Chapter 7 Organohalides: Nucleophilic Substitutions and Eliminations Suggested Problems: 20,22-26,28-38,44-45,47,57

What Is an Organohalide? An organic compound containing at least one carbon-halogen bond (C-X) X (F, Cl, Br, I) replaces H Can contain many C-X bonds Properties and some uses Fire-resistant solvents Refrigerants Pharmaceuticals and precursors

7.1 Naming Alkyl Halides Find longest chain, name it as parent chain (Contains double or triple bond if present) Number from end nearest any substituent (alkyl or halogen)

Naming if Two Halides or Alkyl Are Equally Distant from Ends of Chain Begin at the end nearer the substituent having its name first in the alphabet Name halide as a substituent

10.2 Preparing Alkyl Halides from Alkenes Two best ways: Alkyl halide from addition of HCl, HBr, HI to alkenes to give Markovnikov product Alkyl dihalide from anti addition of bromine or chlorine

10.2 Preparing Alkyl Halides Via Radical Halogenation

Preparing Alkyl Halides Via Radical Halogenation Alkane + Cl2 or Br2, heat or light replaces C-H with C-X but gives mixtures Hard to control Occurs via free radical mechanism It is usually not a good idea to plan a synthesis that uses this method

Radical Halogenation of Alkanes If there is more than one type of hydrogen in an alkane, reactions favor replacing the hydrogen at the most highly substituted carbons (not absolute)

Relative Reactivity Based on quantitative analysis of reaction products, relative reactivity is estimated Order parallels stability of radicals Reaction selectivity is greater with bromine than chlorine i.e. 3o > 2o > 1o

7.2 Preparing Alkyl Halides Addition reactions of X2 and HX with alkenes (Chapter 4) Reaction of an alkane with Cl2 (Chapter 2)

Preparing Alkyl Halides from Alcohols Reaction of tertiary C-OH with HX is fast and effective Add HCl or HBr gas into ether solution of tertiary alcohol (ether is solvent)

Preparing Alkyl Halides from Alcohols Primary and secondary alcohols react very slowly and often rearrange under acidic conditions (with HX), so alternative methods are used usually thionyl chloride (SOCl2) or phosphorus tribromide (PBr3)

7.3 Reactions of Alkyl Halides: Grignard Reagents Reaction of RX with Mg in ether or THF Product is RMgX – an organometallic compound (alkyl-metal bond) R is alkyl 1° ,alkyl 2° , alkyl 3°, aryl, alkenyl X = Cl, Br, I

7.3 Reactions of Alkyl Halides: Grignard Reagents Grignard reagent – magnesium salt of a carbon-based acid Carbon atom is a carbon anion, or carbanion This carbon atom is both nucleophilic and basic Water or protic solvents (eg. ROH) must be excluded

7.4 Nucleophilic Substitution Reactions Aklyl halides (RX) when they react with nucleophiles/bases can undergo Substitution of the X group by the nucleophile Elimination of HX to yield an alkene by the base

The Discovery of Nucleophilic Substitution Reactions In 1896, Walden showed that (-)-malic acid could be converted to (+)-malic acid by a series of chemical steps with achiral reagents This established that optical rotation was directly related to chirality and that it changes with inversion of chirality Reaction of (-)-malic acid with PCl5 gives (+)-chlorosuccinic acid Further reaction with wet silver oxide gives (+)-malic acid The reaction series starting with (+) malic acid gives (-) acid

Reactions of the Walden Inversion retention retention inversion

Significance of the Walden Inversion The PCl5 reactions invert the stereochemistry at the chirality center The reactions involve substitution at that center Therefore, nucleophilic substitution can invert the configuration at a chirality center The Ag2O reactions occur with retention (without inverting the stereochemistry at the chirality center)

Nucleophilic Substitution Reactions Regardless of mechanism, the overall changes during a nucleophilic substitution reaction are the same Nucleophile (Nu: or Nu:– ) reacts with a substrate R— X Substitutes for the leaving group X:– To yield a new product R— Nu

Nucleophiles

7.5 Substitutions: The SN2 Reaction Reaction occurs with inversion at reacting center Takes place in a single step Without intermediates Entering nucleophile is 180˚ from the leaving group Reaction is bimolecular The rate of the reaction depends on the concentration of both the nucleophile and the substrate

SN2 Process The reaction involves a transition state in which both reactants are together

SN2 Transition State The transition state of an SN2 reaction has a roughly planar arrangement of the carbon atom and the remaining three groups Rate = k [Nu][RX] (bimolecular) Alkyl Halide: 1°> 2°>> 3° Backside attack One step

Steric 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.

Order of Reactivity in SN2 The more alkyl groups connected to the reacting carbon, the slower the reaction

The Leaving Group A good leaving group reduces the energy barrier to a reaction Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge Best leaving groups

7.6 The SN1 Reaction Tertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to addition of the nucleophile Called an SN1 reaction – occurs in two distinct steps while SN2 occurs with both events in same step If nucleophile is present in reasonable concentration (or it is the solvent), then ionization is the slowest step

Rates of SN1 Reactions The overall rate of a reaction is controlled by the rate of the slowest step The rate depends on the concentration of the species and the rate constant of this step SN1 reactions are unimolecular The rate depends on the concentration of the substrate (Rate = k[RX]) The substrate must undergo a reaction without involvement of the nucleophile

Rates of SN1 Reactions

Stereochemistry of SN1 Reaction The planar intermediate leads to loss of chirality A free carbocation is achiral Product is racemic or has some inversion

The Leaving Group in SN1 Reactions Critically dependent on leaving group The best leaving groups are those that give the most stable anions

7.7 Eliminations: The E2 Reaction Elimination is an alternative pathway to substitution Opposite of addition Generates an alkene Can compete with substitution and decrease yield, especially for SN1 processes

Zaitsev’s Rule for Elimination Reactions In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates

Mechanisms of Elimination Reactions Eliminations can take place by several different mechanisms differing in the time of C—H and C—X bond breaking

Mechanisms of Elimination Reactions

Mechanisms of Elimination Reactions

E2 Mechanism: Elimination, Bimolecular

7.8 Eliminations: The E1 and E1cB Reactions E1 Reaction: elimination, unimolecular Involves a carbocation intermediate

7.8 Eliminations: The E1 and E1cB Reactions E1cB Reaction: elimination, unimolecular Involves a carbanion intermediate

7.9 A Summary of Reactivity: SN1, SN2, E1, E1cB, and E2

7.10 Substitions and Eliminations in Living Organisms Both substitution reactions occur in biological pathways Among the most common is methylation

7.10 Substitions and Eliminations in Living Organisms All three elimination reactions occur in biological pathways E1cB very common Typical example occurs during biosynthesis of fats when 3-hydroxybutyryl thioester is dehydrated to corresponding thioester