuration Reasonable? incoming nucleophile and negatively charged leaving group are as far apart as they can get. 2) there is more room on the backside of the carbon for the incoming nucleophile to begin to bond to the carbon.

Relative rates for alkyl halides in SN2: CH3-X > 1o > 2o > 3o 37 : 1.0 : 0.2 : 0.0008 The transition state has five groups crowded around the carbon. If the substrate is CH3X then three of the the five groups are Hydrogens. If the alkyl halide is 3o then there are three bulky alkyl groups crowded around the carbon in the transition state. “Steric factors” explain the relative reactivity of alkyl halides in the SN2 mechanism.

CH3 CH3 CH3CCH3 + OH-  CH3CCH3 + Br- + alkene Br OH rate = k [ tert-butyl bromide ] The rate of this reaction depends on only the concentration of the alkyl halide. Therefore the nucleophile is not involved in the RDS here, cannot be SN2 mechanism!? “unimolecular”

Substitution, nucleophilic, unimolecular (SN1) mechanism: Kinetics: rate = k [R-W ]; only R-W is involved in the RDS! 1) 2)

SN1 stereochemistry CH3 CH3 CH3 H Br + NaOH  HO H + H OH (SN1 conditions) C6H13 C6H13 C6H13 (-)-2-bromooctane (+)-2-octanol (-)-2-octanol SN1 proceeds with partial racemization. The intermediate carbocation is sp2 hybridized. The nucleophile can attack the carbocation from either the top or the bottom and yield both enantiomeric products.

SN1 reactivity: 3o > 2o > 1o > CH3 R—Br  R+ + Br- CH3—Br ΔH = 219 Kcal/mole CH3+ CH3CH2—Br ΔH = 184 Kcal/mole 1o CH3CH—Br ΔH = 164 Kcal/mole 2o CH3 CH3C—Br ΔH = 149 Kcal/mole 3o

SN1 order of reactivity = 3o > 2o > 1o > CH3 Stability of carbocations = 3o > 2o > 1o > CH3+ RDS in SN1: R—W  R+ + :W- R—X [ R---------X ]  R+ + X- δ+ δ-

Rearrangement of carbocations. Carbocations can rearrange by 1,2-hydride or 1,2-methyl shifts:   [1,2-H]   --C—C--  --C—C– +   + H H    [1,2-CH3]   --C—C--  --C—C– +   + CH3 CH3

Carbocations can rearrange by 1,2-hydride or 1,2-methyl shifts but only do so when the resultant carbocation is more stable. 1o carbocation will rearrange to 2o 1o carbocation will rearrange to 3o 2o carbocation will rearrange to 3o (only goes “down hill”)

CH3 CH3   CH3CHCHCH3 + NaCN (SN1 conditions)  CH3CCH2CH3 ????? Br CN   CH3 [ 1,2-H shift ] CH3 CH3CHCHCH3  CH3CCH2CH3 + CN- + + 2o carbocation 3o carbocation

SN2 SN1 stereochemistry 100% inversion Partial racemization Kinetic order Rate = k[RX][Z-] Rate = k[RX] Rearrangements None Possible Rates CH3,1o,2o,3o CH3>1o>2o>3o 3o>2o>1o>CH3 Rates RCl,RBr,RI RI>RBr>RCl Rate? temp. Increases rate Rate? 2 x [RX] Doubles rate Rate? 2 x [Z-] No effect

R-X + Z-  R-Z + X- which mechanism?  SN2 - CH3 1o 2o 3o - SN1  SN2 “steric factors” CH3 > 1o > 2o > 3o SN1 carbocation stability 3o > 2o > 1o > CH3

Effect of solvent polarity on SN1/SN2: water = polar ethanol = less polar Solvent: mixture of ethanol/water Add more water = more polar; add more ethanol = less polar. SN1: R-W  R+ + W- ionization favored by polar solvents SN2: Z:- + R-W  Z-R + :X- solvent polarity does not affect rate

Alkyl halide + base  ???? SN2: best with CH3 or 1o RX, concentrated, strong base (SN1: 2o or 3o, dilute, weak base, polar solvent; rearrangements are possible , alkene by-products )

Synthesis of alkyl halides: 1. From alcohols a) HX b) PX3 Halogenation of certain hydrocarbons 3. (later) 4. (later) 5. Halide exchange for iodide

Reactions of alkyl halides: Nucleophilic substitution Best with 1o or CH3!!!!!! R-X + :Z-  R-Z + :X- 2. (later) Preparation of Grignard Reagent R-X + Mg  RMgX Reduction R-X + Mg  RMgX + H2O  R-H R-X + Sn, HCl  R-H