Chemistry 5.

12 Spring 2003
Lectures #1 & 2, 2/5,7/03

Outline
Discuss General Class Information (Professor Imperiali)

General Introduction to Organic Chemistry

I. Review of Lewis Bonding Theory (Read Chapter 1)

A. Ionic Bonding (1-3A,6,8)
B. Covalent Bonding (1-3B,4)
1. Multiple Bonding (1-5)
2. Formal Charge (1-7)
C. Short-Hand for Chemists
1. Line-Angle Formulas: Simplified Structures (1-10)
2. Dashes and Wedges: Molecules in 3-D (2-5)
3. Curved Arrow Formalism: Electrons in Motion (1-14)
II. Resonance (1-9)
A. Rules for Drawing Resonance Structures
B. Relative Energy of Resonance Structures
C. Structure and Reactivity from Resonance

Suggested Problems: 1-25,36,39,41

Problem Set #1 Posted: Due Monday 2/10 by 4pm

Organic Chemistry 5.12 Spring 2003

Prof. Barbara Imperiali Dr. Sarah Tabacco

Text: Organic Chemistry, L.G. Wade, Jr., 5th Ed.

Recitations: Twice a week, beginning second week. Section changes should be made
through the 5.12 website. All changes must be made by Friday 2/14.

Problem Sets: Turn in to TA's box in Chem. Ed. office by 4pm on the due date.
Lowest grade will be dropped. No late work accepted.

Midterms: During class period. Lowest grade will be dropped. No make-up exams.

Exam #1 Friday, 2/21

Exam #2 Friday 3/14
Exam #3 Monday, 4/14
Exam #4 Monday, 5/5

Grading: Upon request, exams can be regraded within one week.

Problem sets will not be regraded.

Problem Sets: 10%

Midterm Exams: 50%
Final Exam: 40%

 Organic Chemistry: What is it?

1780: Organic compounds very complex and only obtained from living sources (vitalism)

Vitalism: Belief that a "magic" vital force, present in plants and animals, is necessary for
the synthesis of organic compounds

1789: Antoine Laurent Lavoisier observed that organic compounds are composed
primarily of carbon and hydrogen

1828: Friedrich Wohler synthesized an organic compound (urea) from inorganic

compounds (lead cyanate and ammonium hydroxide).

O
heat
Pb+NCO NH4+OH NH4+NCO C
H2N NH2
lead ammonium ammonium
cyanate hydroxide cyanate urea

inorganic organic

Modern organic chemistry is the chemistry of carbon compounds.

"The Age of Organic Chemistry"

> 95% of All Known Compounds Composed of Carbon

Organic Chemistry Crucial to Our Way of Life:

Clothing, Materials (Polymers), Petroleum, Medicine, OUR BODIES

> 50% of Chemists Are Organic

STRUCTURE MECHANISM SYNTHESIS

Determining the Way in Understanding the Building Complex
Which Atoms Are Put Reactivity of Molecules: Molecules From Simple
Together in Space to How and Why Chemical Molecules Using
Form Complex Molecules Reactions Take Place Chemical Reactions

 Why Carbon?
Carbon forms a variety of strong covalent bonds to itself and other atoms.

This allows organic compounds to be structurally diverse.

OH OH
O CH3 CH3
NH2

N NH H CH3 H
N

N N O H H H H
N H H
HO O
DNA Bases Hormones
O
OH OH H H H2N CH C OH
O O
H O
OH H CH 2
H HO H 2N CH C OH
H H HO
H OH
OH CH3
H OH
OH OH H

Carbohydrates Amino Acids

Why Does Carbon Bond in This Way?

I. Review of Lewis Bonding Theory (READ CH 1)

Atoms transfer or share electrons to gain a filled valence shell of electrons.

A. Ionic Bonding
Between atoms of widely different electronegativity (EN>2); usually a metal and
a non-metal; atoms held together by electrostatic attraction, not electron sharing

e.g. LiF is ionic (EN: Li = 1.0. F = 4.0)

Li Li+ + e H = +123.6 kcal/mol

(ionization potential)
1s22s1 1s2 = [He]

F + e F H = 78.3 kcal/mol
(electron affinity)
1s22s22pX22pY22pZ1 1s22s22p6 = [Ne]

Using Lewis Dot Structures:

electron
Li + F Li + F LiF (ionic bond)
transfer
Bond Energy ~138 kcal/mol

 B. Covalent Bonding (Electron Sharing)

Very important in organic molecules!
Between atoms of similar electronegativity; usually non-metallic

e.g. CCl4 is covalent . . . Why?

Large thermodynamic penalty for ionization of carbon to C4+

C C4+ + 4e H = +1480.7 kcal/mol

(ionization potential)
1s22s22px12py1 1s2 = [He]

Instead, each chlorine atom shares one valence electron with carbon so that every
atom has a filled octet.
Cl Cl
C 4 Cl Cl C Cl Cl C Cl
Cl Cl
Kekule Drawing
Each chlorine atom still has three unshared pairs of electrons (lone pairs).

lone pair: unshared electron pair; non-bonding pair of electrons

How can you tell how many bonds and how many lone pairs an atom will have?

Count the Valence Electrons!

neutral atom # valence es # bonds # lone pairs

H 1 1 0
C 4 4 0
N 5 3 1
2nd row
O 6 2 2
F 7 1 3

Second row elements want to be surrounded by eight valence electrons (an octet).

e.g. Carbon wants four more electrons (4 bonds).

X X
C 4 X X C X X C X
X X

e.g. Nitrogen wants three more electrons (three bonds, one lone pair).

N 3 X X N X X N X
X X

 1. Multiple Bonding
Two atoms can share more than one pair of electrons to gain a filled shell
(very common in organic molecules)

e.g. Ethylene (C2H4)

H H H H
2 C 4 H C C C C double bond:
2 pairs of electrons
H H H H

e.g. Acetylene (C2H2)

2 C 2 H H C C H H C C H triple bond:
3 pairs of electrons

Each line represents one shared electron pair.

Summary of Bonding (Neutral Atoms)

H C C C C N N N O O F

2. Formal Charge
Not all atoms are neutral in a Lewis or Kekule structure
Formal charges help chemists to keep track of the placement of electrons in molecules
Does not indicate that all of the charge is actually localized on one atom

Formal Charge = (group #) (# non-bonding es) 1/2 (# shared es)

e.g. [H3COH2]+ Which atom has the formal charge?

H H
C: F.C. = 4 0 4 = 0
H C O O: F.C. = 6 2 3 = +1
H H

Oxygen is charged. H H
H C O H3C OH2
H H

Always indicate formal charge on problem sets and exams!

 Summary of Bonding (Charged Atoms)

C C C N N N O O O

not common

3 bonds 4 bonds 3 bonds

C C C N N O

3 bonds 2 bonds 1 bond

Be able to recognize common bonding patterns.

C. Short-Hand for Chemists: Easy Communication

1. Line-Angle Formulas: Drawing Complex Molecules Quickly
H H OH
H CH3 H H3C OH
H C C
H H CH C C H
H 3 H C H H3C H
H H H C C C C
C C C
H C H H H H
H H
C C C C C H H
H H O C C O
H H
H H HH
Propane Testosterone much easier!
(pretty easy) (not so easy)
HO H2C H
H
H3C H O O
CH3 H CH3
O H CH3 O
H H H O
O H
O O H
O O O H
H H
H H H H
O

Brevetoxin A (!!)

 Rules for Drawing Line-Angle Formulas

Bonds are represented by lines (one line = two shared electrons)

Do not draw carbon or hydrogen atoms, except at termini (for aesthetics)

Assume carbon atoms are at ends of lines and where they meet

Assume enough CH bonds to give each carbon atom four bonds (an octet)

Draw heteroatoms and attached hydrogen atoms (N,O,S,P,F,Cl,Br,I, etc.)

e.g. isopropanol: CH3CH(OH)CH3 e.g. cyclohexanone

H O O
H H
H O OH OH C
H H or H C C H
C
C C H3C CH3 H C C H
H H C
H H HH HH

2. Using Dashes and Wedges: Molecules Are Not Flat!

Tetra-Substituted Carbon Is Tetrahedral (more on this later).

lines H
H
CH4 109.5 dash
C
methane H H
H H H wedge
H
lines: in the plane of the paper
dashes: going back into the paper (away from you)
wedges: coming out of the paper (toward you)

e.g. Propane e.g. Isomers of 1,2-Cyclohexanediol

OH OH
H H
H H OH OH

H H
H H

 Representing Molecules

Lewis/Kekule Structures: Represent atoms sharing electrons to form bonds

Line-Angle Structures: Simplify the drawing of complex molecular structures

Dashes and Wedges: Allow chemists to draw molecules in 3-D

BUT! These simplified structures do not accurately represent the

electronic nature or reactivity of organic molecules!

It helps to think about electrons in motion . . .

BUT HOW DO WE REPRESENT ELECTRONS IN MOTION?

3. Curved Arrow Formalism (Arrow Pushing)

Chemists use arrows to represent the motion of electrons within and between molecules.

double arrow: fishook arrow:

2 electrons moving 1 electron moving

1. The tail starts at the electrons that are moving (lone pair or bond).
2. The head shows where the electrons end up (lone pair or bond).

e.g. electron motion in a substitution reaction (much more detail later)

(l.p. to bond)

H2N H3CCl H2NCH3 Cl

(bond to l.p.)

 Sample Problem: Using What You Know

Use what you know about Lewis bonding to predict the product of the
following reaction. Remember to indicate formal charge. Use curved arrows
to show the mechanism (movement of electrons).
H3N BH3 ?

N H Nitrogen atom is nucleophilic (nuclei-loving).

H H
8 electrons nucleophile: electron-rich atom, often negatively
(1 lone pair) charged, with a free lone pair to donate to another atom

H
Boron atom is electrophilic (electron-loving).
B
H H
electrophile: electron-poor atom with a low-lying vacant or
6 electrons
easily vacated orbital; wants to accept electrons from a
(wants 2 more)
nucleophile

H3N BH3 H3NBH3

Formal Charge: N: 5 0 4 = +1
B: 3 0 4 = 1

Chemical reactions generally involve the movement of electrons between two

or more molecules, but electrons also move within a molecule.

II. Resonance: Electronic Motion Within a Molecule

The reactivity of a molecule is not always explained by one Lewis structure.

Molecules can be thought of as hybrids or weighted averages of two or more Lewis

structures, each with a different placement of electrons.

These structures, called resonance structures, are not real or detectable, but they are a
useful conceptual tool for understanding the reactivity of molecules.

 e.g. How can you predict where a nucleophile (such as H2N) will react
with formaldehyde (CH2O)?

O
H2N ?
H H

Use resonance to better understand the electronic nature of formaldehyde . . .

O O O

H H H H H + H
major minor
The minor resonance structure suggests that the carbon atom is
electron-deficient (electrophilic).

The nucleophile will react with the electrophilic carbon atom.

O H2N O
H2N
H + H H H

A. Rules for Drawing Resonance Structures

1. Only electrons move! Nuclei and the sigma- (single bond-) framework are

unchanged (Resonance occurs in the pi-system: conjugated lone pairs and pi-bonds).

2. Every resonance structure must be a valid Lewis structure.

3. Keep track of lone pairs and formal charges.

4. Use arrow-pushing formalism to interconvert and identifiy possible resonance

structures.

5. Always use double-headed arrow ( ) in between resonance structures.

6. Lower energy resonance structures contribute most to the overall structure of the

molecule.

How do you predict the relative energies of resonance structures?

10

 B. Guidelines for Predicting Energies of Resonance Structures

(In Order of Importance)

i) Filled Octets: Second row elements (C, N, O , F) want an octet (filled valence
shell of electrons). Because C is the least electronegative, structures in which C has
6 electrons, 3 bonds and a positive charge are possible (not possible with N, O, F).

ii) Negative charges on most electronegative atoms.

iii) Minimize charge separation.

H2C CH3 H2C CH3 H2C CH3

N N N
CH3 CH3 CH3

major minor minor

follows guidelines violates i violates i

N N N
H3C C H3C C H3C C
O O O

A B C

N N
H3C C H3C C
O O

D E

A: follows guidelines
B: violates iii: 2 formal charges
C: violates ii & iii: negative charge on C; 2 formal charges
D: violates i & iii: 6 electrons on C; 2 formal charges
E: violates i & iii: 6 electrons on C; 2 formal charges

Relative Energy: A << B < C << D ~ E

Relative Importance: A (major) > B > C > D ~ E

minor

11

 Delocalization of Charge = Stabilization

The conjugate base of phenol (phenoxide) is stabilized by resonance.

Because phenoxide ion is stabilized, phenol is more acidic than cyclohexanol.

OH O O O O
H+

pKa 10
phenol

OH O
H+

pKa 17
cyclohexanol

In general, the more resonance structures there are, the greater the stabilization.

Equivalent resonance structures provide more stabilization than inequivalent ones.

C. Structure and Reactivity Info from Resonance Stuctures

e.g. Benzene

Drawn this way, benzene appears to have two types of carbon

expect carbon bonds (single and double).
1.34
Experimental data indicates that all of the carboncarbon bonds
expect in benzene are equivalent and rather unreactive.
1.48 Benzene is approximately 35 kcal/mol more stable than would be
expected because the electrons are delocalized around the ring.

1.397

12

 Chemistry 5.12, Lecture #3, 2/10/03

Outline
III. Review of Molecular Orbital Theory (Read Chapter 2)
A. Atomic Orbitals (2-1)
B. Sigma-Bonding (2-2A)
C. Pi-Bonding (2-2B)
D. VSEPR Theory (2-4)
IV. Hybridization/LCAO
A. sp Hybridization (2-4A)
B. sp2 Hybridization (2-4B)
C. sp3 Hybridization (2-4C)
1. Rotation of Ethane versus Ethylene (2-3,7,8)
Problem Set #1 Due Today by 4pm
Problem Set #2 Posted: Due Tuesday (2/18/03)

Suggested Problems: 2-28,29,31,33

* Read 2-12,13: Survey of Organic Molecules

III. Molecular Orbital Theory

Electrons Are Waves!
They Exist as 3-D Standing Waves (Orbitals).

atomic orbitals: unhybridized orbitals on an atom (s, p, d)

Linear Combination of Atomic Orbitals (LCAO): Individual wave

functions (orbitals) combine to form hybrid atomic orbitals (sp, sp2, sp3)
and molecular orbitals (, *, , *)

Hybrid Atomic Orbital: Combination of atomic orbitals from the same

atom

Molecular Orbital: Combination of atomic orbitals from different atoms

Conservation of Orbitals: When you add orbitals together, you always

end up with the same number of orbitals that you started with.

1
A. Atomic Orbitals
The s- and p-orbitals are the most important in organic compounds.
Orbital pictures are actually electron probability clouds.
y y y y

x x x x

z z z z
s pX pY pZ

s-orbitals: spherical, electrons held close to nucleus, one sign

p-orbitals: two lobes with opposite signs, electrons further from nucleus

Remember, the sign of the orbital does not indicate charge.

It represents the sign of the wavefunction and lets us think
qualitatively about whether orbital interactions are constructive
(bonding) or destructive (anti-bonding).

)
B. Sigma-Bonding (
Sigma-bonding orbitals are cylindrically symmetrical molecular orbitals.
Electron density is centered along the axis of the bond.
Single bonds are sigma-bonds.
e.g. H2 is the simplest sigma-bond

node
bonding: (+/+ or /) electron
* (anti-bonding) density centered between
nuclei

anti-bonding: (+/) generally

has a node between nuclei
H. H.
node: area of zero electron
density

In stable bonding situations,

(bonding) usually only the bonding
orbitals (, ) are occupied.
HH

2
 Sigma bonds aren't necessarily between two s-orbitals.

s+p p+p

node node

* *

pX pX pX
s

These are all examples of single bonds.

)
C. Pi-Bonding (
Pi-bonding orbitals are not cylindrically symmetrical.
Electron density is located above and below the axis of the bond.
Double and triple bonds are pi-bonds.

Double bond = +
node
H H
e.g. Ethylene
* H H

H C C H H C C H
H H H H

pY pY

H C C H or H C C H
H H H H

to simplify drawing of orbitals

3
 Orbital Overlap
Orbitals must have the correct symmetry to overlap.
Orthogonal orbitals do not overlap.
Good Overlap Orthogonal: No Overlap

s s
s
pY

s px
s pz

px px
px
pY

px pz
pY pY

pz pz pY pz

If all bonding occurred between simple s- and p-orbitals, then all bond
angles would be approximately 90.

We know that isn't true!

Most bond angles in organic molecules are ~109, ~120 and ~180.

~180
H
H
H
~109 H ~120
H

How do we account for this?

D. Valence Shell Electron Pair Repulsion (VSEPR)

Electrons repel each other!

Lone pairs and bonds want to be as far apart as possible.

4
 Simply...
Di-substituted Tri-substituted Tetra-substituted
linear (180) trigonal planar (120) tetrahedral (109)
Y Y
Y X Y X X Y
Y Y Y Y

e.g. acetylene e.g. ethylene e.g. methane

180 121.7
H H
109.5 H
H C C H 116.6 C C C H
H H H H

But, how do we think about this in terms of orbitals?

In 1930, Linus Pauling introduced a theory that combines VSEPR with

quantum mechanics (orbitals).

HYBRIDIZATION!
Linus Pauling's Journals: http://osulibrary.orst.edu/specialcollections/rnb/

IV. Hybridization (Linear Combination of Atomic Orbitals)

Atomic orbitals on the same atom combine to form

hybrid atomic orbitals.

Why?

Hybrid orbitals are more directional, so they have more effective bonding
interactions.

Second row elements hybridize using their s- and p-orbitals (sp, sp2, sp3).

Remember conservation of orbitals!

5
 A. sp Hybridization (Linear)

s p 2 sp

two sp-orbitals
180

enhanced e density
in bonding regions

But, we only used one s- and one p-orbital!

There are two more p-orbitals.

Complete Orbital Picture of an sp Hybridized Atom

pY

pZ
sp 2 sp-orbitals
X 2 p-orbitals
sp

How about a molecule?

e.g. Acetylene H C C H

2 H C H C C H

For simplicity, draw lines

connecting p-orbitals to
represent -bonds.

6
 B. sp2 Hybridization (Trigonal Planar)

s 2p 3 sp2

three sp2-orbitals Complete Orbital Picture

pY 3 sp2-orbitals
1 p-orbital
120
X sp2 sp2
X
For practice,
draw the orbitals
enhanced e for ethylene
density in bonding For simplicity, can leave (H2C=CH2).
out small back lobes.
regions

B. sp3 Hybridization (Tetrahedral)

109
X

s 3p 4 sp3

e.g. Methane (CH4) e.g. Ammonia (NH3)

C H N H
H H H H

Sigma-bonds and lone pairs involve hybrid orbitals.

Pi-bonds involve unhybridized p-orbitals.

7
 Assigning Hybridization to Atoms in a Molecule
(You need to be able to do this!)

Count the hybrid atomic orbitals.

# of hybrid orbitals = # of -bonds + # of lone pairs

# hybrid orbitals hybridization geometry approx. bond angles

4 sp3 tetrahedral 109
3 sp2 trigonal planar 120
2 sp linear 180

e.g. What is the hybridization of each non-hydrogen atom in acetonitrile?

Draw the bonding orbitals (leaving out the small back lobes).

H3C C N
a b H

Ca: sp3 (4 -bonds) C C N

H
Cb: sp (2 -bonds) H
N: sp (1 -bond, 1 lone pair)

1. Rotation of Ethane versus Ethylene

Sigma-bonds are cylindrically symmetrical: rotation does not disrupt bonding.
Sigma-bonds rotate freely.
H H HH
H H H
H H H H H
H H H
H H H
Ethane (much more on the
energetics of this rotation
later!)
Pi-bonds require overlap of the p-orbitals: rotation disrupts overlap.
Pi-bonds do not rotate.
H H
H H CH3 H
Ethylene CH3 CH3
H H3C
H
H H 90 H H H
H H H
H This rotation does not occur!
-overlap p-orbitals orthogonal:
no overlap

8
 Handout #3, 5.12 Spring 2003, 2/12/03

Physical Properties: Bond Length, Bond Strength & Acidity

A. Bond Lengths: mostly dependent on atomic size, bond order, and hybridization

Bond Lengths ()
Multiple Bonding: Bond
3 3 3 3 length depends strongly on
sp sp C C 1.54 sp sp C O 1.42
bond order (length: single >
sp2sp2 C C 1.34 sp2sp2 C O 1.22 double > triple)
spsp C C 1.20

Bond Lengths ()

sp3 C H 1.09 sp3sp3 C C 1.54 Effect of hybridization on

length of single bonds: CH
sp2 C H 1.086 sp3sp2 C C 1.50 and CC bonds shorten slightly
sp C H 1.06 sp3sp C C 1.47 with increased s character on
carbon

B. Bond Strengths/Bond Dissociation Energies (BDEs): Energy for homolytic bond

cleavage to uncharged radical fragments

X X X. X.

Bond strengths are bond

energies for a certain bond
averaged over many different
Common Bond Strengths (kcal/mol) molecules.
Bond dissociation energies are
C C 81 C O 79 for a particular molecule and are
dependent on the specific
molecular structure (Bond
C C 145 C O 173 Strength 20 kcal/mol)
Multiple Bonding: Bond
C C 198 C H 98 strength depends strongly on
bond order (strength: single <
double < triple)

Data taken from: Advanced Organic Chemistry, 3rd Edition, F. A. Carey and R. J. Sundberg

 C. Acidity of Organic Molecules

Functional Group Acid Approximate pKaValues Conjugate Base

(in water) increasing
basicity

alkane-sp3
HCH3 48
CH3

alkene-sp2
HCH=CH2 44
CH=CH2

amine
HNH2 38 NH2

hydrogen
HH 35 H

alkyne-sp
HCCH 25 CCH

alcohol
HOCR3 17 OCR3

water
HOH 15.7 OH

thiol
HSR 1011 SR

ammonium
H+NR3 1011 NR3

nitrile (cyanide)
HCN 9.2 CN

phenol
HOAr 811 OAr

carboxylic acid
HOC(O)R 45 OC(O)R

HF 3.17 F

hydronium H+OH2 1.74 OH2

HCl 7 Cl

HI 10 I

increasing
acidity

Acidity increases across a row: HC < HN < HO < HF (electronegativity)

Acidity increases down a period: HF < HCl < HBr < HI (size)
Neutral species less acidic than corresponding positively charged species: HOH < H+OH2
pKa data from: Advanced Organic Chemisry, 4th Ed., J. March
 Handout #6, 5.12 Spring 2003, 2/28/03
Stereochemistry

yes mirror zero How many two or more mirror yes achiral
achiral plane? stereocenters? plane? (meso)
no no
no one no*

non-identical chiral non-identical

mirror image? mirror image?

yes yes

chiral chiral

stereochemistry: study of the spatial characteristics of a molecule

stereocenter: atom bonded to four different groups (has R or S configuration)
internal mirror plane: plane that divides molecule in such a way that two halves are identical

chiral (optically active): possessing a non-identical mirror image (an enantiomer)

achiral: superimposable on its mirror image

enantiomers: non-identical mirror images (same physical properties)

diastereomers: stereoisomers that are not enantiomers (different physical properties)
meso compound: achiral molecule that has stereocenters

* If you can't find a mirror plane, it doesn't mean that there isn't one. Compare mirror images!

Assigning R/S Stereochemistry (CahnIngoldPrelog)

Every stereocenter can be assigned as R or S.

A stereocenter is an atom attached to four different groups.

1. Assign each group a priority (1 = highest).

a) Highest atomic number has priority.
b) Heavier isotopes have priority (D > H).
c) In a tie, move along the chain to the first point of difference.
d) With multiple bonds, break each pi-bond and duplicate the atoms at each end.
2. Put the lowest priority group (4) in back and view along the bond from carbon to group 4.
3. Draw an arrow from 1 to 2 to 3.
a) Clockwise = R (Your car turns right!)
b) Counterclockwise = S (sinister means left in Latin)

Tricks:
1. Taking the mirror image of a stereocenter switches R and S. This means that, if a molecule is
chiral, switching the R/S configuration of every stereocenter will give you the enantiomer.
2. Exchanging any two groups on a stereocenter switches R and S.

1 1 1 switch 2 switch 2

4 2 2 4 4 2 1 and 2 4 1 1 and 3 4 3
3 3 3 3 1
R S R S R
mirror

 Fischer Projections
Useful for comparing stereoisomers with more than one stereocenter.
The Rules:
1. At every intersection, the vertical lines are pointed back (away from you) and the horizontal lines
are pointed up (toward you).
2. Draw the carbon backbone of a molecule as the vertical line with the most highly oxidized carbon
on top.
a) You can think of oxidation as how many bonds carbon has to oxygen. So the ranking goes as
follows: CO2H > (CHO or CRO) > CH2OH > CH3
3. It is legal to rotate Fischer projections by 180 in the plane of the paper.
4. It is not legal to rotate Fischer projections by 90 or out of the plane of the paper.

1 1 1
2 4 2 4
3 4
3 3 2

same different! mirror image!

1 3 1 2 1 switch 1
rotate rotate
2 4 4 2 2 4 3 1 2 4 4 2
180 90 horizontal
3 1 3 4 3 groups 3

Tricks:
1. Exchanging the horizontal substituents on a stereocenter switches R and S.
2. To take the mirror image, just exchange the horizontal substituents at each intersection. If the
molecule is chiral, this will give you the enantiomer.
3. If you can draw a mirror plane through the Fischer projection, then the molecule is achiral.

Using the Lingo

It is important that you use stereochemical terminology correctly. Here
are the proper terms for describing each of the following:

an atom:
an atom with four different groups attached is a stereocenter
stereocenters are also called chirality centers, asymmetric centers, and stereogenic centers
absolute configuration of a stereocenter is assigned using R/S nomenclature

a molecule:
achiral or chiral (optically active)
achiral molecules that contain stereocenters are called meso compounds
optically active molecules can be labelled (+/) or (d/l)

related molecules:
enantiomers (non-identical mirror images)
diastereomers (any stereoisomers that are not enantiomers)
geometric isomers (a specific type of diastereomer)

samples of molecules:
optically pure (only one enantiomer present in sample)
racemate or racemic mixture (mixture containing equal amounts of each enantiomer)
racemic mixtures are not optically active
mixtures in between optically pure and racemic are described by their optical purity or
enantiomeric excess (see section 5-7 in Wade)

Note: It is important not to confuse experimentally derived labels (+/ or d/l) with
structurally derived labels (R/S). They are not related!

 Chemistry 5.12 Spring 2003, Week 3 / Day 2

Handout #7: Lecture 11

Outline

IX. Free Radical Reactions (Read Chapter 4)

A. Chlorination of Methane (4-2)
1. Mechanism (4-3)
B. Review of Thermodynamics (4-4,5)
C. Review of Kinetics (4-8,9)
D. Reaction-Energy Diagrams (4-10)
1. Thermodynamic Control
2. Kinetic Control
3. Hammond Postulate (4-14)
4. Multi-Step Reactions (4-11)
5. Chlorination of Methane (4-7)

Suggested Problems: 4-3537,40,43

IX. A. Radical Chlorination of Methane

H heat () or H
H C H Cl Cl H C Cl H Cl
H light (hv) H

H Cl Cl
or hv or hv etc.
H C Cl H C Cl H Cl Cl C Cl H Cl
Cl Cl Cl Cl
H H H

Why is light or heat necessary?

How fast does it go?
Does it give off or consume heat?
How fast are each of the successive reactions?
Can you control the product ratio?

To answer these questions, we need to:

1. Understand the mechanism of the reaction (arrow-pushing!).

2. Use thermodynamics and kinetics to analyze the reaction.

1
 1. Mechanism of Radical Chlorination of Methane
(Free-Radical Chain Reaction)

Free-radical chain reactions have three distinct mechanistic steps:

initiation step: generates reactive intermediate

propagation steps: reactive intermediates react with stable molecules to generate

other reactive intermediates (allows chain to continue)

termination step: side-reactions that slow the reaction; usually combination of two
reactive intermediates into one stable molecule

Initiation Step: Cl2 absorbs energy and the bond is homolytically cleaved.

(Remember to use fishhook arrows!)

or hv
Cl Cl Cl Cl Cl Cl

chlorine radicals

The first-formed reactive intermediate is a chlorine radical.

reactive intermediate: short-lived species that reacts quickly as it is formed

radical: species with an unpaired electron (usually just draw the unpaired electron)

2
Propagation Steps: The Meat of the Reaction

a) Chlorine radical abstracts a hydrogen from methane to form a methyl radical.

b) Methyl radical abstracts a chlorine from Cl2 to form product and another chlorine radical

H H
a) Cl H C H C H Cl
H H
H methyl
radical
H Cl
b) C Cl Cl H C H Cl keeps the
H H chain going
methyl H
radical

Sum: H Cl
H C H Cl Cl H C H H Cl
H H

The sum of the propagation steps is the overall chlorination reaction.

Termination Steps: Unproductive Steps

Consumption of reactive intermediates (radicals) without generation of new ones.

Cl Cl Cl Cl

H Cl
C Cl H C H
H H
H

H H H H
C C H C C H
H H H H
H H
Termination steps slow down and eventually stop the chain reaction.

Termination reactions become most important at the end of a reaction, when

there are very few reactant molecules left.

Before we investigate the energetics of this particular reaction, let's review

some general thermodynamics and kinetics.

3
B. Thermodynamics: energy changes that accompany chemical and physical
transformations

Thermodynamics are used to describe systems that are in their equilibrium state

A B

[products] [B]
Equilibrium Constant: Keq = =
[reactants] [A]

Gibbs Free Energy: G = H T S = RT(lnKeq)

R = 1.987 cal/Kmol T = temperature (K)

Gibbs Free Energy: G = H T S = RT(lnKeq)

entropy ( S): disorder or freedom of motion; an increase in entropy (S > 0) is

favorable

enthalpy ( H): the amount of heat evolved or consumed in a reaction (bonds

broken/formed)

endothermic: H > 0; need to put energy into the reaction (uphill)

exothermic: H < 0; energy given off by the reaction (downhill)

In the Gibbs Free Energy equation, the enthalpy term (H) is generally much larger
than the entropy term (TS). In other words, the change in enthalpy (bond
breaking/bond formation) usually governs the favorability of a reaction.

4
 Standard Gibbs Free Energy: G = G at 298K and 1 atm

The 1.4 Rule: At 25 C (298 K), every 1.4 kcal/mol change in G results in a
factor of 10 difference in Keq (useful for estimating conversion of a reaction).

conversion: percentage of starting material that is converted to products at equilibrium

[A] [B]

G Keq ratio conversion

[B] : [A] [B]/([B] + [A])
4.2 103 1000 : 1 > 99.9%
2.8 102 100 : 1 99%
1.4 10 10 : 1 91%
0 1 1:1 50%
+1.4 101 1 : 10 9%
+2.8 102 1 : 100 < 1%
+4.2 103 1 : 1000 < 0.1%

Note: Similar rules apply at different

temperatures: 100 C (1.7), 50 C (1.5), 0 C
(1.3), 78 C (0.9), etc.

C. Kinetics: Reaction Rates

reaction rate: how fast products appear and reactants disappear (measured
experimentally)

rate equation: relationship between concentration of reactants and observed reaction

rate (determined experimentally and used to deduce reaction mechanisms)

[A] [B] [C] [D]

observed rate = d[A]/dt = d[C]/dt

= kr[A]a[B]b
(kr = rate constant)

a: order of the reaction with respect to A

b: order of the reaction with respect to B These all depend on the
a + b: overall order of the reaction reaction mechanism.

5
 The rate constant is dependent on the activation energy and the temperature.

Arrhenius Equation: kr = AeEa/RT

A = Arrhenius prefactor

Ea = activation energy (minimum energy the reactants must

have for the reaction to occur)

In this class, we'll also refer to the activation energy of a reaction in terms of
G (free energy of activation).

Enough equations! Now let's look at pictures!

D. Reaction-Energy Diagrams
A reaction-energy diagram is a plot of the potential energy as reactants are
converted to products (also called a reaction-coordinate diagram); very useful
for understanding thermodynamics and kinetics!

X-axis is the progress

transition of the reaction.
state
Y-axis can be either
Ea G or H.
potential energy

(or G)
The transition state
is state of highest
energy between
reactants reactants and products.
H
(or G) Transition states are
transient (written in
brackets).

products Transition states are

unstable, do not have a
reaction coordinate finite lifetime, and
cannot be isolated.

reactants transition products
state

6
 If more than one product is formed in a reaction, what determines the
ratio of products? It depends on the reaction!

Thermodynamic Control: When the reaction is reversible (reactants and products are
in equilibrium), the reaction is said to be under thermodynamic control, and the
product ratio is determined by the relative energies of the products.

[TS B] transition B
[TS C] state B
A

potential energy

transition C
state C

GBC product ratio

A (GBGC) ([B] : [C])

B +4.2 1 : 1000
GBC +2.8 1 : 100

C +1.4 1 : 10

reaction coordinate 0 1:1

[A] [B] [C]

Kinetic Control: When the products are formed irreversibly, the reaction is said to be
under kinetic control, and the product ratio is determined by the difference in the
activation energies (the difference in the energies of the transition states (G)).

transition B
state B
[TS B]
[TS C] A

transition
potential energy

C
G state C

G product ratio
( G B G C) ([B] : [C])

A +4.2 1 : 1000
+2.8 1 : 100
B
+1.4 1 : 10
C
0 1:1
reaction coordinate
[A] [B] [C]

7
 Is there any way to estimate the relative energies of transition states?

Hammond Postulate: Related species that are similar in energy are similar in structure.

The structure of a transition state resembles the structure of the closest stable species.

Endothermic reactions have
close in late transition states.
energy and
potential energy

structure
products In an endothermic reaction,
the transition state is product-
like (close in energy and
G > 0 structure to the product).

In an endothermic reaction,
anything that changes the energy
reactants of the product will also change
the energy of the transition state.
reaction coordinate

Exothermic reactions have
close in early transition states.
energy and
potential energy

structure
reactants In an exothermic reaction, the
transition state is reactant-like
(close in energy and structure to
G < 0 the reactant).

In an exothermic reaction,
anything that changes the energy
products of the reactant will also change the
energy of the transition state.
reaction coordinate

This will come in very handy when we start thinking about radical halogenation reactions!

8
 Multi-step reactions have more than one transition state.

The local maxima are

rate-determining transition states.
TS2 transition state
The local minima are
TS1 reactive intermediates
(short-lived species that are
never present in high
potential energy

concentration because they

TS3 react quickly as they are
int. 1 formed).
G The overall reaction rate
int. 2 is determined by the
reactant highest energy transition
state.

The rate-determining
product step is the step with the
highest energy transition
reaction coordinate state.

5. Reaction-Energy Diagram for Radical Chorination of Methane

Now we have the tools to examine the energetics of a free-

radical halogenation.

We can use bond dissociation energies to estimate H

for each step (p. 134 in Wade).

bond dissociation energy: amount of energy required to homolytically break a bond

initiation step:

or hv
Cl Cl Cl Cl H = BDE = 58 kcal/mol

9
 It is important that the initiation step involves cleavage of a fairly weak
bond like ClCl.

Other than that, the initiation step is not important in the overall
thermodynamics and kinetics of the reaction. This is because one
initiation step starts a chain that can go through thousands of
propagation cycles.

The termination steps are also unimportant in the overall energetic

picture of the reaction, so let's focus on the propagation steps.

Propagation Steps:
H H
1) Cl H C H C H Cl
H H
H
break H3CH: H = +104 kcal/mol

form HCl: H = 103 kcal/mol

step 1: H1 = +1 kcal/mol

H Cl
2) C Cl Cl H C H Cl
H H
methyl H
radical
break ClCl: H = +58 kcal/mol

form H3CCl: H = 84 kcal/mol

step 2: H2 = 26 kcal/mol

overall: Hoverall = 25 kcal/mol

10
 Drawing the Reaction-Energy Diagram:

From BDEs (previous slide):

H3C H Cl
H1 = +1 kcal/mol

H3C Cl Cl H2 = 26 kcal/mol
Ea1
Hoverall = 25 kcal/mol
potential energy

Ea2
H1 CH3 + Cl2 Experimental Values:
CH4 + Cl (cannot predict)

Ea1 = +4 kcal/mol
Ea2 = +1 kcal/mol
Hoverall H2

From this diagram, we know:

The overall reaction is

CH3Cl + Cl exothermic by 25 kcal/mol.

reaction coordinate The rate-determining step is

step #1.
CH4 Cl2 CH3Cl HCl

11
 Chemistry 5.12 Spring 2003, 3/7/03
Handout #8: Lecture 12

Outline

E. Chlorination of Propane (4-13)

1. Inequivalent Hydrogens (1,2,3) (3-3)
2. Relative Reactivity (4-13A)
3. Selectivity
F. Bromination of Propane (4-13C)
1. Selectivity (Hammond Postulate) (4-14)
G. Radical Stability (4-13B, 4-16)
H. General Selectivity of Radical Halogenations

Suggested Problems: 4-39,41,4446,54

E. Radical Chlorination of Propane: Inequivalent Hydrogens

Cl
or hv Cl
Cl Cl
40% 60%
(1) (2)

There are two possible products! Why?

Propane has two inequivalent types of hydrogens that can be abstracted in the
first propagation step.

The first propagation step determines which product will be formed (1 or 2).

 Primary (1): There are six primary hydrogens.

H H H H
Cl H Cl
H H H H H H H
1 radical

Abstraction of a primary hydrogen leads to the primary product.

Secondary (2): There are two secondary hydrogens.

H H H
Cl H Cl
Me Me Me Me
2 radical

Abstraction of a secondary hydrogen leads to the secondary product.

1. Inequivalent Hydrogens (1, 2, 3)

Primary (1) Carbon: carbon that has only one other carbon attached to it

Secondary (2) Carbon: carbon that has two other carbons attached to it

Tertiary (3) Carbon: carbon that has three other carbons attached to it

H R R
R C H R C H R C H
1 2 3
H H R

 We also refer to substituents as primary, secondary or tertiary.

Me
Br
Me Br Me

n-butyl bromide (1) iso-butyl bromide (1)

Me Me
Me
Me Me Br
Br
sec-butyl bromide (2) tert-butyl bromide (3)

Radical Chlorination of Propane (cont.)

Cl
or hv Cl
Cl Cl
1 (40%) 2 (60%)

There are six primary hydrogens and two secondary hydrogens,

but the secondary chloride is favored.

How can we explain the selectivity of this reaction?

Radical formation is under kinetic control, so abstraction of the 2

hydrogen to form the 2 radical must be faster than abstraction of
the 1 hydrogen to form the 1 radical.

In other words, the secondary hydrogens are more reactive

than the primary hydrogens under these conditions!

 2. Relative Reactivity
2
H H H H Cl H
H H or hv Cl H H H
Cl Cl
H H H H H H H H H H H H
1 1
1 chloride (40%) 2 chloride (60%)

Calculating Relative Reactivity:

primary: 40% = 6.67% per H secondary: 60% = 30.0% per H

6 H's 2 H's

secondary 30.0 The secondary hydrogens are 4.5

= = 4.5
primary 6.67 times more reactive than the primary
hydrogens.

Why?

We can answer this using thermodynamics, kinetics, and reaction-energy diagrams!

Primary:
H H H H form HCl: 103 kcal/mol
H H Cl H H H Cl break 1 CH: +98 kcal/mol

H H H H H H H overall: H = 5 kcal/mol
1 radical

Secondary:

H H H
form HCl: 103 kcal/mol
H H Cl H H H Cl break 2 CH: +95 kcal/mol

H H H H H H H H overall: H = 8 kcal/mol
2 radical

2 CH bonds are weaker than 1 CH bonds.

This means that it is thermodynamically more favorable to break a

2 CH bond than a 1 CH bond.

But how does this control the kinetic selectivity?

 Draw the Reaction-Energy Diagram!

Ea 1 kcal/mol
potential energy

1 Ea
2 Ea

Cl

1 radical + HCl
H = 3 kcal/mol

2 radical + HCl
reaction coordinate
This reaction is under kinetic control, so the product ratio is determined by Ea.
How can you predict the value of Ea?

Analyze the Reaction-Energy Diagram!

Comparing the transition states for the two products:

The energy of a transition state will always depend, to differing extents, on the energies of
the reactants and the products.

In this case, the reactants are the same for both processes (same energy).

The only energy difference is in the products: the 2 radical is lower in energy than the 1
radical.

This means that the transition state leading to formation of the 2 radical is slightly lower in
energy than the transition state leading to formation of the 1 radical.

The secondary radical is formed faster!

It is important to remember that Ea depends on, but will never exceed H!

 F. Bromination of Propane: Higher Selectivity

Br
or hv Br
Br Br
3% 97%

Cl
or hv Cl
Cl Cl
40% 60%

Radical brominations are generally much more selctive than radical halogenations.

How can we explain this difference?

Let's start with thermodynamics!

Look at the propagation steps:

Primary:

H H H H form HBr: 88 kcal/mol

H H Br H H H Br break 1 CH: +98 kcal/mol

H H H H H H H overall: H = +10 kcal/mol

1 radical

Secondary:

H H H
form HBr: 88 kcal/mol
H H Br H H H Br break 2 CH: +95 kcal/mol
H H H H H H H H overall: H = +7 kcal/mol
2 radical

The HBr bond (BDE = 88 kcal/mol) is much weaker than the HCl bond (BDE = 103
kcal/mol).

HYDROGEN ABSTRACTION WITH Br IS ENDOTHERMIC!

 Reaction-Energy Diagram : Bromination of Propane

(Propagation Step #1)

Ea > 2 kcal/mol
1 radical + HBr
potential energy
H = 3 kcal/mol

2 radical + HBr

Br

reaction coordinate

This diagram looks slightly similar to the one we drew for the chlorination of propane.

The big difference is that this step is now endothermic. So what?

THINK HAMMOND POSTULATE!

Remember the Hammond Postulate:

In an exothermic reaction, the transition state more closely resembles the reactants.

In an endothermic reaction, the transition state more closely resembles the products.

What this means:

The 3 kcal/mol energy difference between the 1 and 2 radicals will have the biggest
effect on the transition state energies in the endothermic abstraction with bromine.

This is why radical brominations are more selective than radical chlorinations!

 Reaction-Energy Diagrams: Chlorination versus Bromination of Propane

(Propagation Step #1)

H-abstraction with Cl H-abstraction with Br

Ea 1 kcal/mol Ea > 2 kcal/mol

1 radical + HBr
potential energy

potential energy
H = 3 kcal/mol

Cl 2 radical + HBr

1 radical + HCl
H = 3 kcal/mol

2 radical + HCl
Br
reaction coordinate reaction coordinate

exothermic endothermic
(more selective)

G. RADICAL STABILITY!
Why is it easier to break a 2 CH bond than a 1 CH bond?

R3C CR3 R3C CR3 H = BDE

Bond dissociation energies depend on radical stability.

It's easier to homolytically cleave a bond when more stable radicals are formed.

Radical Stability:
R H H H
> > >
R R R R R H H H

Tertiary (3) > Secondary (2) > Primary (1) > Methyl

To understand this trend, we need to take a closer look at the electronic

structure of a radical.

 Closer look at a radical. . .

p
R
R
R

sp2

Radicals are electron-deficient because they have less than an octet.

As you might expect based on this, radical stability depends on hybridization

(effective electronegativity).
Stability: sp3 > sp2 > sp

Alkyl groups stabilize electron-deficient radicals by donating electron density in two ways:
induction and hyperconjugation.

1. Alkyl groups are inductive electron-donating groups (EDGs).

Alkyl substituents donate electron density through the sigma-bond framework.

CH3

H3C CH3

2. Hyperconjugation: Alkyl groups stabilize radicals through overlap

between filled CH orbitals and the half-filled p-orbital.

R H
H
p

 Radicals are also stabilized by resonance!

(just like positive and negative charges)

H H
H H H H BDE = 98 kcal/mol
H H H H H H H
propane

H H H
H H H H H H BDE = 87 kcal/mol
H H H H H H H
propene allylic radical

The allylic radical is more stable because of resonance.

DELOCALIZATION = STABILIZATION

Resonance Stabilized Radicals

H H H
H H
H H H
H

toluene
H H

BDE = 85 kcal/mol H H

benzylic radical

10

 H. General Selectivity of Radical Halogenations

Radical brominations are highly selective when one type of hydrogen is particularly
reactive (resonance-stabilized).
eg. Cyclohexene has thre types of hydrogens:

H BAD: sp2 Radicals are unstable.

BDE
sp2
108 kcal/mol
H H

H H
H BDE
OKAY: These hydrogens act like
2 96 kcal/mol regular 2 hydrogens.
H H
H H

H H H

BDE GOOD: This radical is delocalized

allylic (stabilized by resonance).
87 kcal/mol

HH HH

The radical halogenation of cyclohexene is selective, BUT cyclohexene can react

with Br2 in other ways when the concentration of Br2 is too high.

N-Bromosuccinimide (NBS) is used because it releases bromine slowly.

O O

hv
N Br N H
NBS
O Br O

H Br
O OH OH
Br

N Br N Br Br Br N
released
O O slowly O

But how does it start?

O O
The initially formed bromine radical
abstracts a hydrogen from
hv
N Br N Br cyclohexene to form cyclohexyl radical
and HBr.
O O
This starts the chain!

11

 Chemistry 5.12 Spring 2003, Handout #9

Substitution Reactions (SN2 versus SN1)

SN2 SN1
Mechanism: Concerted Two Steps
(Look for carbocation rearrangements.)

Rate Equation: Rate = kr[RX][Nuc] Rate = kr[RX]

Stereochemistry: Stereospecific Loss of Stereochemistry

(inversion)

Substrate: Sterics Cation Stability

(methyl > 1 > 2) (benzylic > allylic > 3 > 2)
No SN2 with 3! No 1 or methyl R+
Orbital Overlap without extra stabilization!
(methyl benzylic > allylic > 1)

Nucleophile: Strong/Moderate Required Not Important

strong: RS, I, R2N, R2NH, RO, CN
moderate: RSH, Br, RCO2

Leaving Group: Moderately Important Very Important

(same trend as SN1) (OTf >> OTs OMs >>
I > Br > Cl)

Solvent: Polar Aprotic Polar Protic

Elimination Reactions: E2 versus E1

E2 E1
Mechanism: Concerted Two Steps
(Look for carbocation rearrangements.)

Rate Equation: Rate = kr[RX][Base] Rate = kr[RX]

Stereochemistry: Stereospecific Not Stereospecific

(antiperiplanar TS)

Substrate: Alkene Stability Cation Stability

(3 > 2 > 1) (benzylic > allylic > 3 > 2)

Base: Strong Base Required Not Important: Usually Weak

(RO, R2N) (ROH, R2NH)

Leaving Group: Moderately Important Very Important

(same trend as SN1) (same trend as SN1)

Solvent: Wide Range of Solvents Polar Protic

Saytzeff Rule: The most highly substituted alkene usually predominates.

Product Ratio:
Hofmann Product: Use of a sterically hindered base will result in formation of
the least substituted alkene (Hofmann product).

1
 Generic Reaction-Energy Diagrams
Substitution Elimination


X
R RR
+
Nuc X
H RR
R R

B
energy

energy
R
R X
X B
Nuc R
R
R R
R Nuc R
R B H
X
R

reaction coordinate (SN2) reaction coordinate (E2)

Bimolecular

Unimolecular CHR2

RR +
R R + RDS R
RDS X
X + Nuc + R
RR
H
RR RR

B
R
R X
R+ X R
energy

energy
Nuc R
B

R
X B
R X R
R
Nuc R R
R
R B H
R Nuc
X R
reaction coordinate (SN1) reaction coordinate (E1)

Predicting the Products: Substitution versus Elimination

Start

Bimolecular yes no
Is Nuc/Base strong? What kind of substrate?
Reaction
1
2, 3, or
stabilized 1
Unfavorable
Is Nuc/Base bulky? Reaction
yes
Unimolecular
Reaction
no E2
3
yes
What kind of substrate? mostly E1* Is Nuc/Base bulky?
2

methyl or 1 SN2 + E2 no

SN2 mostly SN1*

* Under conditions that favor a unimolecular reaction (weak nuc/base and polar protic solvent),
mixtures of SN1 and E1 are usually obtained.