Binder1 PDF

Chapter 1 Outline
This first slide presentation will include

review from general chemistry therefore it
will cover more information that in the
textbook.
Periodic table & trends
Ionic & covalent bonding
Atomic structure, orbitals and isotopes
Molecular orbitals and hybridization
Acids/base chemistry
s-block (metals), p-block (non-metals)
An ionic bond is formed between metals

and non-metals
Covalent Bonds are Formed by

Sharing Electrons Between Non-Metals
Nonpolar covalent bond = bonded atoms are the same

No difference in electronegativity between atoms
Polar covalent bond = bonded atoms differ in electronegativity
How Many Bonds Does

an Atom Form?
Lewis Structures
Bond Polarity Depends on

the Difference in Electronegativity
Polar Covalent Bonds
Formal Charge
For example, consider oxygen in methanol shown

below.
Oxygen is in group 16, which means a valence
number of 6.
Oxygen has two lone pairs and shares an
electron in each of the two covalent bonds so
FC = 6 4 (4) = 0
Formal Charge
Methyl oxonium ion (the acidic form of methanol) is shown below.

In this structure, oxygen has used one of its lone pair to form a covalent bond
with a proton so the formal charge for oxygen is
FC = 6 2 (6) = +1
Neutral Carbon Forms Four Bonds
if carbon does not form four bonds, it has a charge

(or it is a radical)
A Hydrogen Atom Can Lose or

Gain an Electron
Neutral Nitrogen Forms Three Bonds
Nitrogen has one lone pair.

If nitrogen does not form three bonds, it is charged.
Neutral Oxygen Forms Two Bonds
Oxygen has two lone pairs.

If oxygen does not form two bonds, it is charged.
Hydrogen and the Halogens

Form One Bond
A halogen has three lone pairs.

if hydrogen or halogen does not form one bond, it has a charge
(or it is a radical)
Lewis Structures
In organic chemistry it is common to use lines to represent covalent bonds.

A single line between atoms represents one bond, two lines represents a double
bond, and three lines represents a triple bond.
Drawing Conventions in Organic Chemistry

butane
H H H H
H C C C C H
H H H H
CH3CH2CH2CH3
OH
terminal line implies -CH3
butanol
H H H H
H C C C C OH
H H H H
CH3CH2CH2CH2OH
OH
Learn to use line/bond drawing convention for Lewis structures

Simplifies drawing task
bent line implies -CH2-
Atomic & Molecular Orbitals
The Structure of an Atom

Protons are positively charged.
Neutrons have no charge.
Electrons are negatively charged.
Atomic number = # of protons
Atomic number of carbon = 6
Neutral carbon has six protons
and six electrons.
Isotopes
Isotopes are atoms that have the same atomic number (number
of protons) but differ in mass (differing number of neutrons)
Isotopes may be stable or unstable (radioactive).
Isotopes are widely used to understand chemical mechanism and
as radiotracers
stable
Unstable
(beta emitter)
The Distribution of Electrons in an Atom
The first shell is closest to the nucleus.

The closer the atomic orbital is to the nucleus,
the lower its energy.
Within the same shell, s < p.
-Aufbau principle: An electron goes into the atomic orbital with

the lowest energy.
-Pauli exclusion principle: No more than two electrons can be
in an atomic orbital.
-Hunds rule: An electron goes into an empty degenerate
orbital rather than pairing up.
increasing energy
Reorder such that energy becomes the y-axis
Electrons may be excited from lower to higher energy

orbitals creating excited electronic states
What is an Atomic Orbital?
The Lobes of a p Orbital Have

Opposite Phases
The Three p Orbitals
Molecular Orbitals - Diatomic

Hydrogen
Hydrogen is one of the seven elements that form
diatomic molecules. In order for H2 to form, atomic
hydrogen must come together to form a covalent
bond.
Orbital overlap
1s
+
1s
atomic hydrogen
molecular hydrogen
Atomic Orbitals Combine

to Form Molecular Orbitals
Side-to-Side Overlap of In-Phase

p Orbitals Forms a Bond
Molecular Geometry & Hybridization
The Bonding in Methane
increasing energy
In Order to Form Four Bonds,

Carbon Must Promote an Electron
Four Orbitals are Mixed to Form

Four Hybrid Orbitals
An sp3 orbital has a large lobe and a small lobe.
The Carbon in Methane is sp3
4 sp3 orbitals = tetrahedron

.
The Carbon Hydrogen Bond

When the four sp3 hybrid orbitals of carbon
overlap with four 1s orbitals of hydrogen,
tetrahedral geometry arises
carbon sp3 - hydrogen 1s =
bond
The Bonding in Ethane

H
this line represents a carbon sp3 to hydrogen 1s
bond
this line represents a carbon sp3 to carbon sp3
bond
Graphically, the molecular orbitals of ethane can be represented as:
Bonding in Ethene
Molecular Orbitals in Ethene

one of these lines represents a carbon sp2 to carbon sp2
the other line represents a carbon to carbon bond
H
H
C
bond
this line represents a carbon sp2 to hydrogen 1s bond
sp2
sp2
2p
2p
sp2
sp2
sp2
sp2
C-C
1s
1s
sp hybridized
carbon atom
2 hydrogen atoms
1s
sp2 hybridized
carbon atom
2 hydrogen atoms
C sp2 - C sp2
C sp2 - H 1s
1s
C sp2 - H 1s
An sp2 Carbon Has Three sp2 Orbitals

and One p Orbital
The Carbons in Ethene are sp2
Bonding in Ethyne
2s
2py
2pz
atomic orbitals
ground state
2px
2s
2p
2p
atomic orbitals
excited state
2p
2p
2p
sp
sp
two sp hybrid orbitals

2 unhybridized 2p orbitals
Molecular Orbitals in Ethyne

one of these lines represents a carbon sp to carbon sp bond
the other two lines represents two carbon to carbon bonds
H
this line represents a carbon sp to hydrogen 1s bond
2p
sp
2p
2p
sp
sp
C-C
1s
sp
C-C
1s
sp hybridized
carbon atom
sp hybridized
carbon atom
hydrogen atom
2p
hydrogen atom
C sp - C sp
C sp - H 1s
C sp - H 1s
The Two sp Orbitals Point in Opposite Directions

The Two p Orbitals are Perpendicular
The Carbons in Ethyne are sp
Methyl Cation and Methyl Radical are sp2
Methyl Anion is sp3
Nitrogen Has Three Unpaired Valence Electrons

and Forms Three Bonds in NH3
Nitrogen does not have to promote an electron.
The Bonds in Ammonia (NH3)
The Ammonium Ion (+NH4)
Oxygen Has Two Unpaired Valence

Electrons and Forms Two Bonds in H2O
Oxygen does not have to promote an electron.
The Bonds in Water (H2O)
Overlap of an s Orbital with an sp3 Orbital
The Length and Strength of a

Hydrogen Halide Bond
Summary of Hybridization
orbitals used in bond formation determine the bond angle
Single Bond: 1 Double bond: 1 + 1

Triple Bond: 1 + 2
Hybridization of C, N, and O
Bond Strength and Bond Length
The shorter the bond, the stronger it is.
s Character
The More s Character in the Orbital,

the Shorter and Stronger the Bond
The more s character, the shorter and stronger the bond.
The More s Character in the Orbital,

the Greater the Bond Angle
The more s character, the greater the bond angle.
Hybridization, Bond Angle,

Bond Length, Bond Strength
Summary
The greater the electron density in the region of orbital
overlap, the stronger the bond.
The more s character, the shorter and stronger the bond.
The more s character, the larger the bond angle.
A Bond is Weaker Than a Bond
Dipole Moments of Molecules
Dipole Moments of Molecules
Acids and Bases Reactions in Equilibrium
Two acid base theories will be explored:

Bronsted Lowery acid base theory: loss and
gain of a proton
Lewis acid base theory: donation or
acceptance of a pair of electrons
B.L. AcidBase Reactions in Equilibrium
Equilibrium arrows indicate the if the products or

reactants are favored
An Acid Loses a Proton

A Base Gains a Proton
When an acid loses a proton, it forms its conjugate base.

When a base gains a proton, it forms its conjugate acid.
An Acid and its Conjugate Base

A Base and its Conjugate Acid
The stronger the acid, the weaker its conjugate base.
Acids Have Different Strengths
The stronger the acid, the weaker its conjugate base.
Acid Strength
The stronger the acid, the larger the Ka.

The stronger the acid, the smaller the pKa.
See Simple pKa Chart on course

web for a complete list. You must
know pKa values for exams.
Water & Alcohols Can Act as

Either Acid or Base
Alkoxide
anion
Alcohol
Oxonium
cation
An Amine Can Behave

as an Acid and as a Base
A curved arrow points from the electron donor to the electron acceptor.
An Amine Can Behave

as an Acid and as a Base
Amide
anion
ammonia
Ammonium
cation
Other Amine Acid/Base Chemistry
The Position of Equilibrium

Take Home Concept:
The equilibrium favors formation of the weaker acid.
Determine Position of Equilibrium
First Label the acids
acid
acid

Second, approximate the pKas
Acid
35
Acid
15

Second, approximate the pKas
Acid
35
Acid
15

Second, approximate the pKa value
Equilibrium always favors the weaker acid
(larger pKa value)
The Stronger the Acid,

the Weaker Its Conjugate Base
stable bases are weak bases
Why are Alcohols Stronger Acids Than Amines?
Oxygen is more electronegative than nitrogen.
Why Are Protonated Alcohols Stronger Acids

Than Protonated Amines?
Oxygen is more electronegative than nitrogen.
Substituents Affect the

Strength of the Acid
inductive electron withdrawal
HX vs Substituted Acetic Acid Trends

For substituted carboxylic acids, consider the conjugate base forms.
The area circled in red has a lot of excess electron density. Groups near
this electron density can help stabilize it if they are electronegative.
Since Cl is more electronegative than Br, the conjugate base form of 2chloroacetic acid is more stable - therefore the acid is stronger

Another way to think about it is bond dipoles. Because the singly
bonded oxygen of the carboxylate is negatively charged, that forces the
carbon next to it to be positively charged, which in turn forces the next
carbon to be negatively charged. The more electronegative atom will
stabilize carbon #2 better
pKa 2.81
pKa 2.86
Smaller pKa = stronger acid

Chlorine more electronegative than bromine
pKa ~0
A Substituents Effect on pKa

Depends on Distance

Comparing acids such as HCl to HI, you can think
about the bond strength. The weaker the bond, the
easier to break.
The Length and Strength of a

Hydrogen Halide Bond
Acid
strength
Base
Base strength
pKa
form
3.14
F-
-7
Cl-
-8
Br-
-9
I-
Why is a Carboxylic Acid a Stronger Acid

Than an Alcohol?
delocalized electrons (resonance)
Lab #1 How ionization impacts solubility

like dissolves like
O
O
+ NaOH (aq)
OH
benzoic acid
neutral form
not soluble in water
O Na
sodium benzoate
ionized form
soluble in water
pKa = ?
pKa = ?
O
O
H3C
+ H2O
OH
+ NaOH (aq)
acetic acid
neutral form
soluble in water
H3C
O Na
+ H2O
sodium acetate
ionized form
soluble in water
Red is a greasy hydrocarbon (not soluble in water) Blue is the carboxylic

acid functional group (neutral) and Carboxylate (charged)
Can be used to separate compounds

using extraction techniquies
O
OH
dissolve in Et2O
extract with NaOH (aq)
separate
ether
water
neutralize with HCl (aq)

vacuum flter
The HendersonHasselbalch Equation

Lab the week of Sept 7th. In summary, when the pKa of an acid is equal to the
pH of the solution, then there will be 50:50 distribution between ionized and
unionized forms.
Benzoic Acid has a pKa of 4.20
O
O
50
OH
50
pH = 4.20
Amine-based Drugs are often Salts

acid form
OH
H2N
H2N
Desoxyn
NH3
Adderall
basic form OH
HN
Ephedrine
HN
Methamphetamine
A carboxylic acid is neutral in its acidic form and charged in its basic form.
An amine is charged in its acidic form and neutral in its basic form.
Hybridization Affects Acidity
Mores
character most
electronegative
Lesss
character less
electronegative
The weakest acid has the

strongest conjugate base.
Hybridization Affects Acidity

Electronpairin
sporbital(more
stable)
Electronpairin
sp3orbital(less
stable)
Lewis Acids and Bases

Lewis definitions:
acid: a species that accepts a share in an electron pair
base: a species that donates a share in an electron pair
All Brnsted acids (proton donor) are Lewis acids.

All Brnsted bases (proton acceptor) are Lewis bases.
Lewis Acids and Bases
Chapter3
FunctionalGroups Alkanes
Hydrocarbons
Alkanes,alkenes,alkynes,benzene
cyclic
H H
C C
H H
C
C
C
C
C
C
C C
C
C
C
C
C
C
FunctionalGroups
AlkylHalides,amines,alcohols,ethers
FunctionalGroups
CarbonylCompounds
Aldehydesandketones
Carboxylicacidsandderivatives
FunctionalGroups
Aromatics
OtherAromatics
OH
NH2
H
N
FunctionalGroups
AlkanesandCycloalkanes
Nomenclature/structure acyclic
alkanes with 1-3 carbons
condensed
methane
CH4
ethane
line-bond
one carbon
two carbons
CH3CH3
propane
CH3CH2CH3
three carbons
Nomenclature/structure of acyclic
alkanes with 4-5 carbons
Alkyl Substituents
Replace ane of alkane with yl.
Common Names
Propyl and Isopropyl

CH3CH2CH3
propane
If X = Cl
X
CH3CH2CH2
X
CH3CHCH3
a propyl substituent
a 2-propyl substituent
commonly called isopropyl
Cl
CH3CH2CH2
Cl
CH3CHCH3
1-chloropropane
2-chloropropane
or isopropyl chloride
functional group = alkyl halide
Butyl, isobutyl, sec-butyl, tert-butyl
Primary, Secondary, and Tertiary Carbons

A primary carbon is bonded to one carbon.
A
. secondary carbon is bonded to two carbons.
A tertiary carbon is bonded to three carbons.
A quaternary carbon in bonded to four carbons
Alkanes Systematic Nomenclature
First identify the longest continuous chain

(the parent hydrocarbon).
Add the Name of the Substituent
Number the chain in the direction that gives the

substituent as low a number as possible.
List Substituents in Alphabetical Order
The correct name is the one that contains the

lowest of the possible numbers (5+3 < 4+6)
Multiple Substituents
Chain is numbered in the direction that puts the lowest number in the name.
Start numbering from the end that has the earliest branch point
Substituents are listed in alphabetical order (di- and tri- are not alphabetized).
Cycloalkanes
Skeletal structures do not show Cs and Hs bonded to Cs.
Bond angles in cyclic alkanes
Not 108o
Not 120o
We will revisit this when discussing bond rotations

and eclipssed vs staggered conformations
Angle Strain in cylcoalkanes
Angle strain results from poor orbitalorbital overlap because

bonds have to deviate from the ideal (109.5) bond angle.
Mono-Substituted Cycloalkanes
A number is not needed.
Di-Substituted Cycloalkanes
Substituents are stated in alphabetical order.

Lowest possible sum of substituent numbering
#1 goes to first-listed substituent.
Nomenclature of Alkyl Halides
Nomenclature of Ethers
Common
aprotic solvent
used in
chemical
synthesis
The substituents are listed in alphabetical order.
Nomenclature of Alcohols
1-propanol
2-propanol
2-butanol
Classification of Alcohols
Primary alcohol = OH is on a primary carbon.

Secondary alcohol = OH is on a secondary carbon.
Tertiary alcohol = OH is on a tertiary carbon.
Diols
OH
HO
ethane-1,2-diol
common name = ethylenediol
moderately toxic
HO
OH
propane-1,2-diol
common name = propylenediol
far less toxic
OH
HO
O
glycolic acid
O
OH
HO
O
oxyalic acid
toxic
pyruvic
acid
acetic
acid
lactic
acid
propionaldehyde
Boxed structures are metabolites
Propylene diol used extensively
Systematic Names of Alcohols
Pay attention to the number of the substituent

only if you get the same number for the
functional group in both directions.
Begin numbering from the end of the chain with the earliest branch point
A Substituent is a Prefix
A Functional Group is a Suffix
Classification of Amines
The classification depends on how many groups are bonded to N.
Primary amine
= one group bonded to N
Secondary amine = two groups bonded N
Tertiary amine
= three groups bonded N
Common Names of Amines

NH3
CH3NH2
N
H
CH3NHCH2CH2CH3
ammonia
(CH3CH2)3N
(CH3CH2)4N+
methylamine
methylpropylamine
triethylamine
tetraethylamine
a 1o amine
a 2o amine
a 3o amine
a 4o amine
R NH2
N
H
N
R
Substituents are in alphabetical order followed

by amine.
They are all written as one word.
R
R
N
R
Dont forget acid/base properties

of amines
NH3
ammonia
CH3NH2
methylamine
N
H
methylpropylamine
HCl
triethylamine
ammonia, 1o, 2o and 3o amines are bases
Cl
NH4 Cl
ammonium
chloride
N
H2
methylammonium methylpropylammonium
chloride
chloride
CH3NH3 Cl
Cl
H
N
pKa = 10
triethylammonium
chloride
Some special amines
NH2
HN
N
pyridine
NH
aniline
NH3
imidazole
HN
NH
pyridinium ion
anilinium ion
imidazolium ion
pKa = 5
Summary of Nomenclature
The Structure of an Alkyl Halide
The CX bond of an alkyl halide becomes longer and weaker

as the size of the halogen increases.
The Structure of an Alcohol

Resembles the Structure of Water
An alcohol is structurally like water with one H replaced by an R.
The Structure of an Ether

Resembles the Structure of an Alcohol
An ether is structurally like water with both Hs replaced by Rs.
Boiling Points
The greater the attractive forces between molecules,
the higher the boiling point.
attractive forces
van der Waals forces
dipoledipole interactions
hydrogen bonds
Boiling Points
Methane -167.7 C
Ethane
-88.6 C
Propane -42.1 C
Butane
-0.5 C
Pentane
36.1 C
Hexane
68.7 C
Heptane
98.4 C
Octane
125.7 C
induced dipole-induced dipole

interactions
van der Waals forces
The greater the surface area of the molecule, the higher the bp.
Branching Lowers the Boiling Point
cigar
tennis ball
DipoleDipole Interactions
Dipoledipole interactions are

stronger than van der Waals forces.
Diethylether
35 = oC
Hydrogen Bonds in H2O and NH3
CH4 167.7 C
no hydrogen bonds
H2O 100 C
hydrogen bonds
Hydrogen bonds are stronger than

other dipoledipole interactions.
Compounds with Similar Shapes and Properties

Often Have Similar Physiological Activities
Drugs bind to their receptors by van der Waals interactions,

dipole-dipole interactions, and hydrogen bonding.
Solubility
like dissolves like
Polar compounds dissolve in polar solvents (H2O).

Nonpolar compounds dissolve in nonpolar solvents (hexane).
Solvation
Solvation is the interaction between solute molecules and solvent molecules.
Competing effects with increasing

carbon count
Competing effects with increasing

carbon count
O
O
+ NaOH (aq)
OH
benzoic acid
neutral form
not soluble in water
O Na
sodium benzoate
ionized form
soluble in water
O
H3C
+ H2O
OH
+ NaOH (aq)
acetic acid
neutral form
soluble in water
H3C
O Na
sodium acetate
ionized form
soluble in water
+ H2O
Conformational Analysis of
alkane and cycloalkanes
Rotation Occurs About

Single ()Bonds
Staggered and Eclipsed Conformers

of Ethane
Rotation Can Occur About the

Three CarbonCarbon Bonds in Butane
Rotation About C-2C-3 in Butane
butane.mov
Steric strain is repulsion between the electron clouds of atoms or groups.
Cyclopropane
Cyclobutane
Molecules twist out of a planar arrangement

to minimize angle strain and the number of eclipsed hydrogens.
Cyclopentane
Molecules twist out of a planar arrangement to

minimize angle strain and the number of eclipsed hydrogens.
Chair Conformer of Cyclohexane
The chair conformer of cyclohexane is completely free of strain.

All bond angles are 111 and all adjacent bonds are staggered.
Axial and Equatorial Bonds
Ring Flip
Cyclohexane interconverts between two stable chair conformers.
Ring Flip
Cyclohexane interconverts between two stable chair conformers.
Conformers of Cyclohexane
Ring flip we will only talk about the two chair conformations
Conformers of Monosubstituted
Cyclohexanes
1,3-Diaxial Interactions
Cis and Trans Isomers
Conformers of Disubstituted
Cyclohexanes
cis
trans
1,2
1,3
1,4
1,4-dimethylcyclohexane
trans
cis
CH3
H3C
C1
C4
H
CH3
CH3
?
H
C4
C1
H
CH3
C1
C4
CH3
?
H
H3C
C4
C1
H
CH3
Each Isomer Has

Two Chair Conformers
cis
trans
CH3
CH3
CH3
C3
H
C1
?
H
H3C
C3
C1
CH3
C3
H3C
C1
?
H
C3
C1
CH3
CH3
cis-1-tert-butyl-3-methylcyclohexane
trans-1-tert-butyl-3-methylcyclohexane
Chapter 3
Alkenes&Alkynes
Structure,Nomenclature,andanintroductiontoReactivity
andMechanism
Saturated and
Unsaturated Hydrocarbons
Saturated hydrocarbons have no double bonds.
Unsaturated hydrocarbons have one or more double bonds.
Nomenclature of Alkenes
Replace ane of alkane with ene.
The functional group gets the lowest possible number.
Stereoisomers May Be Named Using

a cis or trans Prefix
Nomenclature of Dienes
two double bonds = diene
Number in the direction so that the functional group

gets the lowest number.
Substituents are stated in alphabetical order.
Nomenclature of Cyclic Alkenes
A number is not needed to denote the position of the C=C functional group;
it is always between C1 and C2.
Vinylic and Allylic Common Names
Double Bonds Have

Restricted Rotation
The six carbon

atoms are in the
same plane
Rotation about a double bond breaks the bond.
Alkenes May Have cistrans Isomers
Cis: The hydrogens are on the same side of the ring.

Trans: The hydrogens are on opposite sides of the ring.
They have different configurations; they can be separated.
Sometimes cis and trans do not work
The E,Z System of Nomenclature
Z = Zusammen (together)
E = Entgegen (opposite)
Relative Priorities
The relative priorities of the two groups depends on the

atomic numbers of the atoms attached to the sp2 carbon.
The E and Z Isomers
(E) 1-chloro-3-(chloromethyl)-4-ethyl-5-methylhex-3-ene
Double Bonds
lower
higher
Break multiple bonds into

equivalent single bonds
Isotopes
Reactions of Organic Compounds
Electrophilic Addition (general)

Hydrohalogenation (more specific, could be HCl, HBr, or HI
Hydrobromination (specific for HBr)
Electrophiles
An electrophile is a Lewis acid and has:

a positive charge or
a partial positive charge or
an incomplete octet.
Nucleophiles
A nucleophile is a Lewis base and has:

a lone pair of electrons and/or
a negative charge
Reactive Intermediates
During the course of a reaction, a reactive
intermediate may be involved. We will limit our
study to the carbocation intermediate.
sp2, trigonal
planar
Empty p orbital
Increasing stability
Carbocation Stability
Alkyl groups:
decrease the concentration of positive charge on the carbon and
increase the stability of the carbocation.
Hyperconjugation Stabilizes a Carbocation
Bond Making and Bond Breaking

Reaction Mechanism
Arrows denote the flow of electrons from the Lewis base

to the Lewis acid
Functional Group Transformation
hydrohalogenation
(transformation)
Learn to recognize
the functional group
transformation.
In this case it is an
alkene going to an
alkyl chloride
Draw Notecards for each reaction

you are expected to learn (see course
handouts)
Me
Cl
HCl (g)
ether
Type: hydrohalogenation
Me
Reaction Mechanism
hydrohalogenation
(mechanism)
The curved arrow

notation is used to
describe bond
making and bond
breaking in a
mechanism
Draw Notecards for each reaction

mechanism you are expected to
learn (see course handouts)
How to Draw Curved Arrows
Exothermic and Endothermic Reactions

Transition
state
Eact
Ignore entropy G H
Reaction coordinate diagram
Bond Enthalpy
Endothermic or Exothermic
Bond
DH (kcal/mol)
Breaking
-bond
62
H-Br
88
COST
150
Bond Making
C-H
C-Br
GAIN
DH (kcal/mol)
101
71
172
150 kcal/mol 172 kcal/mol=22kcal/molorexothermic
Reaction Coordinate Diagrams for Fast and Slow

Exothermic and Endothermic Reactions
Reactions in Chapter 4
name
1. Hydrohalogenation
2. Hydration
class
electrophilic
addition
electrophilic
addition
3. Halogenation
electrophilic
addition
4. Hydrogenation
electrophilic
addition
5. cis Di-hydroxylation oxidation
6. Oxidative cleavage oxidation
7. Epoxidation
oxidation
mechanism
subclass
hydrochlorination, yes
hydrobromination
, hydroiodination
yes
bromination,
chlorination
reduction
yes
no
no
no
no
Refer to the course map in the syllabus when studying the remainder
of the material in this course as we will not cover every reaction in the
textbook. Always refer to the 345 reactions summary in the course
materials folder in Blackboard. If the reaction has a yes under the
mechanism column, you are expected to learn the mechanism that
goes along with the reaction.
Chapter 4
TheReactionsof
Alkenes/Alkynes
TheStereochemistryof
AdditionReactions
AlkeneReactionsinChapter4
name
1.Hydrohalogenation
class
electrophilic
addition
2.Hydration
electrophilic
addition
electrophilic
addition
electrophilic
addition
oxidation
oxidation
oxidation
3.Halogenation
4.Hydrogenation
5.cis Dihydroxylation
6.Oxidativecleavage
7.Epoxidation
subclass
mechanism
hydrochlorination, yes
hydrobromination,
hydroiodination
yes
bromination,
chlorination
reduction
yes
no
no
no
no
Refer to the course map in the syllabus when studying the remainder
of the material in this course as we will not cover every reaction in the
textbook. Always refer to the 345 reactions summary in the course
materials folder in Blackboard. If the reaction has a yes under the
mechanism column, you are expected to learn the mechanism that
goes along with the reaction.
AlkeneSubstitutionPatterns
H
mono
di
tri
tetra
Addition of Hydrogen Halides
Et2O
Et2O
Et2O = diethyl ether = solvent only
Which sp2 Carbon Gets the H+?
Et2O
The Mechanism
Carbocation formation is the rate-limiting step.
Why the Difference in Rate?
The more stable carbocation is formed more rapidly.
The Difference in Carbocation Stability

Determines the Products
Et2O
What Product Will Be Formed?
Formation of a Racemic Mixture

H Br
H
H3C
C C
H
CH3
Carbocation Stability and Product

Distributions
All carbocations are reactive intermediates
Secondary carbocations are less stable than
tertiary carbocations but can form during the
course of a reaction
Products cannot be derived from methyl and
primary carbocations
Methyl carbocations only form under special
circumstances
If a primary carbocation forms, it will quickly
rearrange to a more stable form.
Alkene Hydration: Alcohol Synthesis
Mechanism for the Acid-Catalyzed

Hydration
H2SO4 +
R C
H
CH2
H
O
H
O
H2O
H3O+
H OH2
H
C H
H
R C
H
H
R C
H
H
C H
H
O
R C
H
H
C H
H
O
R C
H
H
O
R C
H
HSO4-
H2O
Step 1 - endothermic
formation of carbocation
H
C H
H
H
C H
H
Step 2 - exothermic
formation of protonated alcohol
H3O+
Step 3, often not shown, regenerates

hydronium and is why the reaction is
catalytic
Formation of an Ether
A Variation of Hydration
Halogenation: Addition of Br2 or Cl2
CCl4
CCl4
Product is a 1,2 dihalide (vicinyl dihalide)
Carbon tetrachloride (CCl4) is the reaction solvent and
does not participate in the reaction
The Mechanism for

the Addition of a Halogen
CCl4
The intermediate is a cyclic bromonium ion.
The Mechanism for

the Addition of a Halogen
Bromonium ion
C
C
H
C
C
C
H
Bromonium ion in 3-D
Addition of a Halogen is an Anti Addition
Formation of a Bromohydrin
A Variation on Halogenation
In this reaction, the solvent is water not CCl4. Since water

is a nucleophile it can ring open the bromonium ion.
Water is in much higher concentration than bromide anion.
Hydrogenation Addition of H2 across

a double bond
catalytic hydrogenation
a reduction reaction
Mechanism for Hydrogen Addition
catalytic hydrogenation
Hydrogenation Undergoes Syn Addition
Cis Dihydroxylation (pg 509-510)

Mechanism proceeds through a osmate
ester. You are responsible for knowing
only the functional group transformation
not the mechanism
H
H
Syn addition
H
a) OsO4 / H2O
OH
OH
b) NaHSO3
H
O
O
Os
O
O
metal ester
OH
OH
H
Cis Dihydroxylation
Draw eclipsed
H
H
H
H
OsO4
H2O
H
OH
OH
H
(2R,3S)-butane-2,3-diol
OH
H
OsO4
H2O
H
HO
(2R,3R)-butane-2,3-diol
Drawn staggered
HO H
HH
Me
Me
OH
OH
H OH
Optically active?
Oxidative Cleavage
Like hydrogenation, products depend on the substitution of the
starting alkene. Note that the intermediate aldehydes cannot be
isolated under these strongly oxidative conditions. Instead, they
are further oxidized to carboxylic acids.
(CO2)
Oxidative Cleavage
Mechanism proceeds through a manganate ester. You
are responsible for knowing only the functional group
transformation not the mechanism
Oxidative Cleavage
Products depend on the substitution of the starting
alkene sp2 to 1s bonds are fully oxidized
H
H
mono
H
H
KMnO4
OH
H3O+
OH
O
tri
KMnO4
CH3
OH
tetra
CH3
KMnO4
KMnO4
H3O+
CH3
H3O+
H3O+
OH
OH
di
CH3
O
O
CH3
O
CH3
OH
Expoxidation
Epoxides are strained three-member cyclic ethers
Like bromonium ions, nucleophiles may ring open
expoxides
MCPBA is a Commonly Used Peroxyacid
CH2Cl2
Precipitates out of
solution as epoxide
is formed
Mechanism for Epoxidation

You are not responsible for knowing this mechanism
the mechanism is similar to that for the addition of Br2
Syn Addition to a cis Isomer

Forms Only the cis Stereoisomers
Syn Addition to a trans Isomer

Forms Only the trans Stereoisomers
Strained Epoxides Ring Open

Recall the formation of a bromohydrin from the ring opening of a
bromonium ion
Nucleophiles can also ring open epoxides with the same

stereochemical result
Formation of cis and trans Diols

Consider the complementary reactions below
2
3
With the chemistry you now have, both products are available to
you.
Nomenclature of Epoxides
Alkynes
Nomenclature
Structure
Reduction
Acid/basechemistry
Carboncarbonbondforming
reactions
Nomenclature of Alkynes
An alkyne is a hydrocarbon that contains a carboncarbon triple bond.
General formula: CnH2n2 (acyclic)
CnH2n4 (cyclic)
The Structure of Alkynes
The triple bond is composed of a sigma bond and two bonds.
Alkynes Are Less Stable and

Less Reactive Than Alkenes
Addition of Hydrogen Forms an Alkane
Stopping at the Alkene
Lindlar Catalyst
Syn Addition
Why Cis?
The catalyst delivers the hydrogens to one side of the triple bond.
Relative Electronegativities of Carbon

Remember from chapter 2:
sp hybridized carbons have 50% s character and 50% p character
sp2 hybridized carbons have 33% s character and 66% p character
sp3 hybridized carbons have 25% s character and 75% p character
A Hydrogen Attached to an sp Carbon

is the Most Acidic
Remember from Chapter 2, the more s character, the closer the electrons are
to the offsetting nuclear charge and that results in the pKa values of alkynes,
alkenes, and alkanes
Amide ion the conjugate base of ammonia

Used to deprotonate acids with pKa values outside of water
pKa = 25
pKa = 35
HO is Not Strong Enough
pKa = 25
pKa = 15
Forming a New CarbonCarbon Bond
Mechanism for Formation of the

CarbonCarbon Bond
Two Steps
Designing a Synthesis
all reactions covered
in chapter 3
?
Me
Et
Me
H 2, Linlar
NaNH 2/NH3
Me
EtBr
Et
Me
Chapter5
DelocalizedElectronsandTheirEffect
onStability,pKa,andtheProductsofa
Reaction
Conceptsanddrawingresonance
structures
AromaticChemistry
ElectrophilicAromaticSubstitution(4
reactions),reduction.andsidechain
oxidation
Curvedarrowsdenoteelectronflow
Bothpositiveandnegativechargemaybedelocalized
DelocalizedElectronsAffect
pKa Values
Delocalizationinacids
Phenolsversus Alcohols
WhyPhenolsareMoreAcidic
AllylicandBenzylic
ResonanceContributorsfor
anAllylicCation
Allylic notaprimarycarbocation
aBenzylicCation
aBenzylicCation
DelocalizationEnergy
Thedelocalizationenergyistheextrastabilityacompoundhas
asaresultofhavingdelocalizedelectrons.
Electrondelocalizationisalsocalledresonance.
Delocalizationenergyisalsocalledresonanceenergy.
Theresonancehybridismorestablethananyofits
resonancecontributorsispredictedtobe.
Benzene extremedelocalization
Heatsofhydrogenation
Thedelocalizationenergyofbenzeneis36kcal/mol.
Benzene anaromatic molecule
CriteriaforaCompoundtoBeAromatic
Mustbecyclic
All atomsmustbesp2 hybridized flat
Musthave2,6,10... electrons(Huckelnumber)
PolycyclicAromaticHydrocarbons
e
2
6
10
14
18
etc.
10e
14e
ExamplesofCompounds
ThatareNotAromatic
e
2
6
10
14
18
etc.
CyclobutadienedoesnthaveaHuckelnumber ofelectrons.
Cyclooctatetraeneisnotplanar.
Aromaticions
e
2
6
10
14
18
etc.
cyclopentadiene
cyclopentadienylanion
Anionisaromatic
HeterocyclicAromaticCompounds
e
2
6
10
14
18
etc.
pyrimidine
purine
caffeine
nicotine
LSD
OrbitalStructureofPyridine
OrbitalStructureofPyrroleandFuran
Pyrrolesimilartocyclpentadienylanioninstructure
ProtonatedAnilinesversus
ProtonatedAmines
NitrogenContainingHeteroaromatics
H+
pKa = 5
N
N
H
pyridine - a base
lone pair not part of the aromatic system - able to form a bond to a proton
H+
N
N
pKa = 2
N
H
pyrimidine a base
lone pair not part of the aromatic system - able to form a bond to a proton
e
2
6
10
14
18
etc.
CombiningConcepts:
WithdrawingElectronsbyResonance
WithdrawingElectronsbyResonance
Combiningconcepts hydrohalogenation
andresonancedelocalization
WhytheDifferenceinRate?
Localizedvs.delocalized
ReactionsofBenzene
ElectrophilicAromaticSubstitution(EAS)
1. Halogenation
2. Nitration
3. Acylation
4. Alkylation
Redoxreactionsofsubstitutedbenzenes
6. Sidechainoxidation
7. Reductionofnitrobenzene
TheNomenclatureofSubstituted
Benzenes
somemonosubstitutedbenzenesarenamed
justbyaddingthenameofthesubstituenttobenzene
TheNomenclatureofSubstituted
Benzenes
Mostaromaticcompoundsarecommonlynamed.
ElectrophilicAromaticSubstitution
Aromaticcompoundssuchasbenzeneundergoelectrophilic
aromaticsubstitutionreactions(EAS).
OfthefourEASreactionsthatwillbediscussed,allproceedwith
themechanismshownabove onlydifferingintheidentityof
theelectrophile
NobelPrizeinChemistry2016
JeanPierreSauvage
J.FraserStoddart
BernardL.Feringa
NobelPrizeinChemistry2016
JeanPierreSauvage
J.FraserStoddart
BernardL.Feringa
Substitution not addition
The electronsarenucleophilic(likeelectrophilicaddition)
Aromaticityisrestoredintheproductfromelectrophilicsubstitution.
CommonEASmechanism
1.Halogenation ofBenzene
Bromination orchlorination ofbenzenerequiresaLewisacidcatalystbecause

benzenesaromaticitycausesittobelessreactivethananalkene.
Iron(III)oraluminiumchloridesorbromidesarethetypicalLewisacidcatalysts.
EASmechanism halogenation
M=metal=aluminumoriron(III)
Br+ orCl+ istheelectrophile
(e.g.,FeCl3 orFeBr3)
H
+
Br
H
Br
Base
Br
2.NitrationofBenzene
EASmechanism nitration
Sulfuricacidprotonatesnitricacid.
Protonatednitricacidloseswater
toformtheelectrophile(thenitroniumion).
3.EASAcylation
An acid (acyl) chloride is the source of the acyl group

Acid chlorides are easy to make with thionyl chloride
EASmechanism acylation
Theacylium ionistheelectrophile.
EASacylation intramolecular
Cycliccompoundsareformedfromintramolecularreactions.
Formationoffive andsixmemberedringsarefavored.
4.EASAlkylation
Analkyhalideisthesourceofthealkylgroup.
ALewisacid(AlCl3)isrequired.
EASmechanism alkylation
Acarbocationistheelectrophile.
Thisreactionislimitedtoalkylhalidesthatcanformcarbocations
5.Sidechainoxidation no mechanism
functionalgrouptransformation=alkylbenzenetobenzoicacid
Alkylbenzenemusthaveatleastonebenzylichydrogen
Multiplesidechainscanbeoxidized
orKMnO4
orKMnO4
6.Nitrobenzenereduction no
mechanism
Nitrobenzenereduction functionalgrouptransformation
Nitrobenzenetoaniline
NomenclatureofDisubstitutedBenzenes
Therelativepositionsoftwosubstituentscanbeindicated
bynumbersorbytheprefixesortho (1,2),meta (1,3)orpara (1,4)
TheEffectofSubstituentsonReactivity
EASrequiresthe electronsinringtoattackelectrophile
ElectronDonatingGroups(EDG)donateelectrondensitytothebenzeneringincreasing
benzenesnucleophilicityandstabilizingthecarbocationintermediate.
ElectronWithdrawingGroups(EWG) withdrawelectrondensitytothebenzenering
decreasingbenzenesnucleophilicityanddestabilizingthecarbocationintermediate.
ElectronDonatingGroups(EDG)
Themethoxygroupiselectrondonating.
Sameargumentastowhyphenolisastrongeracidthancyclohexanol
electrondelocalization
O
ElectronWithdrawingGroups(EWG)
Thenitrogroupiselectronwithdrawing
Anatomdirectlyattachedtotheringthatisdoublyortriplybondedtoan
electronegativeatomwithdrawselectronsbyresonance.
Comparedwithbenzene
Electrondonatinggroups
EDGdonateelectrondensitytothebenzeneringincreasingbenzenes
nucleophilicityandactivating towardsEAS.
Electronwithdrawinggroups
EWGwithdrawelectrondensitytothebenzeneringdecreasingbenzenes
nucleophilicityanddeactivating towardsEAS
Electroniceffects
EWG:Substituentsthatwithdrawelectrondensityhaveafullorpartial
positivechargenexttothearomaticring
EDG:Substituentsthatdonateelectrondensityhaveaalkylgroupora
heteroatom(lonepair)nexttothearomaticringandactivatethecompound
towardsadditionalEAS
O
CH3
CH3
same concept
Remember that alkyl groups can donate electron density

this was used to explain the order of carbocation stability
Synthesisofdisubstituted
aromatics directingeffect
Allactivatingsubstituentsareorthoparadirectors.
Activation meansthattoluenewillbebrominatedfaster comparedwith

benzene
MetaDirectors
Alldeactivatingsubstituentsaremetadirectors.
Deactivationmeansthatnitrobenzenewillbebrominatedslower compared
withbenzene
Halogensareunique
Halogens withdraw electron density (more electronegative than carbon)
but have lone pair electrons so they are deactivating but ortho/para
directors. This is the only exception
Nitrationofphenol
OH
OH
ortho
OH
H
NO2
H
NO2
OH
OH
H
NO2
OH
OH
H
NO2
OH
NO2
ortho
OH
OH
meta
H
NO2
H
NO2
H
NO2
OH
OH
OH
O2N H
O2N H
O2N H
NO2
OH
para
OH
O2N H
NO2
para
Brominationofnitrobenzene
O
O
H
NO
Br 2
NO2
ortho
NO2
NO2
H
Br
NO2
H
Br
NO2
NO2
NO2
Br
Br
NO2
NO2
meta
H
Br
H
Br
NO2
NO2
H
Br
NO2
Br
NO2
para
Br H
Br H
O2Br
N H
Br H
Br
meta
Positivecharge(+)alwaysisortho andpara
tosp3 carbonofintermediate
Positivecharge(+)alwaysisortho and
para tosp3carbonofintermediate
EWG
H
(+)
(+) (+)
H
(+)
(+) (+)
(+)
(+) (+)
EWG
ortho
EWG
para
very destabilizing
meta
less destabilization
TheOrderoftheReactionsisImportant
starting from toluene, draw a synthesis of 4-chlorobenzoic acid
CO2H
CHR2
KMnO4
Cl
Cl2, AlCl3
toolkit
side chain oxidation
EAS chlorination
CO2H
CO2H
CH3
CH3
CH3
Cl
CO2H
Cl
Cl
CO2H
Cl
Cl
TheOrderoftheReactionsisImportant
starting from toluene, draw a synthesis of 4-chlorobenzoic acid
CO2H
CHR2
KMnO4
Cl
Cl2, AlCl3
toolkit
side chain oxidation
EAS chlorination
CO2H
CO2H
CH3
CH3
CH3
Cl
CO2H
Cl
Cl
CO2H
Cl
Cl
RecognizeEWGandEDG andextendto
othersystems
ExplainthetrendofpKavalues
Chapter 6 - Stereochemisty
Why You Care

Frances Oldham Kelsey
1914-2015
Thalidomide
Pioneering Work
Tartaric acid salts
Louis Pasteur
1822-1895
Concept of isomerism
Carvone - Different Smells
spearmint
Caraway seed
Carvone - Different Smells
Isomers
Compounds that have the
same molecular formula but
different structures.
Constitutional Isomers
Constitutional isomers differ in the way the atoms are connected.
CisTrans Isomers in Rings

Cistrans isomers result from restricted rotation.
Cyclic structures restrict rotation.
Cis: The substituents are on the same side of the ring.

Trans: The substituents are on opposite sides of the ring.
CisTrans Isomers in Alkenes

Double bonds restrict rotation.
Cis: The hydrogens are on the same side of the double bond.
Trans: The hydrogens are on opposite sides of the double bond.
Stereochemistry, Odd Terminology but

Easy Concepts
Chiral, chirality, chiral center, achiral
Plane of symmetry
Asymmetric center
Enantiomer, diastereomer, meso compound
Absolute configuration
Fischer projections
Optical activity, plane polarized light
Racemic
Stereoisomers: Chiral and Achiral

Objects
Chiral objects
Achiral objects
Chiral Molecules
A chiral center is an atom that is attached to four different groups.
Finding a Chiral Center
4-octanol
Look for a carbon bound to 4 different groups
Enantiomers
Enantiomers are different compounds but can be difficult to separate.

Enantiomers have the same physical and chemical properties.
Enantiomers
Plane-Polarized Light
A Chiral Compound is Optically Active
A chiral compound rotates

the plane of polarization of plane-polarized light.
If it rotates the plane clockwise = (+)
If it rotates the place counterclockwise = ()
Chiral and Achiral Molecules
Chiral compounds have nonsuperimposable mirror images.

Achiral compounds have superimposable mirror images
(there is a plane of symmetry).
Chiral and Achiral Molecules
achiral
achiral
chiral
Tetrahedral carbon with 4 different groups is just a

shortcut to thinking about symmetry.
Chiral compounds lack a plane of symmetry
Achiral compounds possess a plane of
symmetry
How to Draw Enantiomers

Wedge and Dash
Fischer projections
Fischer projections are just another way of showing a tetrahedral center
Naming Enantiomers
Assign relative priorities to the four groups.

1 = highest priority; 4 = lowest priority
Naming Enantiomers
Prioritize Groups
1 = highest priority
4 = lowest priority
Identify chiral carbon, assign priorities 1 and 4 first. Evaluate connections for
assigning priorities 2 and 3.
Naming Enantiomers
clockwise = R
and
counterclockwise = S
Naming Enantiomers
draw an arrow from 1 to 2 to 3
if the lowest priority group is on a hatched wedge, then

clockwise = R
and
counterclockwise = S
Naming Enantiomers
(S)
(R)
Swapping two groups (but only two groups) will give the
opposite enatiomer.
Sometimes it is easier to draw the R enantiomer and
convert to S.
R and S Versus (+) and ()

Some R enantiomers are (+) and some are ().
Some S enantiomers are (+) and some are ().
Compounds with Two Asymmetric Centers

maximum # of stereoisomers = 2n
(n = # of asymmetric centers)
1 and 2 are enantiomers.
Diastereomers
Diastereomers are stereoisomers that are not enantiomers.

1 and 3 are diastereomers.
Diastereomers have different physical and chemical properties.
Chirality in Rings
Two Asymmetric Centers,

Four Stereoisomers
The cis stereoisomers are a pair of enantiomers.

The trans stereoisomers are a pair of enantiomers.
Identifying an Asymmetric Center
An asymmetric center is attached to four different groups.
two asymmetric centers, four stereoisomers
No Asymmetric Centers
There are only two stereoisomers: cis and trans.
Two Asymmetric Centers: Three Stereoisomers

(a meso compound and a pair of enantiomers for
symmetrically substituted compounds)
A Meso Compound Has a

Superimposable Mirror Image
Meso compounds are optically inactive even though they have asymmetric centers.
A Meso Compound Has a

Plane of Symmetry
A Meso Compound
A compound with two asymmetric centers that have the same four groups
bonded to each asymmetric center will have three stereoisomers:
a meso compound and a pair of enantiomers.
Naming Stereoisomers
Naming Stereoisomers
Physical Properties of Stereoisomers
Stereochemistry Presents Challenges to Synthetic Chemistry

In the 90s, over 30 teams worked to achieve a total synthesis
C
D
Paclitaxel was harvested from

the pacific yew, a species that
is near threatened
The pacific yew
Stereochemistry Presents Challenges to Synthetic Chemistry

In the 90s, over 30 teams worked to achieve a total synthesis
C
D
Annual sales reached US$1.6

billion in 2000; Paclitaxel is now
available in generic form.
K. C. Nicolaou
R. H. Holton
Contrave weight-loss formulation FDA approved 9/10/14
Bupropion Wellbutrin
Antidepressant/smoking cessation
HO
N
CH3
H
HO
Naltrexone an
opioid antagonist:
binds opioid receptor
with higher affinity
than the agonist
without activating the
receptor
Morphine an opioid
agonist: binds opioid
receptor with
activation
Controlling Stereochemistry is Critical in Drug Manufacture.

Top 5 Drugs in 2013
Chapter 7
Substitution&EliminationReactionsof
AlkylHalides
We will start considering alkyl halides with X being Cl, Br, or I
Alkyl halides can undergo subsitition and

elimination
Substitution reactionthe electronegative group is replaced by another group.
Elimination reactionthe electronegative group is eliminated along with a hydrogen.
More precisely called a nucleophilic substitution reaction

because the atom replacing the halogen is a nucleophile.
Leaving Group
Nucleophile
A Substitution Reaction
Relative Rates of an SN2 Reaction
Does not
undergo
SN2
Tertiary alkyl halides do not undergo SN2 substitution.
If the halogen is bonded to an chiral sp3 cabron,

the product will have the inverted configuration.
Leaving Group
Nucleophile
Inverted Configuration
Summary of the Experimental Evidence

for the Mechanism of an SN2 Reaction
1. The rate of the reaction is dependent on the concentration
of both the alkyl halide and the nucleophile.
2. The relative rate of the reaction is
methyl > primary > secondary
tertiary alkyl halides do not undergo SN2 reactions.
3. If the starting alkyl halide is chiral at the halogen, the

configuration of the product will be inverted.
The Mechanism
back-side attack
Inversion!
Why Bimolecular?
Why Do Methyl Halides React the Fastest

and Tertiary Halides are Unreactive?
steric hindrance
Why the Configuration of the Product

is Inverted
The Weakest Base is the Best Leaving Group
The Rate of an SN2 Reaction

is Affected by the Leaving Group
Steric Hindrance Decreases Nucleophilicity
Even though the tert-butoxide ion is a

stronger base, it is a poorer nucleophile
because
nucleophilic
attack
is
more
sterically hindered than proton removal.
SN2 Reactions Can Be Used to Make

a Variety of Compounds
The reactions are irreversible because a strong base displaces a weak base.
Tertiary Alkyl Halides & SN1
A tertiary alkyl halide will not undergo SN2 but

will react by an alternate mechanism called SN1
The Product is a Pair of Enantiomers

No inversion (unlike SN2)
Racemization (loss of control over stereochemistry) in SN1
If a halogen is bonded to a chiral center,

the product will be a pair of enantiomers.
Summary of the Experimental Evidence

for the Mechanism of an SN1 Reaction
1. The rate of the reaction depends only on the
concentration of the alkyl halide.
2. Tertiary alkyl halides react the fastest.
3. If the halogen is attached to an asymmetric center

the product will be a pair of enantiomers.
The Mechanism
The leaving group departs before the nucleophile approaches.
Rate-Determining Step
Most SN1 reactions are solvolysis

reactions; the nucleophile is the solvent.
The Rate of an SN1 Depends Only on the

Concentration of the Alkyl Halide
Rate-Determining Step
The Slow Step is Formation of the Carbocation
Tertiary alkyl halides react the fastest

they form the most stable carbocations.
Primary alkyl halides do not undergo SN1 reactions
they form the most unstable carbocations.
Why a Pair of Enantiomers?
The Weakest Base is the Best Leaving Group
pKa
HF
3
HCl -7
HBr -9
HI
-11 Most acidic (most stable X)
Benzylic and Allylic Halides

Undergo SN2 Reactionsbut

Can Also Undergo SN1 Reactions
The SN1 Reaction of Allylic Halides

Can Form Two Products
Vinylic and Aryl Halides

Cannot Undergo SN2 Reactions
Vinylic and Aryl Halides

Cannot Undergo SN1 Reactions
Summary of Alkyl Halide Reactivity
Substrate
Substitution Mechanism
methyl and 1o
SN2 only
allylic, benzylic, and 2o
Both SN2 and SN1
3o
SN1 only
vinylic and aryl halides
Neither SN2 or SN1
Intermolecular versus Intramolecular

SN2 Reactions
The Intramolecular Reaction is Favored When

a Five- or Six-Membered Ring Can Be Formed
3-Membered and 4-Membered Rings

are Less Stable
Three-membered rings are generally formed faster than 4-membered rings.
EliminationReactionsofAlkylHalides
CompetitionBetweenSubstitutionandElimination
Alkyl Halides Undergo

Substitution and Elimination Reactions
In an elimination reaction, a halogen is removed from one carbon
and a hydrogen is removed from an adjacent carbon.

A double bond is formed between the two carbons
from which the atoms were removed.
An E2 Reaction
The Halogen Comes off the Alpha Carbon;

the Hydrogen Comes off the Beta Carbon
All elimination reactions are elimination. The double

bond always forms between the and carbons
Stereochemistry
180o
Leaving group and hydrogen must have a

dihedral angle of 180o also called antiperiplanar
Energy
Anti Elimination is Preferred
Like SN2, an E2 is a one-step reaction.

The base and the substrate must come together to form the transition state
thus giving the kinetic profile
Anti Elimination
The alkene with the bulkiest groups on opposite sides

of the double bond will be formed in greater yield,
because it is the more stable alkene.
An E2 Reaction is Regioselective
A disubstituted alkene
A monosubstituted alkene
The major product is the most highly substituted alkene.
RecallAlkeneSubstitutionPatterns
H
mono
di
tri
tetra
More E2 Reactions
-Identify all carbons

-All possible products will have a bond between the and carbons
-Major product will be the most highly substituted alkene
Conjugation is preferred
The conjugated alkene is the more stable alkene.
An E1 Reaction
Recall the Stabilities of Carbocations
doesnt
form
The Mechanism for an E1 Reaction
An E1 Reaction is Regioselective
The major product is the more substituted alkene.

Undergo E2 & E1 Reactions
Conjugated Dienes

Undergo E2 & E1 Reactions
Both E2 and E1
Compare these elimination reactions
E2 and E1 Reactions are Regioselective

E2
E1
All elimination reactions are eliminations and

the most substituted alkene is preferred
trans is preferred to cis
E2 Elimination from Six-Membered Rings
Both groups being eliminated must be in axial positions.
H and Cl Must Both Be Axial

-Lowestenergychair
-E2notpossibleinthisringconforma on
H
C
-Highestenergychair
-E2possibleinthisringconforma on
-Two hydrogensat180o toleavinggroup
H
C
C
H
Cl
C
H
E2
Cl
Neomenthyl Chloride is Faster

CH(CH3)2
C
Cl
CH3
C
H
CH
C
CH3
Cl
Cl
H3C
disubs tuted
minor
trisubs tuted
major
C
CH
CH3
Menthyl Chloride is Slower

CH(CH3)2
Cl
C
H
Cl
CH3
CH
Cl
CH3
H
C
H
CH
H 3C
disubs tuted
onlyproduct
CH3
SN2 and E2 can compete
2o undergo both E2 and SN2
Under SN2/E2 Conditions

Primary Alkyl Halide = Primarily Substitution
Steric Hindrance Favors Elimination

Secondary Alkyl Halide = Substitution and Elimination
Substitution is favored by a weak base.

Elimination is favored by a strong base.

Tertiary Alkyl Halide = Only Elimination
Under SN1/E1 Conditions Tertiary Alkyl Halides

Undergo Substitution and Elimination
Tertiary (SN1/E1): Substitution is Favored

Tertiary (SN2/E2): Only Elimination
Weak base
Strong base
William Ether Synthesis:

an SN2 Reaction
Forming an Alkoxide Ion
Synthesizing Butyl Propyl Ether
Synthesizing Ethyl Isopropyl Ether

synthesizeethylisopropyletherusingaWilliamsonethersynthesis:
Firstbreakapartintonucleophile(alkoxide)andelectrophile(alkylhalide)
Therearetwopossible"disconnects"
O
O
Br
Br
O
analysis: SN2islimitedbystericsinthetransi onstatesothebestrouteisusingthe1o alkyl

halidebromoethaneandisopropoxide
Synthesizing an Alkene
The more hindered group should be provided by the alkyl halide.
Hydration of an alkene/dehydration of
an alcohol
Dilute vs. concentrated acid

Lots of water
Not very much water
Same mechanism run in reverse
Converting an Alkene to an Alkyne

A special case
Br
Br NaNH2/NH3
Br2
3 eq
NaNH2
NaNH2
Br
NaNH2
Driving force is deprotonation of alkyne
Chapter 8
ReactionsofAlcohols,Ethers,
Epoxides,andThiols
Manyreactionsinthischapterare
extensionsfromchapter7.
Strongly Basic Leaving Groups

Cannot Be Displaced
alcohols
Acid Converts the Poor Leaving Group

into a Good Leaving Group
Alcohols have to be protonated or converted into good leaving groups

SN2 chemistry
alcohols
The Reactions of Secondary and Tertiary Alcohols

with Hydrogen Halides are SN1 Reactions
alcohols
The Reactions of Primary Alcohols

with Hydrogen Halides are SN2 Reactions
alcohols
Why is It Important to Be Able

to Convert Alcohols to Alkyl Halides?
All SN2 reactions

alcohols
Other Methods to Convert

Alcohols into Alkyl Halides
NEW REACTIONS!
phosphorus tribromide & thionyl chloride
You do not need to know the mechanism of these reactions
alcohols
Sulfonate Esters in SN2 reactions

o
alcohols
A Sulfonate Ester is a good leaving group
alcohols
Stereochemical Considerations
2 inversions
1 inversion
alcohols
Two SN2 Reactions or

One SN2 Reaction?
inversion
inversion
inversion
Stereochemistry is important here.
alcohols
Dehydration of an Alcohol
Dehydration of an alcohol either E1 or E2

depending on the substitution of the alcohol
alcohols
Dehydration is a Reversible Reaction
The difference between concentrated and dilute acids
alcohols
Dehydration of Secondary and Tertiary

Alcohols are E1 Reactions
alcohols
Dehydration (E1) is a Regioselective

Reaction
The major product is the more stable alkene.

alcohols
Dehydration of a Primary Alcohol

is an E2 Reaction
alcohols
Dehydration is Stereoselective
The major product is the stereoisomer with the

largest groups on opposite sides of the double bond.
alcohols
A better way to eliminate an alcohol
Non-acidic conditions
alcohols
Ethers are alkylated alcohols
ethers
Ethers react with hydrogen halides
ethers
Ethers Are Common Solvents

Because They React Only with Hydrogen Halides
Common solvents
ethers
Devise a mechanism that accounts for the

following reaction
THF is a common organic solvent that is stable under many reaction
conditions except those including HCl, HBr, and HI. Under these strongly
acidic conditions, THF undergoes the following reaction. Draw a mechanism
that accounts for the formation of product using the curved arrow notation to
show all bond making and bond breaking.
ethers
Devise a mechanism that accounts for the

following reaction
Under these strongly acidic conditions (1 equivalent of HI), What would
happen with 2 equivalents of HI?
What mechanism is shown above?
ethers
Tert-butyl ethers are often used to reversibly

protect the hydroxyl group
When isobutylene gas is reacted with a compound containing a hydroxyl
group in the presence of a non-aqueous acid, a tert-butyl ether may be
formed as shown below. Devise a mechanism that accounts for the formation
of this product.
ethers

Start by remembering electrophilic addition of the proton to the alkene to
give the tert-butyl cation. The cation is attacked by the hydroyl group to give
the ether.
ethers

This reaction is reversible depending on conditions.
H+
(TFA)
ethers
Recall synthesis of an epoxide

from a per-acid
Naming epoxides: add oxide to the end of the alkene name.

For example, cyclohexene is converted to cyclohexene oxide when
reacted with m-chloroperbenzoic acid (mCPBA) in dichloromethane.
epoxides
Synthesis of an Epoxide from a

halohydrin intramolecular SN2
chlorohydrin
epoxides
Epoxides can be easily ring opened

with SN2 or SN1 type chemistry
because of ring strain
When the epoxide isnt symmetric
epoxides
The Acid-Catalyzed Mechanism

SN1-like
epoxides
If the Epoxide is Not Symmetrical,

Which Carbon Does the Nucleophile Attack?
The nucleophile attacks the more substituted epoxide carbon.

epoxides
Under Acidic Conditions the Nucleophile Attacks

the More Substituted Ring Carbon
epoxides
Under Neutral or Basic Conditions the

Nucleophile Attacks the Less Substituted Carbon
SN2-like
epoxides
Using Epoxides in Synthesis
P.T.
P.T. = proton transfer

epoxides
Forming a trans-1,2-Diol
enantiomers
1,2-diols
Forming a cis-1,2-Diol
: :
: :
Sulfur containing compounds
Nomenclature of Thiols
Chemistry of thiols
Acid/base & SN2
Thiols have pKa values of about 10.

The conjugate base form (thiolates) are excellent nucleophiles and less
prone to elimination chemistry
Chemistry of thiols
Redox
O
HS
O
OH
OH
NH2
NH2
cysteine
methionine
Chemistry of sulfides
Redox
Polar aprotic solvents

SN2
Sulfonate esters are good leaving

groups
O
S Cl
O
Me
OH
OTs
NaN3
N3
TsCl
O
O S
O
Me
O
Me
O S
O
stable conjugate base
O
HO S
O
Me
pKa <0
good leaving group

which means
which means
Secondary Alcohols can be

oxidized to ketones
Redox chemistry
Primary alcohols can be oxidized

to acids and aldehydes
aldehyde
Redox chemistry
Tertiary Alcohols Cannot Be Oxidized

to a Carbonyl Compound
Redox chemistry
Carbonyl Chemistry
Chapter9 ReactionsofAldehydesand
Ketones
Reactionsof,UnsaturatedCarbonylCompounds
Lookingforward,Chapter10coverscarboxylicacidsand
derivativesandChapter11coversenolandenolate
chemistry
Carbonyl Overview
Three areas:
aldehyde & ketone chemistry
carboxylic acids & derivatives
enol/enolate chemistry
Note that Y is not a leaving group in this chapter
common nomenclature
3
3
3
3
synthesis via oxidation of alcohols

1o and 2o alcohols may be oxidized using chromic
acid, chromate salts, dichromate salts, or
permanganate. Note that primary alcohols do not stop
at the aldehyde but rather oxidize to the carboxylic
acid.
No Mechanism Required
synthesis via oxidation of alcohols

To oxidize a primary alcohol to an aldehyde without
over oxidizing to the carboxylic acid, PCC is used.
PCC may also be used to oxidize secondary alcohols
to ketones.
No Mechanism Required
O
O Cr Cl pyridinium chlorochromate = PCC
O
N
H
OH
OH
PCC
CH2Cl2
PCC
CH2Cl2
CHO
Aldehydes and ketones are

attacked by nucleophiles
The partial positive charge on the carbonyl carbon causes it to be
attacked by nucleophiles:
nucleophilic attack on the carbonyl
carbon
O
C
Nu
Nu
chapter 10: carboxylic acids and

derivatives: Y = Leaving Group
O
C Y
R
Nu
O
C
common tetrahedral
intermediate
OH
C Y
R
Nu
chapter 9: aldehydes and ketones
irreversible
alcohol syntheses
Grignard, hydride reduction
reversible reactions
imines and acetals
Grignard Chemistry
Grignard reagents have inverted polarity at the carbon bound to

magnesium thereby making that carbon nucleophilic.
Grignard reagents are formed by reacting the alkyl (or other) halide
with magnesium metal in the aprotic solvent ether
Nomenclature
Name the organic group, then the metal.
MgBr
phenylmagnesium bromide
ethylmagnesium chloride
MgCl
vinylmagnesium bromide
MgBr
allylmagnesium chloride
benzylmagnesium bromide
MgCl
MgBr
Grignard reagents react as if they were

carbanions
Grignard reagents are strong bases. If

Grignard reagents are exposed to water,
they are destroyed
Grignard reagents are nucleophiles

SN2 chemistry
Carbonyl addition chemistry
Girgnard and formaldehyde, aldehyde, ketone, and epoxide a

synthesizing alcohols
Girgnard reagents combined with formaldehyde,

aldehydes, ketones, and epoxides are all ways
of synthesizing alcohols
Aldehydes and ketones may be reduced to

alcohols using nucleophilic hydride
Sodium Borohydride NaBH4
H
H
B
H
H
Na
O
HO
+
H3O
Hydrogen is added in two steps:

first hydride then proton
Different flavors of hydride

NaBH4 and LiAlH4 are both sources of nucleophilic hydride.
LiAlH4 is a more powerful reducing reagent able to reduce
carboxylic acids and derivatives such as esters to alcohols.
These reactions will be discussed in the next chapter
OH
O
no reaction
NaBH4
MeOH
Me
a. LAH, ether
b. H3O+
NaH, sodium hydride is only used as a strong base.
HO
Me
Both Grignard reactions and hydride

reduction are irreversible reactions
A
When the Eact reverse is

too great the reaction is
considered irreversible
Eact fwd
Eact rev
Eact rev
Grignard reactions and

hydride reductions of
aldehydes and ketones are
irreversible
Irreversible Reactions
Grignard reagents react with aldehydes & ketones to give alcohols
Hydride reduction
Reversible reactions of aldehydes and

ketones
We will cover two reversible reactions:

Imine bond formation
Acetal formation
You are required to demonstrate knowledge of the
mechanism of each of these reactions.
aldehydes and ketones give imines

with 1o amines
Imine bond formation is reversible
Mechanism for Imine Formation
Imine formation is reversible

imine hydrolysis
Imines are like carbonyl compounds

and can be reduced
When formation and reduction are coupled:
The reactions of alcohols with aldehydes

and ketones - formation of acetals
Formation remove water

Hydrolysis add water
The reactions of alcohols with aldehydes

and ketones - formation of acetals
P.T.
H3C
HO
H3C
CH3
P.T.
H
O OH
P.T.
H3C
O OH
P.T.
H3C
H
O O H
Hemiacetal
("half-acetal")
CH3
H3C
H3C
O O H
H3C
acetal
H3C
OH
Removing water drives formation
-H2O
H3C
resonance stablilized
cation
The reactions of diols with aldehydes and

ketones - formation of cyclic acetals
The attack of the second hydroxyl oxygen in

intramolecular
Like imines, acetals can be hydrolyzed
Dilute acid drives hydrolysis
Only cyclic hemiacetals are stable
Sugar Units in Carbohydrates

are Held Together by Acetal Groups
Cyclic Acetals are Protecting Groups
Using Protecting Groups in Synthesis
LiAlH4 will reduce the ester to an alcohol, but the keto group will also be reduced.
The keto group is protected as a ketal in the following synthesis:
,-Unsaturated Aldehydes and Ketones

Have Two Electrophilic Sites
Direct Addition to ,-Unsaturated

Aldehydes and Ketones
1,2-addition
Y: = RMgBr, H:
Conjugate Addition to ,-Unsaturated

Aldehydes and Ketones
1,4-addition
Weak Bases Form

Conjugate Addition Products
In a Chemoselective Reaction,
One Functional Group Reacts Preferentially
4
3
Retrosynthetic analysis
Starting from propene, draw a synthesis of 4-methylpentan-2-ol. Hint:
Grignard chemistry is a key step
When assigned such a problem, the key is to determine where to
disconnect so that you can work backwards towards the starting material.
Only practice will help with this analysis. For the purpose of this lecture, the
disconnection is shown with the wavy red line.
Each disconnect is a heterolytic bond cleavage (one partner takes the
electrons in the covalent bond) therefore there are always two possibilities of
electrophile/nucleophile pair
Here are those two possibilities with the given product
At this point, you should realize that these anion/cation pairs likely
cant be formed, but we can use synthetic equivalents. You have
seen this with alkyl halide chemistry using SN2
O
O
base
C2H2
not possible
While we cant form the primary carbocation, we can use a alkyl halide
that is synthetically equivalent to the cation. This was the basis of alkyl
halides in SN2 chemistry.
The best disconnect is boxed below
Synthesis:
mcpba
CH2Cl2
HBr
ether
key bond
O
Br
O
Mg
ether
BrMg
H3O+
product
Sometimes these type problems are presented as road maps that tether
your analysis
Roadmap problems are in turn, linked functional group transformations. The
key it to recognize the transform use notecards and study in groups.
Roadmap problems are in turn, linked functional group transformations. The
key it to recognize the transform.
Chapter 10
ReactionsofCarboxylicAcidsand
CarboxylicAcidDerivatives
Carbonyl Overview
The next three chapters cover the chemistry of the carbonyl group
that are focused on:
carboxylic acid & derivative chemistry
aldehyde & ketone chemistry
enol/enolate chemistry
chapter 18
OH
C
enol
Y
enolate
Nomenclature of carboxylic acids
Carboxylic acids
Nomenclature of Carboxylate Ions
Carboxylic acids
Two basic reactions of carbonyl compounds
Nucleophilic acyl substitution
Carboxylic acids and

Derivatives
R
OH
carboxylic acid
carboxylate
O
R
thioester
O R
O
acyl phosphate
amide R
ester
O
O P
Cl
acyl chloride
acid anhydride
The structure of a carbonyl compound
The carbonyl carbon is electrophilic
For carboxylic acids and derivatives, Y is a leaving group
Carbonyl resonance contributors
A Nucleophilic acyl substitution reaction
Y = Leaving Group
Z = nucleophile
The relative reactivities towards nucleophilic acyl

substitution depend on the Leaving Group
Acid/Base and properties

pKa values, solubility - review
Carboxylic acids
Synthesis of acids
Oxidative cleavage (review)
Oxidation of primary alcohol (review)
Grignard with CO2 (new reaction)
Hydrolysis of derivatives (new reaction,
covered throughout the chapter)
Carboxylic acids
New synthesis of a carboxylic acid
Add to your Grignard notecards:

Grignard + formaldehyde = primary alcohol
Grignard + epoxide = primary alcohol
Grignard + aldehyde = secondary alcohol
Grignard + ketone = tertiary alcohol
Grignard + CO2 = acid
Carboxylic acids
Closer look at
Carboxylic acid derivatives
Carboxylic acids can be converted into the
following derivatives
carboxylic acid chlorides
carboxylic acid anhydrides
esters
amides
anhydrides
nitriles
All carboxylic acid derivatives can be

hydrolyzed back to carboxylic acids
Synthesis & Reactions of acid chlorides

Carboxylic acid chlorides are easily synthesized from
carboxylic acids upon reaction with thionyl chloride (SOCl2).
Acid chlorides can themselves be used to synthesize:
acid anhydrides, esters, & amides
O
C
O
SOCl2
C
OH pyridine R
Cl
hydrolysis
HNR'2 (2 eqivalents)
R'OH
O
C
O2CR'
OR'
O
C
O
C
O
C
NR'2
Acid chlorides
Nomenclature of acid chlorides
Acid chlorides
Ester synthesis via acid chloride

R
O
C
O
C
Cl
Nu
O
C
R
Cl
Nu
O
C
Nu
Cl
O
O
HCl
C
C
H 3C
H 3C
Cl
H3C
OEt
O
H
Et
sythesis of ethyl acetate from acetyl chloride
H
Et
Cl O
Esterification Lab
H3C
O
C
O
Cl
acetyl chloride
OH
isopentyl alcohol
O
isopentyl acetate
"banana ester"
Acid chlorides
Amide synthesis via acid chloride
Acid chlorides
Amides cannot be synthesized by

combining an acid and amine directly
A carboxylic acid is an acid and an amine is a base,

so an acid-base reaction occurs.
Anhydride synthesis via acid chloride
Acid chlorides
Nomenclature of acid anhydrides
Acid anhydrides
Acid Anhydrides are Less Reactive than Acyl Chlorides

but More Reactive Than Esters
Acid anhydrides
Reactions of Acid Anhydrides
As you will see, acid anhydrides are for the

most part, interchangeable with acid chlorides
Acid anhydrides
The Mechanism
Acid anhydrides
Esters can be prepared using a concentrated

acid-catalyst
O
OH
CH3OH
conc'n acid
(H+,
OCH3
e.g., H2SO4)
P.T.
P.T.
OH
Ph
OH
Ph
OH
H
H
H2O
OH
CH3
P.T.
OH
Ph
H P.T.
O
O H
OH
OCH3
CH3
CH3
This ester synthesis is called Fischer esterification and complements

your prior synthesis via an acid chloride
Nomenclature of Esters named as

carboxylates
cyclic esters are called lactones

O
Cyclic ester = lactone

O
tetrahydro-2H-pyran-2-one
-valerolactone
esters
The Reaction of an Ester with Water
esters
The Carbonyl Oxygen is the Oxygen That is Protonated
+ H3O+ ClProtonation of the carbonyl carbon increases the electrophilic character of the carbon
Less electrophilic
Resonance forms
+
More electrophilic
Resonance forms
esters
The Mechanism for the

Acid-Catalyzed Hydrolysis of an Ester
Proton Transfer
P.T.
esters
Protonation Makes the Leaving Group

a Better Leaving Group
esters
Use Excess Water

to Drive the Reaction to the Right
esters
The Mechanism for Hydroxide-Ion Promoted

Hydrolysis of an Ester
esters
The Reaction of an Ester with an Alcohol
important in biochemistry and biodiesel fuel production

esters
The Reaction of an Ester with a Grignard

From chapter 12
Esters react with two equivalents of Grignard to give tertiary alcohols via a
ketone intermediate
LG at tetrahedral intermediate
first equivalent
EtO O
Ph OH
MgBr EtO
O
MgBr
ketone more
electrophilic than
starting ester
second tetrahedral
intermediate
esters
Summary of Grignard Reactions

for 345
For final exam
Grignard + formaldehyde = primary alcohol
Grignard + epoxide = primary alcohol
Grignard + aldehyde = secondary alcohol
Grignard + ketone = tertiary alcohol
Grignard + CO2 = acid
2 equivalents of Grignard + ester = tertiary alcohol
Nomenclature of Amides
Cyclic amide = lactam

amides
Nomenclature of Amides
The substituent attached to the nitrogen is stated first.
Amide bonds are peptide bonds
amides
The Mechanism for the

Acid-Catalyzed Hydrolysis of an Amide
amides
Amide Hydrolysis Can Be Promoted

by Hydroxide Ion
Draw a mechanism. Which do you think is more resistant to basic

hydrolysis, an ester or an amide?
amides
Nomenclature of Nitriles
Nitriles dont look like other carboxylic acid derivatives but

they can be considered a dehydrated amide
nitriles
Acid-Catalyzed Hydrolysis of a Nitrile
Amide tautomer
nitriles
Another synthesis of a carboxylic acid
Compare to Grignard and CO2
nitriles
Reduction of carbonyl systems
Chainsaw
reduction
Reduction of carbonyl systems
LAH is strong enough to reduce all common carbonyl systems

LAH is strongly basic and must be used under anhydrous conditions like
Grignard reagents
LAH transfers two hydride atoms per carbonyl group
reduction
Fats and Oils are Formed by

Esterifying Glycerol with Fatty Acids
Fats/soaps
Fats/soaps
2014 Pearson Education, Inc.
Hydrolysis of Fat or Oil in a

Basic Solution Forms a Soap
A soap is a sodium or potassium salt of a fatty acid.

The reaction is called saponification and you
will run this reaction in lab.
Fats/soaps
A Micelle
Long-chain carboxylate ions form micelles.
Fats/soaps
Summary
Lots of substitution and hydrolysis reactions all the same mechanism
All carboxylic acid derivatives can be made from the acid chloride by choosing
the appropriate nucleophile
All carboxylic acids can be hydrolyzed with the nucleophile is water (aq acid
conditions) or hydroxide (aq base conditions)
Summary
Nitriles can be installed via SN2 chemistry and although they do not
look like other carbonyl compounds, they react the same.
Nitriles can be considered dehydrated amides
2
2
You have two methods of synthesizing esters: via the acid chloride
and an alcohol and by using Fischer esterification
Lithium aluminum hydride LiAlH4 is a source of nucleophilic hydride
and can reduce all carboxylic acids and derivatives. LiAlH4 must be
used under anhydrous conditions.
Chapter 11
Reactionsatthe
CarbonofCarbonylCompounds
Whatisan carbon?
enolateandenolconsiderations
carbon reactivity
a base can remove a proton from an carbon to form an

enolate ion
KEY POINT = electron delocalization is possible with
enolates
KEY POINT = enolate ions are nucleophiles
A Hydrogen Attached to an sp3 Carbon adjacent to a

Carbonyl Carbon have pKa values from 16-25
You can approximate the pKa value of any -hydrogen

to be 20
A hydrogen attached to an sp3 carbon adjacent to TWO

carbonyl carbon have pKa values of about 10
More electron delocalization

More stable conjugate base
Electron delocalization
3
Why?
Electron delocalization
in both compounds, the non-bonding electron can be

delocalized onto an electronegative atom
Enol equilibrium - tautomers
Tautomers differ in the location of a double bond and a hydrogen
Tautomers are in equilibrium
Tautomers are not resonance structures
Acid catalysis promotes enol formation
Enolates are nucleophiles
NaNH2
this method can be used to alkylate the -carbon of

ketones, esters, and nitriles
5 reactions from Chapter 11

halogenation
-acidic conditions
-basic conditions
2. aldol condensation
3. Claisen condensation
4. malonic ester synthesis
5. acetoacetic ester synthesis
6. Michael reaction (not new)
-you have already seen this reaction in chapter 9
Halogenation
only one -hydrogen is replaced by Br
Mechanism for
Acid-Catalyzed Halogenation
The halogen of the -carbon of an aldehyde

or ketone can undergo SN2
strong bases cannot be used for this reaction otherwise

E2 would predominate
-halogenation products can also eliminate to

give conjugated double bonds
Pyridine is a non-nucleophilic base
Methyl ketones the Haloform reaction

-halogenation under basic conditions
Each successive enolate is more stable

Final step is simple hydrolysis
Aldol reaction
aldehydes and ketones undergo aldol addition reactions

one molecule of the carbonyl carbon is an electrophile
and the other is a nucleophile
Aldol addition reactions
the product has twice as many carbons as the reactant
Aldol mechanism
recall
Same mechanism enolate is nucleophile
-hydroxyaldehydes and ketones can

undergo elimination
Crossed/Mixed Aldol additions

can give a mess
the crossed/mixed aldol addition forms 4 possible products
Some crossed/mixed aldols

will form 1 major product
the carbonyl compound with -hydrogens is added slowly

to a solution of the carbonyl compound without -hydrogens
and a base
Some crossed/mixed aldols

will form 1 major product
Your lab
A Claisen Condensation
a condensation reaction of two molecules of an ester
Mechanism for the Claisen Condensation

O
H
O
H
R'O
OR'
H H
O
H
H
form enolate
formation of new enolate

drives reaction
H H
O
R'O
OR'
H
O
OR'
OR'
OR'
OR'
H
H
H H
tetrahedral intermediate
loss of alkoxide, reform
carbonyl center
H
H
H
O
O
H
OR'
generate -keto ester,

pKa about 10
1,3-dicarbonyl
hydrogen
A Crossed Claisen Condensation

to a solution of the carbonyl compound without -hydrogens
and a base
A Crossed Condensation Between

a Ketone and Diethyl Carbonate

to a solution of the carbonyl compound without -hydrogens and a
base
Intramolecular Claisen condensations
1,3-dicarbonyl
Intramolecular Claisen condensations
Same mechanism
O
OCH3
Intramolecular Aldol Additions
No!
Followed
by
Dehydration
2 different enolate ions can be formed

formation of a 5-membered ring is favored over formation of
a 3-membered ring

No!
2 different enolate ions can be formed
Followed
by
Dehydration
formation of a 5-membered ring is favored over formation of

a 7-membered ring
Followed
by
Dehydration
Followed
by
Dehydration
3-Oxocarboxylic Acids Can be

Decarboxylated
Mechanism decarboxylation
You will not be tested on the mechanism for decarboxylation.

But know that 3-oxocarboxylic acids will decarboxylate when heated
structure of a 3-oxocarboxylic acid
O
Y 3
can be a 1,3-diacid
O
2
1 OH
HO
-CO2
OH
HO
can be a 1,3-ketoacid
O
R'
OH
R
-CO2
R'
The Malonic Ester Synthesis
a malonic ester synthesis forms a carboxylic acid

with two more carbons than the alkyl halide used in the synthesis
The Steps in the

Malonic Ester Synthesis
Malonic ester forming rings

O
EtO
NaOEt/EtOH
EtO
OEt
Br
Br
OEt
Sn2
H H
diethylmalonate
pKa = 10
O
EtO
OEt
H
Br
O
O
O
NaOH (aq)
saponification
EtO
EtO
HO
diester
HO
diacid
OEt
Br
second enolate
intramolecular Sn2
OH
OH
decarboxylation
OEt
HCl (aq)
bond tautomers
OH
The Acetoacetic Ester Synthesis
an acetoacetic ester synthesis forms a methyl ketone with three

more carbons than the alkyl halide used in the synthesis
The Steps in the Acetoacetic

Ester Synthesis
Same mechanism as
Malonic Ester Synthesis
O
NaOEt/EtOH
Br
Br
OEt
OEt
Sn2
H H
acetoacetic ester
pKa = 10
OEt
H
Br
O
O
O
OEt
NaOH (aq)
OEt
saponification
diester
second enolate
intramolecular Sn2
HCl (aq)
Br
OH
OH
decarboxylation
bond tautomers
diacid
Acid/base chemistry to enolate, Sn2 (or two), saponification, decarboxylation
,-unsaturated aldehydes and ketones

undergo direct addition and conjugate addition
From Chapter 9
1,2 addition
1,4 addition
REVIEW ALERT FROM CHAPTER 9:

Weak Bases Form
Conjugate Addition Products
Michael Reactions
Look for the
1,5-dicarbonyl
substructure
when the nucleophile is an enolate ion,

the reaction is called a Michael Reaction
The Mechanism for a Michael Reaction
Robinson Annulation a Michael

reaction followed by an aldol
condenations
a Robinson annulation forms a product with a

fused 2-cyclohexenone ring
retrosynthetic analysis
O
O
OH
O
O
O

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Chapter 1 Outline

This first slide presentation will include

s-block (metals), p-block (non-metals)

An ionic bond is formed between metals

Covalent Bonds are Formed by

Nonpolar covalent bond = bonded atoms are the same

Polar covalent bond = bonded atoms differ in electronegativity

How Many Bonds Does

Bond Polarity Depends on

Polar Covalent Bonds

For example, consider oxygen in methanol shown

Methyl oxonium ion (the acidic form of methanol) is shown below.

Neutral Carbon Forms Four Bonds

if carbon does not form four bonds, it has a charge

A Hydrogen Atom Can Lose or

Neutral Nitrogen Forms Three Bonds

Nitrogen has one lone pair.

Neutral Oxygen Forms Two Bonds

Oxygen has two lone pairs.

Hydrogen and the Halogens

A halogen has three lone pairs.

In organic chemistry it is common to use lines to represent covalent bonds.

Drawing Conventions in Organic Chemistry

Learn to use line/bond drawing convention for Lewis structures

bent line implies -CH2-

Atomic & Molecular Orbitals

The Structure of an Atom

The Distribution of Electrons in an Atom

The first shell is closest to the nucleus.

-Aufbau principle: An electron goes into the atomic orbital with

Reorder such that energy becomes the y-axis

Electrons may be excited from lower to higher energy

What is an Atomic Orbital?

The Lobes of a p Orbital Have

The Three p Orbitals

Molecular Orbitals - Diatomic

Atomic Orbitals Combine

Side-to-Side Overlap of In-Phase

Molecular Geometry & Hybridization

The Bonding in Methane

In Order to Form Four Bonds,

Four Orbitals are Mixed to Form

An sp3 orbital has a large lobe and a small lobe.

The Carbon in Methane is sp3

4 sp3 orbitals = tetrahedron

The Carbon Hydrogen Bond

The Bonding in Ethane

The Bonding in Ethane

this line represents a carbon sp3 to hydrogen 1s

this line represents a carbon sp3 to carbon sp3

Graphically, the molecular orbitals of ethane can be represented as:

The Bonding in Ethane

Molecular Orbitals in Ethene

this line represents a carbon sp2 to hydrogen 1s bond

An sp2 Carbon Has Three sp2 Orbitals

The Carbons in Ethene are sp2

two sp hybrid orbitals

Molecular Orbitals in Ethyne

this line represents a carbon sp to hydrogen 1s bond

The Two sp Orbitals Point in Opposite Directions

The Carbons in Ethyne are sp

Methyl Cation and Methyl Radical are sp2

Methyl Anion is sp3