CHEM 494 University of Illinois Special Topics in Chemistry at Chicago UIC

CHEM 494 - Lecture 7

Prof. Duncan Wardrop October 22, 2012 CHEM 494 University of Illinois Special Topics in Chemistry at Chicago UIC

Halogenation of Alkanes Methods and Mechanism

Chapter 39 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 494, Spring 2010 3 Illinois at Chicago UIC Lecture 7: October 22 Stabilizing Effects on Alkyl Radicals

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

University of Slide CHEM 494, Spring 2010 4 Illinois at Chicago UIC Lecture 7: October 22 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 =

H3C CH2 • less selective = 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 494, Spring 2010 5 Illinois at Chicago UIC Lecture 7: October 22 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 494, Spring 2010 6 Illinois at Chicago UIC Lecture 7: October 22 Self Test Question

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

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 494, Spring 2010 7 Illinois at Chicago UIC Lecture 7: October 22 De"ning Regioselectivity

Regioselectivity (regioselective) A regioselective reaction is one in which one direction of bond making or breaking occurs preferentially over all other possible directions. Reactions are termed completely (100%) regioselective if the discrimination is complete, or partially (<100%), if the product of reaction at one site predominates over the product of reaction at other sites. The discrimination may also semi-quantitatively be referred to as high or low regioselectivity.

IUPAC Compendium of Chemical Terminology 2nd Edition (1997)

Br

O N O

CCl , hν 4 Cl Cl Cl

Regioselective Chlorination...... not stereoselective!

University of Slide CHEM 494, Spring 2010 8 Illinois at Chicago UIC Lecture 7: October 22 Mechanism of Alkane Chlorination

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 ~1,000,000 cycles electrons

g per initiation step a p o

r halogen

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

University of Slide CHEM 494, Spring 2010 9 Illinois at Chicago UIC Lecture 7: October 22 Factors Governing Regioselectivity

Cl Cl2 + Cl hν 45% 55% • Strength of C-H Bond Broken

Cl2 Cl + Cl • Number & Type of Substrate C-H Bonds hν

63% 37% • Strength of C-X Bond Formed and X-X Bond Broken Br Br2 + Br hν >99% <1%

University of Slide CHEM 494, Spring 2010 10 Illinois at Chicago UIC Lecture 7: October 22 Bromination is More Selective Than Chlorination

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

‡ • chlorine radicals are higher in energy than bromine radicals = ∆Ea (bromination) H H ‡ • transition states in chlorination are earlier = Br look more like reactants = H3C CH3 • H H • less difference in TS energy = less selective = H C CH • 3 2 • greater mixture H † = 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 494, Spring 2010 11 Illinois at Chicago UIC Lecture 7: October 22 Quantifying Selectivity of Halogenation

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 494, Spring 2010 12 Illinois at Chicago UIC Lecture 7: October 22 Self Test Question

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

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 494, Spring 2010 13 Illinois at Chicago UIC Lecture 7: October 22 CHEM 494 University of Illinois Special Topics in Chemistry at Chicago UIC

Nomenclature & Stereoisomerism in Alkenes The Terms Alkene and Ole"n are Synonymous

H H • Alkenes are hydrocarbons that are C C characterized by a C-C double bond • Also called “ole!ns” H H • General molecular formula = CnH2n • Described as unsaturated since they have two fewer H atoms than ethylene equivalent alkanes C2H4

University of Slide CHEM 494, Spring 2010 15 Illinois at Chicago UIC Lecture 7: October 22 Index of Hydrogen De"ciency (IHD)

IHD is synonymous with degrees of unsaturation and indicates the number of double/triple bonds and/or rings in a molecule IHD = 1 (1 double bond)

IHD = 4 (3 double bonds & 1 ring)

IHD = 2 (2 rings)

IHD = 1 (one ring)

University of Slide CHEM 494, Spring 2010 16 Illinois at Chicago UIC Lecture 7: October 22 Calculating IHD

1. Hydrocarbons (CnHx) and Oxygenates (CnHxOy): Ignore O (2n+2) - X IHD = 2

2. Compounds with N (CnHxNy): Subtract # N from # H (2n+2) - (X-Y) IHD = 2

3. Halogens (CnHxXy): Add # Halogens to # H (2n+2) - (X+Y) IHD = 2

University of Slide CHEM 494, Spring 2010 17 Illinois at Chicago UIC Lecture 7: October 22 IHD & The Chemistry of Margarine

Employing equation 1 (slide 12)...... O linolenic acid OH m.p. -11 °C C18H30O2 IHD = 4

H2 / Ni O linoleic acid OH m.p. -5 °C C18H32O2 IHD = 3

H2 / Ni O oleic acid OH m.p. 16 °C

C18H34O2 IHD = 2

H2 / Ni O stearic acid OH m.p. 71 °C

C18H36O2 IHD = 1

University of Slide CHEM 494, Spring 2010 18 Illinois at Chicago UIC Lecture 7: October 22 IUPAC Naming of Alkenes

Cl H H 2 C C H CH CHCH 1 4 2 3 3 5 Cl 4-chloro-1-pentene or 4-chloropent-1-ene Steps: 1. Number longest chain that includes both alkene carbons so that they have the lowest locants. 2. Replace -ane ending of parent alkane with -ene (alkene). 3. In the name, list the locant of only the !rst alkene carbon. Conventions/Rules: • alkenes have higher priority over alkane and halide substituents when numbering the longest chain • alcohols have higher priority over alkenes when numbering the longest chain • locant may be placed in front of parent name (e.g. 2-pentene) or in front of suffix (e.g. pent-2-ene).

substituent 1st alkene locant parent base “ene” alphabetically locant

University of Slide CHEM 494, Fall 2012 19 Illinois at Chicago UIC Lecture 7: October 22 IUPAC Naming of Alkenols

OH 1 2 H3C CH2CHCH3 5 3 C C 6 4 OH H3C H 4-hexen-2-ol or hex-4-en-2-ol Steps: 1. Number longest chain that contains both the alkene and the alcohol and so that the alcohol group has lowest locant value. 2. Replace -ane ending of parent alkane with -ene (alkene). 3. In the name, list the locant of only the first alkene carbon. Conventions/Rules: • alkenes have higher priority over alkane and halide substituents when numbering the longest chain • alcohols have higher priority over alkenes when numbering the longest chain • locant may be placed in front of parent name (e.g. 2-pentene) or in front of suffix (e.g. pent-2-ene). • when “ene” does not occur at the end of a name, drop the last “e” alkene -OH parent base “en” “ol” locant locant

University of Slide CHEM 494, Fall 2012 20 Illinois at Chicago UIC Lecture 7: October 22 IUPAC Functional Group Priorities for Numbering Longest Chains

Priority Functional Group Suffix Substituent Name

3 halide n.a. halo

3 alkane -ane alkyl

Increasing Priority 2 alkene -ene -en (or alkenyl)

1 alcohol (-OH) -ol hydroxy We will add to this table as we encounter more functional groups in IUPAC nomenclature.

University of Slide CHEM 494, Spring 2010 21 Illinois at Chicago UIC Lecture 7: October 22 Common Alkenyl Group Names

H H C Methylene Vinylic R R H-atoms R R

H H C Vinyl C R R H

H H H Allylic C C Allyl H-atoms H C R R H

H H H

H C Propenyl C R R H

University of Slide CHEM 494, Spring 2010 22 Illinois at Chicago UIC Lecture 7: October 22 Alkene Structure & Bonding

• carbons in an alkenes are sp2 hybridized • bond angles are ~120º around sp2 hybridized carbons • geometry around sp2-carbons is planar ($at)

110 pm H H 134 pm 117.2° C C H H 121.4°

University of Slide CHEM 494, Spring 2010 23 Illinois at Chicago UIC Lecture 7: October 22 Double Bond = 1 π-Bond + 1 σ-Bond

A double bond is formed by two orbital overlaps

1 pi (π) bond side-to-side overlap of two p-orbitals; 2 π-electrons

1 sigma (σ) bond head-to-head overlap of two sp2-orbitals

University of Slide CHEM 494, Spring 2010 24 Illinois at Chicago UIC Lecture 7: October 22 Bond Rotation of Alkanes vs. Alkenes

CH H3C 3 H3C H H H H

E H H H CH3 H e v i t Ea a l CH e 3 -1 r H3C H H H Rotational Barrier = 19.26 kJmol H H (rotation about single C-C bond) H CH H H 3 CH anti-butane 3

H CH3

H3C H trans-butene E

e v i t E -1 a a

l Rotational Barrier = 260 kJmol e r (rotation involves breaking C=C bond) H H

H3C CH3 cis-butene

University of Slide CHEM 494, Spring 2010 25 Illinois at Chicago UIC Lecture 7: October 22 Alkenes Resist Rotation Round C=C Bond

90º rotation

• π-bond prevents full rotation around double bond • 90º rotation would break π-bond to generate diradical • substituents on alkene “locked” in spacial relationships • some rotation is possible through pyramidalization (more on this topic later)

University of Slide CHEM 494, Spring 2010 26 Illinois at Chicago UIC Lecture 7: October 22 Photolysis Mediates C=C Bond Rotation

H light (hν) H H H H H H CH3 C C CH H C H3C 3 3 CH3 H3C CH3 H3C H

diradical has C-C mixture of cis and trans single bond

π* antibonding M.O. C C

light (hν) promotion of electron to antibonding orbital cancels out C=C bond

C C π bonding M.O.

University of Slide CHEM 494, Spring 2010 27 Illinois at Chicago UIC Lecture 7: October 22 Geometrical Stereoisomers of Alkenes

H CH H C H H CH2CH3 3 H3C CH3 3 C C C C C C C C H H H CH3 H H H CH3

1-Butene 2-Methylbutene cis-2-Butene trans-2-Butene

H CH H CH2CH3 3 Identical C C C C Identical H H No possible H CH3 stereoisomers

1-Butene 2-Methylbutene

• restricted rotation around double bond gives cis and trans geometrical isomers (stereoisomers) • cis and trans: relationship between two vicinal groups on alkene • cis: same side; trans: opposite sides

University of Slide CHEM 494, Spring 2010 28 Illinois at Chicago UIC Lecture 7: October 22 Constitutional vs. Con"gurational Isomers

isomers

Do the molecules have the same connectivity? constitutional no yes (structural) stereoisomers

Can the molecules be trans (E) interconverted by rotation around single bonds?

cis (Z) yes no

conformational configurational

University of Slide CHEM 494, Spring 2010 29 Illinois at Chicago UIC Lecture 7: October 22 Stereoisomers

stereoisomers

Can the molecules be interconverted by rotation around single bonds? yes no

conformational configurational

Is the isomerism at a doulbe bond? yes trans (E) no geometrical optical cis (Z)

University of Slide CHEM 494, Spring 2010 30 Illinois at Chicago UIC Lecture 7: October 22 E-Z Nomenclature for Alkenes

Higher ranked Higher ranked substitutuents on the substitutuents on the same side opposite side

Higher Cl Br Higher Higher Cl F Lower C C C C Lower H F Lower Lower H Br Higher

Z configuration E configuration

• Groups are ranked according to atomic number • Higher atomic number = higher rank • Z (zusammen) = together; highest priority group on each alkene carbon on same side • E (entgegen) = opposite; highest priority group on each alkene carbon on opposite sides

University of Slide CHEM 494, Spring 2010 31 Illinois at Chicago UIC Lecture 7: October 22 Cahn-Ingold-Prelog (CIP) Rules for Prioritizing

–C(C,H,H) –C(C,H,H) –C(C,H,H)

Br Br

Cl Cl

–C(C,H,H) –C(H,H,H) –C(C,C,H) Z E

• when geminal atoms are identical, compare “forward” atoms attached to these on the basis of atomic weight (list in decreasing order) • work outward (one atom at a time) until point of difference is reached

University of Slide CHEM 494, Spring 2010 32 Illinois at Chicago UIC Lecture 7: October 22 Cahn-Ingold-Prelog (CIP) Rules for Prioritizing

–C(O,O,C)

Cl O

H3C O HO –C(O,C,H) E

• an atom that is multiply bonded to another atom is listed as two separate atoms for nomenclature purposes • remember to list attached atoms in decreasing order of atomic weight • highest priority = highest atomic weight at "rst point of difference

University of Slide CHEM 494, Spring 2010 33 Illinois at Chicago UIC Lecture 7: October 22 Why Alkene Geometry Matters

Geometry in$uences molecular shape and, in turn, physical, chemical & biological properties. . . .

Z Configuration HO OMe Vascular targeting agent MeO MeO OMe

Combretastatin A4 (CA-4)

MeO

OMe HO E Configuration OMe Biologically Inactive! Combretum caffrum OMe

epi-Combretastatin A4 (CA-4) S.A. bush willow tree

University of Slide CHEM 494, Spring 2010 34 Illinois at Chicago UIC Lecture 7: October 22 IUPAC: Stereoisomeric Alkenes

2 4 3 H CH2CH3 1 5 C C

H3C CH3

(E)-3-methyl-2-pentene or (E)-3-methylpent-2-ene Steps: 1. Number the longest chain. 2. Replace -ane ending of parent alkane with -ene or -en, depending on priority. 3. In the name, list the locant of only the first alkene carbon. 4. Indicate geometrical isomers with (Z) or (E) at the beginning of the name. Conventions/Rules: • Z and E are italicized • Z and E are placed within parentheses at beginning of name: (Z) & (E). • cis and trans may be substituted for E/Z when alkene is 1,2-disubstituted

“(E)” alkene parent base “ene” “(Z)” locant

University of Slide CHEM 494, Fall 2012 35 Illinois at Chicago UIC Lecture 7: October 22 CHEM 494 University of Illinois Special Topics in Chemistry at Chicago UIC

Relative Stabilities of Alkenes Relative Stabilities of Alkenes

Observations: • more stable = lower in energy = lower heat of combustion • cis alkenes higher in energy than trans alkenes • more alkyl group on alkene = more stable

University of Slide CHEM 494, Spring 2010 37 Illinois at Chicago UIC Lecture 7: October 22 Relative Stabilities of Alkenes

1. Steric Effects

van der Waals strain strain between cis groups

H

H H H

(Z)-2,2,5,5-tetramethylhex-3-ene (E)-2,2,5,5-tetramethylhex-3-ene

(less stable) (more stable)

Energy Difference = 44 kJmol-1

University of Slide CHEM 494, Spring 2010 38 Illinois at Chicago UIC Lecture 7: October 22 Relative Stabilities of Alkenes

2. Substituent Effects alkyl groups stabilize alkenes through donation (via induction and hyperconjugation) to the more electronegative sp2-hybridized carbon atoms

H R H R H R C C C C C C Stability H H H R R H geminally vicinally monosubstituted disubstituted disubstituted

R R R R C C C C H R R R trisubstituted tetrasubstituted

University of Slide CHEM 494, Spring 2010 39 Illinois at Chicago UIC Lecture 7: October 22 CHEM 494 University of Illinois Special Topics in Chemistry at Chicago UIC

Preparation of Alkenes Elimination

Chapter 19 β-Elimination Reactions

Summary of β-Elimination (1,2-elimination) Reactions

1 1 2 2 X C C Y C C + X Y α β α β

1 1 2 Dehydrogenation 2 H C C H C C + H H α β α β

1 1 2 Dehydration 2 H C C OH C C + H OH α β α β

1 1 2 Dehydrohalogenation 2 H C C X C C + H X α β α β

University of Slide CHEM 494, Spring 2010 41 Illinois at Chicago UIC Lecture 7: October 22 Dehydrogenation

• limited to industrial synthesis of ethylene, propene, 1,3-butadiene and styrene • important economically, but rarely used in laboratory-scale syntheses • living systems utilize enzymes to catalyze this process

University of Slide CHEM 494, Spring 2010 42 Illinois at Chicago UIC Lecture 7: October 22 Strong Acids Catalyze the Dehydration of 2° & 3 ° Alcohols

H H2SO4 β OH • H2SO4 and H3PO4 are 140 ºC most common acids used for dehydration: protonation of OH OH H PO 3 4 group is "rst step Hβ 140 ºC • dehydration is reversible (hydration) in aqueous acid OH KHSO 4 (Chapter 6)

Hβ 140 ºC

University of Slide CHEM 494, Spring 2010 43 Illinois at Chicago UIC Lecture 7: October 22 Industrial Example of Dehydration

NMe2 NMe2 NMe2

O H2SO4 O O

OH

 OH Tamoxifen (Nolvadex )

Tamoxifen mimics estrogens, H such as estradiol, and inhibits their binding to the estrogen H H receptor in breast tissue HO Estradiol

Tamoxifen blocks cancer cell growth

University of Slide CHEM 494, Spring 2010 44 Illinois at Chicago UIC Lecture 7: October 22 Dehydration can be “Coupled” with Other Chemical Transformation

Cl Cl Cl OH O HF HF N N N

N N N Me Me Me

Loratidine (Claritin)

Two-step, one-pot transformation involves a Friedel-Crafts reaction (see, Chapter 12) and dehydration of the resulting 3° alcohol

University of Slide CHEM 494, Spring 2010 45 Illinois at Chicago UIC Lecture 7: October 22