The Art of Writing Reasonable Organic Reaction Mechanisms
Robert B. Grossman
University of Kentucky
Professor of Chemistry
Synthetic Organic Chemistry
1987 B.A., Princeton University
1992 Ph. D., Massachusetts Institute of Technology
1992-1994 Post-doctoral Fellow, Cambridge University
課程須知
參考書目
Robert B. Grossman
University of Kentucky
Organic Synthesis
Michael B. Smith
University of Connecticut
Organic Reaction Mechanisms
A. C. Knipe
University of Ulster
課程須知
授課大綱
一、有機化學反應機制的基本原則
(Basics of Organic Reactions)
二、鹼性條件下的有機化學反應
(Reactions under Basic Conditions)
三、酸性條件下的有機化學反應
(Reactions under Acid Conditions)
四、環化反應
(Pericyclic Reactions)
五、自由基反應
(Free Radical Reactions)
*六、過渡金屬催化有機反應
(Metal-Catalyzed Reactions)
評量方式
期中考
期中考
期末考
隨堂測驗
期末報告
30%
30%
30%
20%
10%
期末考範圍:
整學期授課內容
隨堂測驗:
每節課開始, 共兩題。
期末報告:
最後一節課分組報告，兩人一組，
每組5分鐘，並於課後繳交報告。
課程須知
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 for
organic reactions. The general approach is to familiarize you with the classes and types of
reaction 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.
Chapter One
The Basics of Organic Chemistry
Common Abbreviations for Organic Substructures
Formal Charge
Formal Charge
Formal 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 Structure
Resonance Structure
For each σ bonding pattern, there are often several ways in which π and nonbonding electrons
can 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
Resonance Structure
Types of Resonance Structure:
1. Look for a electron-deficient atom adjacent to a π bond.
Which structure is more important?
2. Look for a radical adjacent to a π bond.
3. Look for a lone pair adjacent to a π bond.
5. The two electrons of a π bond can be divided
evenly or unevenly between the two atoms
making up that bond .
Draw the reasonable resonance structure
of following compounds?
4. In aromatic compounds, π bonds move around to
form new resonance structure.
naphthalene
Hyperconjugation: The bonding pair of electrons in the σ orbitals can delocalize into partly
P orbital.
Stability
>
3o cabocation
9 adjacent C-H bonds
>
1o cabocation
2o cabocation
6 adjacent C-H bonds 3 adjacent C-H bonds
Molecular Shape: Lewis Structure and Molecular Orbitals
Lewis Structure
1. 劃出分子結構，並使所有原子符合八隅體(H例外)，統計其電子數A
2. 計算所有原子的價電子數總和B
3. (A- B)/2為共用電子對，一般形成共用電子對的方法為環、雙鍵或三鍵
Linear
Trigonal
Tetrahedron
SP
SP2
SP3
eg. COCl2
A= 26
B= 4+6+(7*2)= 24
(26-24)/2= 1
SP2
trigonal
Draw the Lewis structure for following molecules and determinate the molecular shape?
HI, C22-, CH3OH, SiO2, O2, CS2, CN-
Molecular Orbitals
Hybrid Orbitals
1. Atomic Orbital(A.O.)
H2
Antionding
Molecular Orbital(M.O.)
Why hydrogen exits as H2, but helium is monoatomic?
Bonding
2. sp hybrids produce linear structure: 1800 degree results from minimizes electron repulsion
BeH2
Be 1S22S22P0
.
2 H+
Molecular Shape
Hybrid Orbitals
3. sp2 hybrids create trigonal structure
BH3
B 1S22S22P1
4. sp3 hybridization explain the shape of tetrahedral carbon compounds
CH4
Structure and Stability of Organic Compounds
Bond energy and bond length
C-C
C=C
bond length(pm)
154
134
120
bond energy(kJ/mol)
348
614
839
Determine the hybridization of C, N, O, B and F atoms in each of following compounds?
NH3, H2O, BF3,
Aromaticity
Aromatic
1. Cyclic. 2. P orbitals. 3. Planar. 4. total e- = 4n+2
Stability: cyclic > acyclic
>
Aromatic compounds
naphthalene
azulene
phenanthrene
furan thiophene pyrrole
indole
Cyclopentadienide tropylium pyrylium
Explain why they are nonromatic compounds?
Structure and Stability of Organic Compounds
Antiaromatic
1. Cyclic. 2. P orbitals. 3. Planar. 4. total e- = 4n
Stability: acyclic > cyclic
>
Nonaromatic
Nonaromatic
If there is no cyclic array of continuously overlapping p orbitals, then the compound is
nonaromatic.
Acidity
Acidity
stability
1. Electronegativity
HF and H2O
electronegativity: F > O acidity: HF > H2O
2. Size
HI, HBr and HCl
Size: I- > Br- > Cl- acidity: HI > HBr > HCl
3. Resonance
Resonance forms:
pKa Values
Acidity
+
pKa = -log
−
H [X ]
[HX]
Indicate which of each pair of compounds is likely to be more acidic and why?
Kinetics and Thermodynamics
Kinetics and Thermodynamics
Chemical thermodynamics: determine the reaction will happen or not.
ΔH0 is easier to measure and TΔS0 is small compared with ΔH0 for most reaction(T<100oC).
Chemical Kinetics: determine how fast of the reaction.
TS
ΔG‡
ΔG‡: activation energy
TS: trasition state
Kinetic or thermodynamic control
Kinetic or thermodynamic control
Endo Rule
Originate from an attractive interaction between the
π system of the diene and dienophile.
endo
exo
One of the joys of orgaic chemistry is designing condition under
which only the kinetic or themodynamic product is obtained.
*Common error alert: Don’t confuse TS and Intermediate.
TS
Intermediate
Basics in Drawing a Mechanism
Getting Started in Drawing a Mechanism
Classes of Overall Transformation
Classes of Overall Transformation
1. In a addition reaction, two S.M. combine to give a single product. Usually a π bond in one
S.M. is replaced by two σ bond.
2. In a elimination reaction, one S.M. is divided into two products. Usually two σ bond in
one S.M. are replaced by a new π bond.
Classes of Overall Transformation
Classes of Overall Transformation
3. In a substitution reaction, an atom or group that is σ bond to the rest of S.M. is replaced
by another σ bond atom or group.
4. In a rearrangement, one S.M. gives one product with a different structure.
Classes of Mechanisms
Classes of Mechanisms(polar, radical, pericyclic, metal-mediated reaction)
1. Polar Reaction: The chemistry of nuclephiles and electrophiles.
Nuclephile
a. Nucleophilicity increase as you go down the period table(polarizability).
eg. I- > 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 Reaction
Types of nuclephile
a. Lone pair: N, O, S…
b. Sigma bond: MHX, RMgBr, RLi, R2CuLi
c. Pi bond: weak nuclephile and weak electrophile. When π bonds attach a electron-pull
heteroatoms, it become much better nuclephile.
Nu
E+
Polar Reaction
Types of electrophile
a. Lewis acid(BF3, AlCl3), Carbocation
b. Sigma bond electrophile: Good leaving group(X)
c. Pi bond: When π bonds attach a electronwithdrawing 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
No R2O+H present
Acidic condition
No RO- present
Free H+ and R3C+
should not be
drawn under basic
conditions
Good base and acid can’t
exist in one structure.
Free-Radical Reaction
Generation of Free-radical
a. Sigma bond homolysis and peroxide compounds
b. One-electron reagents:
Oxidative: DDQ, p-Chlornail, CAN, Pb(OAc)4, Mn(OAc)3…
Reductive: Na, Li, SmI2, …
c. The cycloaromatization
Free-Radical Reaction
Chain Reaction
Overall reaction
a. Initiation
Initiators:
Br2, AIBN, (BzO)2, (t-Buo)2, AIBN with light
b. Propagation
c. Termination
dimerization
elimination
more stable
Pericyclic Reaction
a. Electro cyclic reactions(ring opening or ring closing)
b. Cycloadditions(two π bonds change to two σ bonds)
c. Sigmatropic(σ bond cleavage)
d. Ene reaction(six electrons, [4+2]cycloaddition and [1, 5]sigmatropic, allylic H)
Exercises
Define the classes of the following pericyclic reaction?
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 Reactions
Pd, Os, Co, Rh, Ir, Cu…
Exercises
Classify each of the following reactions as polar, free radical, pericyclic or transition-metalmediated.
a.
b.
c.
d.
e.
f.
h.
g.