Organic Chemistry I The Chemistry of Alkyl Halides Unit 10

1. Organic Chemistry IThe Chemistry of Alkyl HalidesUnit 10 Dr. Ralph C. Gatrone Department of Chemistry and Physics Virginia State University

2. Objectives • Nomenclature • Preparation • Reactions • Organometallic Reagents • Nucleophilic Substitution Reactions • Elimination Reactions

3. What Is an Alkyl Halide? • An organic compound containing at least one carbon-halogen bond (C-X) • X = F, Cl, Br, I • Can contain many C-X bonds • Entirely halogenated = perhalo • Wide-spread in nature • Common industrial chemicals • Properties and some uses • Fire-resistant solvents • Refrigerants • Pesticides • Pharmaceuticals and precursors

4. Nomenclature • Name is based on longest carbon chain • (Contains double or triple bond if present) • Number from end nearest any substituent (alkyl or halogen)

5. Nomenclature with Multiple Halogen • If more than one of the same kind of halogen is present, use prefix di, tri, tetra • If there are several different halogens, number them and list them in alphabetical order

6. Naming if Halides Are Equidistant • Begin at the end nearer the substituent whose name comes first in the alphabet

7. Common Names • Chloroform • Carbon tetrachloride • Methylene chloride • Methyl iodide • Trichloroethylene

8. Structure of Alkyl Halides • C-X bond is longer as you go down periodic table • C-X bond is weaker as you go down periodic table • C-X bond is polarized • some positive charge on carbon • some negative charge on halogen • The carbon is an electrophilic center

9. Electrophilic Carbon

10. Preparation • Alkyl halide - addition of HCl, HBr, HI to alkenes to give Markovnikov product (see Alkenes chapter) • Alkyl dihalide from anti addition of bromine or chlorine

11. Allylic Bromination of Alkenes • N-bromosuccinimide (NBS) selectively brominates allylic positions • Requires light for activation • A source of dilute bromine atoms

12. Use of Allylic Bromination • Bromination with NBS creates an allylic bromide • Reaction of an allylic bromide with base produces a conjugated diene, useful in synthesis of complex molecules

13. Alkyl Halides from AlcoholsTertiary Alcohols • Reaction of tertiary C-OH with HX is fast and effective • Add HCl or HBr gas into ether solution of tertiary alcohol • Primary and secondary alcohols react very slowly and often rearrange, so alternative methods are used

14. Alkyl Halides from AlcoholsPrimary and Secondary Alcohols • Specific reagents avoid acid and rearrangements of carbon skeleton • Thionyl chloride converts alcohols into alkyl chlorides • SOCl2 : ROH to RCl • Phosphorus tribromide converts alcohols into alkyl bromides • PBr3: ROH to RBr

15. Reactions of Alkyl HalidesThe Grignard Reagent • RX reacts with Mg in ether or THF • Product is RMgX • an organometallic compound • alkyl-metal bond • R : alkyl (1°, 2°, 3°), aryl, alkenyl • X = Cl, Br, I

16. The Grigard Reagent Polarity is reversed Electrophilic Carbon becomes Nucleophilic Carbon

17. Organo-Metallic Compounds • RX + Zn gives R2Zn • RX + Li gives RLi • RX + Al gives R3Al • Behave similar to Grignard • Others use RLi

18. Organo-Metallics • RLi + CuI gives R2CuLi • Organocuprate • Useful coupling reaction • R2CuLi + RX gives R-R • RLi + CdCl2 gives R2Cd

19. Observations Optical rotation is related to chirality Optical rotation and chirality are changing

20. Significance of the Walden Inversion • Stereochemistry at the chiral C is inverted • The reactions involve substitution at that center by a nucleophile • Therefore, nucleophilic substitution appears to invert the configuration at a chiral center • The presence of carboxyl groups in malic acid led to some dispute as to the nature of the reactions in Walden’s cycle

21. Stereochemistry of Nucleophilic Substitution • Isolate step so we know what occurred (Kenyon and Phillips, 1929) using 1-phenyl-2-propanol • Only the second and fifth steps are reactions at carbon • Inversion occurs during the substitution step

22. Kinetics • Review Chapter 5 • Reactions are considered fast or slow • How fast is given by reaction rate • Reaction rates are measurable • Relationship between rate and concentration

23. CH3Br + HO- CH3OH + Br- • Rate determined at given temp and [conc] • Double [HO-] – rate doubles • Double [CH3Br] – rate doubles • Double both – rate increases by 4X • Rate is dependent upon both [reactants] • Second order kinetics • Rate = k[RX][Nu] • k is the rate constant

24. What We Know • Substitution reaction • Inversion of stereochemistry • Second-order kinetics • Proposed mechanism SN2 • Substitution, nucleophilic, bimolecular • Single step from SM to Product • Primary and secondary alkyl halides

25. The SN2 Reaction • Reaction - inversion at reacting center • Follows second order reaction kinetics • Ingold nomenclature to describe characteristic step: • S=substitution • N (subscript) = nucleophilic • 2 = both nucleophile and substrate in characteristic step (bimolecular)

26. SN2 Process • The reaction must involve a transition state in which both reactants are together

27. Mechanism Nu attacks from opposite face as leaving group departs leading to inversion of stereochemistry Substrate and nucleophile appear in rate determining step

28. SN2 Transition State • The transition state of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups

29. Sensitive to steric effects Methyl halides are most reactive Primary are next most reactive Secondary might react Tertiary are unreactive by this path No reaction at C=C (vinyl halides) Additional Observations: SN2 Reaction

30. Influencing a Reaction • To increase the rate of a reaction • raise the energy of the reactants • lower the energy of the transition state • To slow a reaction, • Lower the energy of the reactants • Raise the energy of the transition state

31. Reactant and Transition-state Energy Levels Affect Rate Higher reactant energy level (red curve) = faster reaction (smallerG‡). Higher transition-state energy level (red curve) = slower reaction (largerG‡).

32. Variables that Influence the Reaction • Substrate • Nucleophile • Leaving Group • Solvent

33. SubstrateSteric Effects on SN2 Reactions The carbon atom in (a) bromomethane is readily accessible resulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower SN2 reactions.

34. Substrate: Transition State • In the Transition State • Bonds between C and Nu are forming • Bonds between C and LG are breaking • Approach to hindered C raises TS energy

35. Substrate: Transition State Energy • Steric effects destabilize transition states • Severe steric effects can also destabilize ground state Very hindered

36. Substrate: Order of Reactivity in SN2 • The more alkyl groups connected to the reacting carbon, the slower the reaction

37. Substrate • Aryl – do not react • Vinyl – do not react • Recall: acetylide anion reacts with methyl or primary alkyl halides • Better bases lead to elimination reactions

38. Nucleophile • Neutral or negatively charged Lewis bases • Reaction increases coordination at nucleophile • Neutral nucleophile acquires positive charge • Anionic nucleophile becomes neutral

39. Nucleophiles • Depends on reaction and conditions • Nucleophilicity parallels basicity • Nucleophilicity increases down a group in the periodic table (Cl < Br < I) • Anions are usually more reactive than neutrals

40. The Leaving Group • A good leaving group reduces the barrier to a reaction • Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge • Negative charge builds in LG

41. TosylateThe Best Leaving Group • TsO- supports negative charge • Resonance stabilized anion

42. Poor Leaving Groups • If a group is very basic or very small, it prevents the reaction from occurring

43. The Solvent • Solvents that can donate hydrogen bonds (-OH or –NH) slow SN2 reactions by associating with reactants • Energy is required to break interactions between reactant and solvent • Polar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reaction

44. Protic Polar Solvents • Protic polar solvents bind to X- • Hydrogen Bonding • Solvent cage around nucleophile • Stabilizes negative charge • Lowering ground state energy • Increases rate of reaction

45. Aprotic Polar Solvents • Bind to M+ • X- is unsolvated • More reactive • At a higher energy • Decreases rate of reaction

46. SN2 Review • Favored • Basic Nu: • By aprotic polar solvents • Stable anions as leaving groups • Disfavored • In protic solvents (water, alcohol) • Sensitive to steric factors • Second Order Kinetics

47. ROH + HX RX + H2O • Observations • 3o > 2o > 1o >> CH3 • Protic solvent used • Acidic to neutral conditions utilized • Non-basic nucleophiles • Substitution by nucleophile

48. ROH + HX RX + H2O • Rate is affected by changes in [ROH] • Rate is unaffected by changes in [H2O] • Rate expression • Rate = k[ROH] • First Order Kinetics • Rate Determining Step involves ROH not Nu • Rate Determining Step is slowest step of reaction and nothing occurs slower

49. Mechanism • Data suggests: • Intermediate = R+ (carbocation) • SN1 mechanism • R+ reacts fast with Nu

50. SN1 Energy Diagram Step through highest energy point is rate-limiting (k1 in forward direction) • Rate-determining step is formation of carbocation Rate = k[RX]