CHEM 232 University of Illinois Organic Chemistry I at Chicago UIC

Organic Chemistry 1 Lecture 8

Instructor: Prof. Duncan Wardrop Time/Day: T & R, 12:30-1:45 p.m. February 04, 2010

1 Self Test Question

Which of the following transformations is unlikely to generate the product indicated?

OH HCl Cl a. 25 ºC

primary alcohols HCl A. a. and HCl are insufficiently x b. OH 25 ºC Cl reactive B. b.

SOCl2 O O c. OH Cl C. c. K2CO3

Cl D. d. d. Cl2 hν

University of Slide CHEM 232, Spring 2010 2 Illinois at Chicago UIC Lecture 8: February 4 2 Compound “b.” is a primary alcohol, which are insufciently reactive to undergo reaction with hydrogen chloride. Primary alcohols do, however, react with thionyl chloride (SOCl2) to form chlorides and so the transformation shown in “c” will proceed successfully Compound “a” is tertiary alcohol and consequently reacts with HCl. Substitution Reaction hydroxyl group halide

R O H + H X R X + H O H

alcohol hydrogen alkyl water halide halide

Hydroxyl group is being substituted (replaced with) a halide

University of Slide CHEM 232, Spring 2010 3 Illinois at Chicago UIC Lecture 8: February 4 3 CHEM 232 University of Illinois Organic Chemistry I at Chicago UIC

Mechanisms of Substitution Reactions

Sections: 4.8-4.11

4 Substitution: How Does it Happen?

break bond break bond make bond make bond

R O H + H X R X + H O H

alcohol hydrogen alkyl halide water halide

mechanism: a generally accepted series of elementary steps that show the order of bond breaking and bond making

elementary step: a bond making and/or bond breaking step that only involves one transition state

University of Slide CHEM 232, Spring 2010 5 Illinois at Chicago UIC Lecture 8: February 4 5 Ingold-Hughes Mechanistic Designators

Designates # molecularity Designates type of process Letter Nucleophilic N or E or Electrophilic

Example

Me Me Substitution, H-Br Me Me nucleophilic, OH Br SN1 Me Me 1st order

Rate = k x [t-BuOH]

University of Slide CHEM 232, Spring 2010 6 Illinois at Chicago UIC Lecture 8: February 4 6 Nucleophilic Substitution (SN1)

Step One Proton Transfer (Protonation)

fast & reversible H O H Cl O Cl H H

pKa = -3.9 alkyloxonium ion

University of Slide CHEM 232, Spring 2010 7 Illinois at Chicago UIC Lecture 8: February 4 7 this is an acid-base reaction; product is an alkoxonium ion

exothermic and fast (proton transfer is among the fastest processes in organic chemistry)

rate of individual step =k x [alcohol] x [HX]; two reactants = bimolecular (2nd order)

oxonium ion is an intermediate in the overall reaction Step One Potential Energy Diagram

Step One Proton Transfer (Protonation) transition state: energy maximum along reaction coordinate for one elementary step; usually involves partial bond making and partial bond breaking

intermediate: energy minimum along the reaction coordinate; species with a finite lifetime; neither reactant, nor product

Hammond Postulate: structure of the transition state “looks” most like its closest energy reactant or intermediate

University of Slide CHEM 232, Spring 2010 8 Illinois at Chicago UIC Lecture 8: February 4 8 Mechanism: Nucleophilic Substitution (SN1)

Step Two Dissociation (Ionization)

slow H Me Me O H2O H Me carbocation (t-butyl cation)

University of Slide CHEM 232, Spring 2010 9 Illinois at Chicago UIC Lecture 8: February 4 9 breaking a carbon-oxygen bond

slowest (rate determining) step in entire mechanism; endothermic

rate=k[oxonium ion]; one reactant = unimolecular (1st order) Step Two Potential Energy Diagram

Step Two Dissociation (Ionization) • largest activation energy (Ea) • endothermic, slowest • carbocation intermediate is much higher in energy than an oxonium ion • carbocations do not have a full octet, whereas oxonium ions do • structure of transition state most resembles the closest energy neighbor, the carbocation (Hammond Post.)

University of Slide CHEM 232, Spring 2010 10 Illinois at Chicago UIC Lecture 8: February 4 10 Mechanism: Nucleophilic Substitution (SN1)

Step Three Carbocation Capture

Me Me fast Cl Cl Me

carbocation t-butyl chloride (t-butyl cation)

Cation = Electrophile Anion = Nucleophile

University of Slide CHEM 232, Spring 2010 11 Illinois at Chicago UIC Lecture 8: February 4 11 exothermic and fast; neutral products much lower in NRG

small activation energy; negative charge to positive charge

transition state looks most like carbocation since they are closest in energy

rate = k x [carbocation][halide]; two reactants = bimolecular Step Three Potential Energy Diagram

Step Three Carbocation Capture • fast step because small activation energy; positive and negative atoms bond fast • products are much lower in energy since they are neutral; exothermic reaction • transition state looks most like its closest neighbor, the carbocation intermediate (very little C-Cl bond formation at transition state) (Hammond Postulate)

University of Slide CHEM 232, Spring 2010 12 Illinois at Chicago UIC Lecture 8: February 4 12 Nucleophiles Add to Electrophiles

nucleophile: nucleus loving; Lewis base; electron pair donor; forms bonds with a nucleus that can accept electrons; does not necessarily have to be negatively charged; has available, !lled orbitals!

electrophile: electron loving; Lewis acid; electron pair acceptor; forms bonds by accepting electrons from other atoms; does not necessarily have to be positively charged; has available, empty orbitals!

Cation is Electrophile Me Me empty 2pz orbital Cl Chloride is Nucleophile Me filled n orbital (: = lone pair)

University of Slide CHEM 232, Spring 2010 13 Illinois at Chicago UIC Lecture 8: February 4 13 Complete Mechanism

fast & reversible H O H Cl O Cl H H alkyloxonium ion

slow Me Me fast Cl Cl Me

carbocation H O t-butyl chloride (t-butyl cation) 2

University of Slide CHEM 232, Spring 2010 14 Illinois at Chicago UIC Lecture 8: February 4 14 Complete Potential Energy Diagram

• mechanism only valid for 3º & 2º alcohols

• reaction is only as fast as its slowest step

rate • slowest step (largest Ea) = determining step (RDS) rate determining step (RDS)

• here, slowest step is carbocation formation

• here, RDS is unimolecular Protonation carbocation formation carbocation capture

University of Slide CHEM 232, Spring 2010 15 Illinois at Chicago UIC Lecture 8: February 4 15 Naming the Mechanism: Ingold Notation

R O H + H X R X + H O H alcohol hydrogen alkyl halide water halide

SN1 1: 1st order S: Substitution N: Nucleophilic (unimolecular) the RDS is the alcohol the halide doing the carbocation functional groups is substitution is a formation; this step is being substituted nucleophile unimolecular (1st with a halide order)

University of Slide CHEM 232, Spring 2010 16 Illinois at Chicago UIC Lecture 8: February 4 16 Self Test Question

Consider the SN1 mechanism for the formation of 2- bromobutane. Which structure best represents the highest energy transition state in this mechanism?

Br a. c. + A. a. O H Br H O H H H δ+ δ− B. b. C. c. δ+

+ Br + Br D. d. b. O d. O H H H H δ+

University of Slide CHEM 232, Spring 2010 17 Illinois at Chicago UIC Lecture 8: February 4 17 Structure of Carbocations

• carbocations are high energy intermediates; hard, but not impossible to isolate 2pZ • carbon is sp2-hybridized with a single, H unoccupied 2pZ orbital; 6 valence electrons H3C C • planar structure : three bonds to carbon are H at 120º angles from each other and 90º to empty p-orbital; VSEPR • nucleophiles add to either lobe of the empty carbocations can be stabilized by inductive effects and hyperconjugation p-orbital; since it is "at, there is no preference to which side nucleophile adds

University of Slide CHEM 232, Spring 2010 18 Illinois at Chicago UIC Lecture 8: February 4 18 Stability of Carbocations

1. Inductive Effects electron withdrawal or electron donation that is transmitted through σ- bonds; polarization of σ-bonds

• electron donation through 1º cation σ-bonds toward δ+ carbocation delocalizes δ+ H charge (spreads out) • C-C σ-bonds are more H3C C polarizable, therefore δ+ donate more electron H density through σ-bonds • more C-C σ-bonds = more stable carbocation

University of Slide CHEM 232, Spring 2010 19 Illinois at Chicago UIC Lecture 8: February 4 19 Stability of Carbocations

1. Inductive Effects Since C-C σ-bonds are more polarizable than C-H bonds, the additional of more alkyl groups leads to stabilization of the cation

2º cation 3º cation

δ+ δ+ δ+ CH3 δ+ CH3 H3C C H3C C H δ+ CH3 δ+

University of Slide CHEM 232, Spring 2010 20 Illinois at Chicago UIC Lecture 8: February 4 20 Stability of Carbocations

2. Hyperconjugation stabilizing interaction that results from the interaction of the electrons in a σ-bond (C–H or C–C bond ) with an adjacent empty (or partially !lled) orbital. Leads to the formation of an extended molecular orbital that increases the stability of the system

filled σ orbital • stabilization results from σ-donation to empty p orbital of planar carbocation empty • electron donation through σ-bonds H p orbital toward carbocation delocalizes charge H (spreads out) C C H H • methyl cations cannot be stabilized by hyperconjugation since σ-bonds are H perpendicular to the empty p orbital 1º cation

University of Slide CHEM 232, Spring 2010 21 Illinois at Chicago UIC Lecture 8: February 4 21 Stability of Carbocations

2. Hyperconjugation

filled empty σ orbital 2pZ orbital

empty C-H 2pZ H p orbital bonding

y (filled) g

H r e C C n E H H Stabilization resulting from H σ hyperconjugation

University of Slide CHEM 232, Spring 2010 22 Illinois at Chicago UIC Lecture 8: February 4 22 Stability of Carbocations

H H CH3 H H H3C

CH2 CH2 CH2 C C C C C C H H H CH2 H CH2 H H H H CH3

H

2º carbocation 3º carbocation 3º carbocation 2 C-H bond 3 C-H bond 3 C-C or C-H bond hyperconjugative hyperconjugative hyperconjugative donors donors donors

University of Slide CHEM 232, Spring 2010 23 Illinois at Chicago UIC Lecture 8: February 4 23 i>Clicker Question

Rank the following carbocations in order of increasing stability?

A. a,b,c,d a. b. c. d. CH3 H B. c,d,b,a H H H3C C C. d,c,a,b H H H D. b,c,a,d 2º 3º 1º methyl E. d,a,c,b

University of Slide CHEM 232, Spring 2010 24 Illinois at Chicago UIC Lecture 8: February 4 24 Stabilizing Effects on Carbocations

• smallest inductive effect • largest inductive effect • no hyperconjugation • most hyperconjugation

University of Slide CHEM 232, Spring 2010 25 Illinois at Chicago UIC Lecture 8: February 4 25 How Carbocation Stability Effects Rate of Reaction

• more stable (lower energy) carbocation = • more stable (lower energy) transition state (Hammond Post.) = • lower activation energy (Ea) = • faster reaction

University of Slide CHEM 232, Spring 2010 26 Illinois at Chicago UIC Lecture 8: February 4 26 Why are 1° & 2° Alcohols Less Reactive?

H-X EA too high H H O OH H H

simple 1° and 2° alcohols do not Ea undergo substitution by the SN1 OH + HCl Ea mechanism since methyl and

OH primary carbocations are too high in energy to be intermediates in nucleophilic substitution reactions = transition state RCl + H2O

an alternative mechanism is required......

University of Slide CHEM 232, Spring 2010 27 Illinois at Chicago UIC Lecture 8: February 4 27 Bimolecular Substitution - SN2 Mechanism

H fast H H3C O H H3C O Br H3C H H H Br slow (rate-determining)

Step 1 ‡ Protonation CH3 δ- H H3C Br + Step 2 Br C O δ+ H H H Nucleophilic Attack H H O

• C-O bond breaks at the same time the nucleophile (Br) forms the C-X bond

• RDS is nucleophilic attack; bimolecular, therefore Ingold notation = SN2 • fewer steps does not mean faster reaction

University of Slide CHEM 232, Spring 2010 28 Illinois at Chicago UIC Lecture 8: February 4 28 Self Test Question

Which rate equation below best describes the rate determining step (RDS) in an SN2 mechanism?

H H3C O Br H A. rate = k[oxonium ion] B. rate = k[carbocation] ‡ CH3 δ- H Br C O δ+ C. rate = k[oxonium ion][halide] H H H D. rate = k[carbocation][halide] E. rate = k[alcohol][HX] H3C Br

University of Slide CHEM 232, Spring 2010 29 Illinois at Chicago UIC Lecture 8: February 4 29 CHEM 232 University of Illinois Organic Chemistry I at Chicago UIC

Halogenation of Alkanes Methods and Mechanism

Sections: 4.14-4.17 You are responsible for Section 4.16 & 4.18 (Be able to perform this calculation!)

30 Halogenation of Alkanes

Fluorination (F2): Highly Exothermic (Explosive !)

Chlorination (Cl2): Exothermic

Bromination (Br2): Slightly Exothermic Reactivity Increasing Iodination (I2): Endothermic

University of Slide CHEM 232, Spring 2010 31 Illinois at Chicago UIC Lecture 8: February 4 31 Radical Chain Mechanism

Step One Initiation via Homolysis

homolysis Cl Cl Cl + Cl light (hν)

free radical half-headed arrow homolysis heterolysis “"shhook” (homolytic cleavage) (heterolytic cleavage) unpaired electron; stabilized by same movement of a single cleavage of a covalent cleavage of a covalent factors that stabilized electron, not a pair bond so that each atom bond so that one atom carbocations in the bond retains one in the bond retains both electron electron Cl

University of Slide CHEM 232, Spring 2010 32 Illinois at Chicago UIC Lecture 8: February 4 32 Radical Chain Mechanism

Step Two Propagation vis H-Atom Abstraction alkyl hydrogen radical H abstraction H Cl H C CH3 C CH3 + HCl H H chlorine 7 valence radical electrons

• Cl radical abstracts H atom from most substituted C atom • alkyl radical is an intermediate in the mechanism ˛ • alkyl radicals are stabilized by same factors that stabilize carbocations • note that radical is generated - propagation!

University of Slide CHEM 232, Spring 2010 33 Illinois at Chicago UIC Lecture 8: February 4 33 Radical Chain Mechanism

Step Three Propagation vis Cl-Atom Abstraction halogen H abstraction H

Cl Cl C CH3 Cl C CH3 + Cl H H chlorine chlorine alkyl radical alkyl chloride molecule radical

• alkyl radical abstract a halogen from a 2nd X2 molecule • chlorine radical product continues on in chain; starts the cycle over again by abstracting hydrogen from another alkane • radical chain mechanisms are faster than a stepwise mechanism which would require initiation in each step

University of Slide CHEM 232, Spring 2010 34 Illinois at Chicago UIC Lecture 8: February 4 34 Complete Mechanism

homolysis n o i Cl Cl Cl + Cl t a

i light (hν) t

i 7 valence

n electrons I

hydrogen H abstraction H Cl H C CH3 C CH3 + HCl

n H H o i

t 7 valence

a electrons g a p o

r halogen

P H abstraction H Cl Cl C CH 3 Cl C CH3 + Cl H H

University of Slide CHEM 232, Spring 2010 35 Illinois at Chicago UIC Lecture 8: February 4 35 Structure of Alkyl Radical Intermediates

• radicals are high energy intermediates; 7 valence electrons; cannot be isolated • sp2-hybridized; contain one empty p- orbital; unpaired electron in the p- C H orbital; H C 3 H • approximately planar: three bonds to carbon are at ~120º angles from each other and ~90º to half-!lled p-orbital alkyl radicals can be stabilized by inductive effects and hyperconjugation; • stabilized by inductive effects and similar to carbocations hyperconjugation

• Stability: 3º > 2º >> 1º > CH3

University of Slide CHEM 232, Spring 2010 36 Illinois at Chicago UIC Lecture 8: February 4 36 Stabilizing Effects on Alkyl Radicals

• smallest inductive effect • largest inductive effect • no hyperconjugation • most hyperconjugation

University of Slide CHEM 232, Spring 2010 37 Illinois at Chicago UIC Lecture 8: February 4 37 Bromination is More Selective Than Chlorination

H H † Cl † ∆Ea (chlorination) Hammond Postulate H3C CH3

‡ • chlorine radicals are higher in energy than bromine radicals = ∆Ea (bromination) H H ‡ • transition states in chlorination are earlier= Br H3C CH3 • look more like reactants = H H • less difference in TS energy = less selective = H3C CH2 • H • greater mixture † = early transition state structures

‡ = late transition state structures H3C CH3 • bromine radicals are lower in energy than ∆Ea (bromination) > ∆Ea (chlorination) chlorine radicals = Bromination is more selective. • transition states in bromination are later=

Relative Rates (krel) of Halogenation • look more like products (radical interm.) = R3CH R2CH2 RCH3 • greater difference in TS energy = (tertiary, 3º) (secondary, 2º) (primary, 1º) more selective = chlorination 5.2 3.9 1.0 • bromination 1640 82 1.0 • less of a mixture

University of Slide CHEM 232, Spring 2010 38 Illinois at Chicago UIC Lecture 8: February 4 38 Quantifying Selectivity

Relative Rates (krel) of Halogenation R3CH R2CH2 RCH3 (krel) x (statistical factor) (tertiary, 3º) (secondary, 2º) (primary, 1º) % = chlorination 5.2 3.9 1.0 total bromination 1640 82 1.0 Predicted Product Ratios

Product Relative Yield Absolute Yield

H A (2 2º H’s) 2 x 3.9 = 7.8 7.8/13.8 = 57% H H Cl2 H Cl H + H3C CH3 H3C CH3 H3C CH2 B (6 1º H’s) 6 x 1 = 6.0 6.0/13.8 = 43% Cl A: 57% B: 43% Sum 13.8 100% chlorination

A (2 2º H’s) 2 x 82 = 164 164/170 = 96% H H Br2 H Br H H + B (6 1º H’s) 6 x 1 = 6.0 6.0/170 = 4% H3C CH3 H3C CH3 H3C CH2 Br Sum 170 100% A: 96% B: 4% bromination

University of Slide CHEM 232, Spring 2010 39 Illinois at Chicago UIC Lecture 8: February 4 39 Self Test Question

Determine the predicted product distribution for A in the following clorination.

Br2 A. 99% + Br Br B. 97% C. 95% A B D. 93%

Relative Rates (krel) of Halogenation R3CH R2CH2 RCH3 E. 91% (tertiary, 3º) (secondary, 2º)(primary, 1º) chlorination 5.2 3.9 1.0 bromination 1640 82 1.0

University of Slide CHEM 232, Spring 2010 40 Illinois at Chicago UIC Lecture 8: February 4 40 CHEM 232 University of Illinois Organic Chemistry I at Chicago UIC

Next Lecture. . .

Chapter 5: Sections 5.1-5.9

41