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The Art of Writing Reasonable Organic Reaction MechanismsRobert B. Grossman

University of KentuckyProfessor of ChemistrySynthetic Organic Chemistry

1987 B.A., Princeton University1992 Ph. D., Massachusetts Institute of Technology1992-1994 Post-doctoral Fellow, Cambridge University

Michael B. SmithUniversity of ConnecticutA. C. KnipeUniversity of Ulster

Organic Reaction MechanismsOrganic SynthesisRobert B. GrossmanUniversity of Kentucky

(Basics of Organic Reactions)

(Reactions under Basic Conditions)

(Reactions under Acid Conditions)

(Pericyclic Reactions)

(Free Radical Reactions)

* (Metal-Catalyzed Reactions)30%30%30%20%10%:

: ,

: 5

Mechanisms are the means by which organic reactions are discovered, rationalized, optimized, and incorporated into the canon. They represent the framework that allows us to understand organic chemistry.

The purpose of this book is to help you learn how to draw reasonable mechanisms fororganic reactions. The general approach is to familiarize you with the classes and types ofreaction mechanisms that are known and to give you the tools to learn how to draw mechanisms for reactions that you have never seen before.

*Common error alerts are scattered throughout the text to warn you about common pitfalls and misconceptions that bedevil students. Pay attention to these alerts, as failure to observe their strictures has caused many, many exam points to be lost over the years.

The Basics of Organic ChemistryChapter OneCommon Abbreviations for Organic Substructures

Formal ChargeFormal ChargeFormal charges are a useful tool for ensuring that electrons are not gained or lost in the course of a reaction.

EX:

Calculate the formal charge of Al, N, Br, C*Common error alert: Formal charges are not a reliabe guide to chemical reactivity.CH3+ NH4+ which is more stable?6e-8e-Resonance StructureResonance StructureFor each bonding pattern, there are often several ways in which and nonbonding electronscan be distributed. These different ways are called resonance structures. The true electronic picture of a compound is a weighted average of the different resonance structures.

Benzene is neither this nor this.(1+2)/2= 1(1/2) bond

Diazomethane is neither this nor this.Which structure is more important?

Electronegativity: F> O> N> Cl

Types of Resonance Structure:1. Look for a electron-deficient atom adjacent to a bond.Resonance Structure

2. Look for a radical adjacent to a bond.Which structure is more important?

3. Look for a lone pair adjacent to a bond.

4. In aromatic compounds, bonds move around to form new resonance structure.

5. The two electrons of a bond can be divided evenly or unevenly between the two atoms making up that bond .

Draw the reasonable resonance structure of following compounds?

naphthaleneHyperconjugation: The bonding pair of electrons in the orbitals can delocalize into partlyP orbital.

3o cabocation9 adjacent C-H bonds2o cabocation6 adjacent C-H bonds1o cabocation3 adjacent C-H bonds>>Stability10Molecular Shape: Lewis Structure and Molecular Orbitals1. (H)A2. B3. (A- B)/2Draw the Lewis structure for following molecules and determinate the molecular shape?

HI, C22-, CH3OH, SiO2, O2, CS2, CN-Lewis Structureeg. COCl2A= 26B= 4+6+(7*2)= 24(26-24)/2= 1

SP2trigonal

Linear SPTrigonal SP2Tetrahedron SP3Molecular OrbitalsHybrid Orbitals1. Atomic Orbital(A.O.) Molecular Orbital(M.O.)Why hydrogen exits as H2, but helium is monoatomic?

BondingAntiondingH2

2. sp hybrids produce linear structure: 1800 degree results from minimizes electron repulsionBeH2

Be 1S22S22P0

2 H+.

Molecular ShapeHybrid Orbitals3. sp2 hybrids create trigonal structure

BH3

4. sp3 hybridization explain the shape of tetrahedral carbon compounds

CH4

B 1S22S22P1Structure and Stability of Organic CompoundsDetermine the hybridization of C, N, O, B and F atoms in each of following compounds?NH3, H2O, BF3,

Bond energy and bond lengthbond length(pm)bond energy(kJ/mol)C-C154348C=C134614120839

AromaticityAromatic1. Cyclic. 2. P orbitals. 3. Planar. 4. total e- = 4n+2 Stability: cyclic > acyclic >

Aromatic compounds

furan thiophene pyrrole indolenaphthalene azulene phenanthrene

Cyclopentadienide tropylium pyrylium

Explain why they are nonromatic compounds?

15Stability: acyclic > cyclic >

NonaromaticIf there is no cyclic array of continuously overlapping p orbitals, then the compound is nonaromatic.

Antiaromatic1. Cyclic. 2. P orbitals. 3. Planar. 4. total e- = 4nStructure and Stability of Organic Compounds

Nonaromatic

AcidityAcidity

stability1. ElectronegativityHF and H2Oelectronegativity: F > O acidity: HF > H2O

2. SizeHI, HBr and HClSize: I- > Br- > Cl- acidity: HI > HBr > HCl

3. Resonance

Resonance forms:

pKa ValuesAcidity

Indicate which of each pair of compounds is likely to be more acidic and why?

Kinetics and ThermodynamicsKinetics and ThermodynamicsChemical thermodynamics: determine the reaction will happen or not.

H0 is easier to measure and TS0 is small compared with H0 for most reaction(T Cl- , Et2S > Et2O

b. Nucleophilicity decrease with increase steric effect.eg. EtO- is good base and nuclephile, but tBuO- is good base bad nuclephile.Poor nuclephile and good base:LDA, LiN(SiMe3)3, DBU, TEA, EtN(i-Pr)2, t-BuLi

c. Nucleophilicity increase in polar aprotic solvent.

Polar ReactionTypes of nuclephile

a. Lone pair: N, O, S

b. Sigma bond: MHX, RMgBr, RLi, R2CuLi

c. Pi bond: weak nuclephile and weak electrophile. When bonds attach a electron-pull heteroatoms, it become much better nuclephile.

Nu

E+Polar ReactionTypes of electrophile

a. Lewis acid(BF3, AlCl3), Carbocationb. Sigma bond electrophile: Good leaving group(X)

c. Pi bond: When bonds attach a electron-withdrawing group.

Polar Reaction*Common error alert: If a reaction is under acidic conditions, no strong bases can be present! If a reaction is under basic conditions, no strong acids can be present!

Basic condition

Acidic condition

No R2O+H present No RO- present

Good base and acid cant exist in one structure.Free H+ and R3C+ should not be drawn under basic conditionsFree-Radical ReactionGeneration of Free-radical

a. Sigma bond homolysis and peroxide compounds

b. One-electron reagents:

c. The cycloaromatization

Oxidative: DDQ, p-Chlornail, CAN, Pb(OAc)4, Mn(OAc)3Reductive: Na, Li, SmI2,

Chain Reaction

Overall reactionFree-Radical Reaction

a. Initiation

b. Propagation

c. Termination

more stableInitiators:Br2, AIBN, (BzO)2, (t-Buo)2, AIBN with lightdimerizationeliminationPericyclic Reactiona. Electro cyclic reactions(ring opening or ring closing)

b. Cycloadditions(two bonds change to two bonds)

c. Sigmatropic( bond cleavage)

d. Ene reaction(six electrons, [4+2]cycloaddition and [1, 5]sigmatropic, allylic H)

Define the classes of the following pericyclic reaction?Exercises

Transition-Metal-Mediatd Reactions*Common error alert: a. TiCl4, FeCl3, AlCl3, AgOTf, ZnCl2 are common Lewis acids. b. FeCl2, TiCl3, SmI2, (NH4)2Ce(NO)6(CAN) are one-electron reducing or oxidizing agents.Transition-Metal-Mediated ReactionsPd, Os, Co, Rh, Ir, Cu

Classify each of the following reactions as polar, free radical, pericyclic or transition-metal-mediated.Exercises

a.b.c.d.e.f.h.g.