Chem E2b - Organic Chemistry II

Read syllabus before asking any questions…please.

3 midterms (100 pts each)
6-7 quizzes or take-home test questions
Final exam
Lab grade

There are NO make-up exams for the midterms!!!

There are NO make-up quizzes!!!

What is Organic Chemistry?

The chemistry of molecules

associated with living organisms

The Chemistry of C, H, N, O, S, & P-

Containing molecules

Natural Loads of FUN!!

Products
Unnatural Polymers, Consumer
Bioactive Materials Products:
Molecules, From Food to
eg Drugs to the Package that
Contains it!

1
 What Molecules Are Important? All of them…

H3C O CH3
Me
O2N NO2
H3C MeO O-Na+

O
O NO2
tri-nitrotoluene naproxen sodium
testosterone
(TNT) (alleveTM)
NH2
Cl
OH N N
O
O
O O N N
Cl O
OH OH OH
HO HO
Cl NH NH2
HO sucralose HO OH
tryptophan
(SplendaTM) adenine

short-hand drawings:
H H
CH3CH2CH3 H C H
C C H3C CH3
propane H H H H

E2a Review: Things You Should Already Know for this Class

1. Hybridization
2. Molecular Orbitals: orbital types and interactions, diagrams
3. Conformational analysis: drawing chair conformations and Newman projections
4. Functional group names and nomenclature
5. Stability of carbocation and anion intermediates
6. Resonance
7. Curved arrow mechanism, identifying electrophiles and nucleophiles
8. Acidity and Basicity
9. Kinetics and thermodynamics: reaction coordinate diagrams
10. Relative Reactivity
11. Stereochemistry
12. Reagents and Reactions of: alkenes, dienes, alkynes, alkyl halides and alcohols,
substitution and elimination reactions

2
 Review - Molecular Orbitals
Bonding in ethene:

Review - Acidity
Brønsted–Lowry Acids and Bases: acid donates a proton, base accepts a proton

• Strong reacts to give weak

• Weaker base = stronger
conjugate acid
• Stable bases (anions) are
weak bases

Lewis Acids and Bases

• Lewis acid: non-proton-donating acid;
will accept two electrons
• Lewis base: electron pair donors

3
 Review - Acidity and Anion Stability
Factors that influence anion stability (more stable conjugate anion is a better acid):
1) Size of atom - applies only to comparison within columns of periodic table
2) Electronegativity - applies to comparison in rows, as well as carbon hybridization
3) Resonance - more resonance is more stable
4) Electron-withdrawing groups stabilize (inductive effect), electron-donating groups
destabilize
5) Aromaticity - an anion is more stable if it is aromatic

CH3CH2OH most
pKa = 15.5 acidic

Strongest Weakest
conjugate base conjugate base

Review: Carbocation Stability

• Carbocations are important intermediates in electrophilic additions to alkenes, and in
SN1and E1 reaction mechanisms.

1) hyperconjugation: more substituted carbocation is more stable

2) Resonance/conjugation: carbocation with more resonance is more stable
3) Electron-donating groups stabilize, electron-withdrawing groups destabilize
4) Aromaticity: an aromatic carbocation is very stable

H H H H
+ + + +
CH3 > CH3 > CH3 > CH3
H3C H3C O
N O H3C H3C
CH3 O
more electron-donating less electron-donating
substituent substituent

4
 Review - Resonance
Localized vs. delocalized electrons:

Examples of resonance contributors:

Phenol is more acidic than cyclohexanol because the phenoxide ion is stabilized by resonance:

(conjugate base of phenol)

Review - Conformational Analysis

0°

CH3 HCH3 CH3 H CH3 CH3

H3C CH3 H CH3 H H H3C H
Conformations of n-Butane: H H H
CH3 H H
(Newman projections) H
H
H H
H
H H
H CH3
H H3C
H
H
H
H

A staggered conformer eclipsed gauche anti gauche

is more stable than an A B C D E F

eclipsed conformer

Chair conformations:

Steric strain of 1,3-diaxial interactions

makes axial conformer less stable

5
 Review: Thermodynamics and Kinetics
Reaction coordinate diagrams:

∆G° = ∆H° – T∆S°

∆G° = Gibbs standard free energy change
Enthalpy (∆H°) = the heat given off or
absorbed during a reaction
Entropy (∆S°) = a measure of freedom of
motion (usually ∆S° is small compared to
∆H° and ∆G° ~ ∆H°)

∆G‡ = (∆G of transition state) – (∆G of reactants)

∆G‡ = energy of activation

Two “Rules of 1.4”:

1) Increasing ∆G‡ by 1.4 kcal/mol
decreases the rate by a factor of 10
2) changing ∆G˚ by 1.4 kcal/mol
changes the product ratio by a factor
of 10

The rate-limiting step controls the overall rate of the reaction

The highest hill on the reaction coordination diagram is the rate-limiting step

Review: Stereochemistry

Cl Cl
CH3 Enantiomers CH3

Cl Cl

Diastereomers Diastereomers

Cl Cl
CH3 Enantiomers CH3

Cl Cl
lowest priority
group oriented behind
1
Cl Cl
Enantiomers Br
CH3 CH3 2 H
H3C H3C H3CH2C
Cl Cl CH3
3
'
Diastereomers Diastereomers
1-2-3
Cl Cl counterclockwise = S
CH3 MESO CH3
H3C H3C
Cl Cl

6
 Functional Group Review
H
CH3
R R R R
R O
alkane alkene alkyne diene benzene epoxide

R F R Cl R Br R I R SH R CN
alkyl fluoride alkyl chloride alkyl bromide alkyl iodide thiol nitrile
(cyano group)

Me
R R R
R N O
H R OH R O R S
R O O R
amine alcohol ether
sulfonate ester aromatic compounds
(OTs, tosylate) (substituted benzenes)

carbonyl compounds
O O O O O O O
O
R R
R N R O R OH R H R R R Cl R
R O
H
amide ester carboxylic aldehyde ketone acid anhydride
acid chloride

Review: Polar Organic Reactions (anions and cations)

• Reactions involving cations: electrophilic addition to an alkene, SN1 and E1, etc

• Reactions involving anions: anything with a nucleophile (SN2, E2, etc)

• Curved arrow mechanism: from an electron-rich center to an electron-poor center

(Robinhood rule)

Movement of a Movement of one electron

pair of electrons “fish-hook arrow”

7
 Reactions of Benzene

Z
+
Y Y
R Y Z R Z- R

(a)
H H addition Z
H
H Y (path a) Y
Y Z + H Z- H

(b) benzene +Y-Z

(nonaromatic)
substitution
(path b)

H
Y
+ H-

benzene (- H+) + (Y+)

(aromatic)

Electrophilic Substitution is Thermodynamically Favored

First step is rate determining

8
 Sidenote: Synthesis of Aspirin from Crude Oil

OH OH O O O Me O O

[O] CO2/base OH Me O Me OH

acetyl salicylic acid

(Aspirin)
oil well Willow Trees:

Relieves Fever,
Upsets Stomach

Summary of Electrophilic Additions

X
Halogenation FeX3/X2

NO2
HNO3/H2SO4
Nitration

SO3
H2SO4/∆
Sulfation

Friedel-Crafts RCOCl/AlCl3 R
Acylation

R
Friedel-Crafts RCl/AlCl3
Alkylation

9
 Halogenation of Benzene

• In general, benzene is less reactive than most alkenes.

• Alkenes generally react with neutral electrophiles, e.g. Br2, Hg(OAc)2, etc.
• Benzene generally reacts with cationic electrophiles, which are more reactive due to the
positive charge

Br
Br
R Br Br R

H
Br
Br Br X

FeBr3

H
Br H Br
+ - -
Br Br Fe Br + Br Br Fe Br
Br Br

Nitration of Benzene

O O O
+ O
H N+ H2SO4 HSO4- H N+ +N H H
O O- O+ O-
O
HNO3 H

H O O
O
N+ N+
N + + O -
O- H2SO4
H HSO4- +
O

10
 Friedel-Crafts Acylation

O +
Cl O Cl O O
Cl
R Cl Al Al + + AlCl4-
Cl Cl R Cl+ - Cl R
R
an acyl chloride
an acylium ion

+ H O O
O
R R
H
R
AlCl4-

AlCl3

Friedel-Crafts Alkylation

R Cl H
R ClCl
+
R Cl Al Al
-+
+ AlCl4-
Cl Cl R Cl Cl R R
an alkyl chloride
a carbocation

H R R
H
+ R R
R R H

AlCl4-

H+ AlCl4-

11
 Carbocation Rearrangements Occur During Friedel-Crafts
Alkylations

R H
Cl +
+ AlCl4-
R Cl Al R R
Cl Cl

1,2 alkyl shift

1,2 hydride shift
ring expansion

Me Me
Me AlCl3 Me
Cl Me
Me
Me
Me Me

O% 100%
H
Me +
H Me
Me + Me
Me Me

Friedel-Crafts Acylation/Reduction: Net Alkylation

H H
H H AlCl3
+ R
R Cl X
H2; Pd/C

O
O
+ AlCl3 R
R Cl

• Because of the problems associated with rearrangements, etc, primary alkyl groups are best
introduced by a Friedel-Crafts Acylation, followed by reduction to replace the carbonyl group
with two H’s
• The use of H2/Pd only works with carbonyl groups with benzene rings on one or both sides.

12
 Disubstituted Benzenes

Br Br Br
Br

Br
1,2-dibromobenzene 1,3-dibromobenzene
ortho-dibromobenzene meta-dibromobenzene
o-dibromobenzene m-dibromobenzene
Br
1,4-dibromobenzene
para-dibromobenzene
p-dibromobenzene

NO2
ortho Z ortho NO2 Br

Br Cl
meta meta
1-bromo-3-nitrobenzene 2-bromo-4-chloro-
meta-nitrobenzene 1-nitrobenzene
para

Reactions of Benzene Substituents

Br NaOH OH
SN2 (& SN1)

Br

E2 (& SN1) Me KOt-Bu

H2; Pd/C Me
Alkene Reduction:

Carbonyl Reduction: H H2; Pd/C OH

O
N+ NH2
Nitro Reduction: O- H2; Pd/C

13
 Effect of Substituents on Reactivity
R R
R
H -H+ E
E+ + E

R
H
+ E

R
E

• Electrophilic Substitution reactions proceed via carbocation intermediates.

• Carbocation formation is the rate limiting step, so the stability of the carbocation that is
formed determines the speed of the reaction

Substituent Effects on Reactivity

R = Electron Withdrawing (Slower)

R=H
R = Electron Donating (FASTER)

R
H
+ E
R

• Electron donating groups help stabilize positive charge, so they make benzene rings more
reactive
• Electron withdrawing substituents destabilize positive charge, so they make benzene rings
less reactive

14
 Inductive Effects on Benzene Reactivity

electron donating electron withdrawing

group group

Z H Y

> >
MORE REACTIVE LESS REACTIVE
(Electrophilic Substitution) (Electrophilic Substitution)

• As with acidity, inductive effects are generally WEAKER than resonance effects
• Z = NR2, OR: Strongly Activating (resonance)
• Z = NHCO2R, OCO2R: Moderately Activating (inductive)
• Z = R (Alkyl, vinyl): Weakly Activating (inductive)
• Y = F, Cl, Br, I: Weakly Deactivating (inductive withdrawal/resonance donation)
• Y = CO2R: Moderately Deactivating (resonance)
• Y = CN, SO2R, NO2: Strongly Deactivating (resonance)
• Y = NH3+: Strongly Deactivating (inductive, positively charged)

Effects of Substituents on Orientation

1) All activators are o,p-directors Me
Me Me Me
Br
FeBr3/Br2

Br
Br
o-bromotoluene p-bromotoluene m-bromotoluene
NOT OBSERVED
2) Weak deactivators (halogens) are o,p-directors.
Br Br Br Br
Br
FeBr3/Br2

Br
Br
o-dibromobenzene p-dibromobenzene m-dibromobenzene
NOT OBSERVED
3) All moderate and strong de-activators are m-directors
O Me
O Me O Me O Me

NO2
HNO3/H2SO4

NO2
NO2
m-nitroacetophenone o-nitroacetophenone p-nitroacetophenone
NOT OBSERVED NOT OBSERVED

15
 Substituent Effects: Ortho/Para Directors
MeO MeO MeO
MeO
H
+ E
+ E+ -OR- + H -OR- +
E H
H H E
stable resonance form ortho meta para
+ MeO
MeO MeO MeO MeO
H H H H -H+ E
ortho: + E E E E
+ +

MeO MeO MeO

MeO
-H+ NOT
meta: + + OBSERVED
+ H H H
E E E
E
H H H

MeO MeO MeO + MeO MeO

+ -H+
para: + +
H H H H
H E H E H E H E E

stable resonance form

Substituent Effects: Meta Directors

NO2 NO2 NO2
NO2
H
+ E
+ E+ -OR- + H -OR- +
E H
H E
unstable resonance form ortho meta para

NO2 NO2 NO2 NO2

H H H -H+ E
ortho: + E E E
+ +
NOT OBSERVED

NO2 NO2 NO2

NO2

+ + -H+
meta: H H H
+
E E E
E
H H H

NO2 NO2 NO2 NO2

+
+ -H
para: + +
H H H
H E H E H E E NOT OBSERVED

unstable resonance form

16
 Hill Diagram Summary: Activation and Direction

O O R
H +N H
+ N+ S R R
R O-
O
H O
N
R = Deactivating/m-directing R

o,p - m frontier

R = weakly deactivating/o,p-directing F, Cl, Br, I

R=H activation frontier
R = Activating/o,p-directing
H
N R O R
R R

H O O
R + E R
+
H N OR
E H R

Halogens are Ortho/Para Directors

Cl
Cl Cl Cl Cl
E+ H -H+ E
+ E -OR- -OR-
+
H
H E
E
+ + Cl NO2
MeO
H H H
+ E
E E

MeO + Cl + NO2

+
H H H
H E H E H E
Cl behaves like MeO for directing substitution (resonance)
Cl behaves slightly like NO2 for activation (induction)
As with acidity, resonance is more important than induction!

17
Sample Problem: Planning A Synthesis with Aromatic
Substitution
SO3H

Br

Sample Problem: Planning A Synthesis with Aromatic Substitution

O Me

NO2

18
Arenediazonium Salts: Selective Monosubstitution

NO2 CN

CuCN

X
H2; Pd/C
CuX
NH2 N2+ (X = Cl or Br)

NaNO2/HCl I
Cl-
("HONO") KI
(X = Cl or Br)

OH

HCl/H2O

Synthesis with Arenediazonium Salts

Me Me Me

FeCl3/Cl2 Cl

Cl
o-chloroethylbenzene p-chloroethylbenzene

Me Me Me

NaNO2/HCl CuCl
Cl-
("HONO")
NH2 N2+ Cl
p-chloroethylbenzene

19
 Nucleophilic Aromatic Substitution (SNAr)
R R R
E+ E
+ H+

E
X Nu
Nu-
+ X-

Cl OH
NaOH/∆
pH 14
"Nu-"

NO2 NO2

Cl OH
H2O
O2N NO2 O2N NO2
pH 7

NO2 NO2

Mechanism of Nucleophilic Aromatic Substitution

HO- X OH
NaOH/∆
pH 14

NO2 NO2

addition elimination
HO X HO X
-

NO2 NO2

other
resonance
forms

• X needs to be Small (F and Cl are best), and the benzene ring needs to be highly activated (at
least one NO2).

20
 Benzyne
Cl NH2
NaNH2
SNAr?

Cl NH2
H2N - H * NaNH2 H *

AND
H
elimination
H2N *
-
H2N NH3 NH2
* - *
NH3

-NH2 -
H2N *
Benzyne
Intermediate

Structure of Benzyne

R R
Alkyne
Benzyne

21
 Heteroaromatics

5-membered heterocycles
N O S
H
pyrrole furan thiophene

6-membered heterocycles N
N N
pyridine quinoline isoquinoline

6,5-fused heterocycles
N O S
H
indole benzofuran benzothiophene

All of these heterocycles are aromatic (recall rules of aromaticity & Hückels Rule)

They all participate in Electrophilic Aromatic Substitution (EAS) Reactions

EAS: 5-Membered Heterocycles

3
O O
4 O
EAS: H3C O CH3
5 2 CH3 +
N1 N H3C OH
H H O
2-acetylpyrrole
4
EAS occurs
3
Br2 preferentially
5 2 at the C2-position
O1 O Br
2-bromofuran
4 3
HNO3
5 2
H2SO4 NO2
S S
1
2-nitrothiophene

Consider Mechanism:
EAS at C2 E E E
N H N H N H
H H H
20-allylic carbocation 20-allylic carbocation
+ E+
N E E
H H H
EAS at C3 N N
H H
20-alkyl carbocation

22
 Relative Reactivities of 5-Membered Heterocycles in EAS

> > >

N O S
H

Pyrrole, furan, and thiophene are all more reactive than benzene as heteroatom lp
can better stabilize the carbocation intermediate

Relative reactivities are reflected in L.A. needed to mediate Friedel-Crafts acylations

O
O
AlCl3
AlCl3: Strong L.A. + CH3
H3C Cl H2O

O
SnCl4
SnCl4: Weaker L.A. +
H3C Cl H2O CH3
S S
O O
BF3
BF3: Weak L.A. +
H3C Cl H2O CH3
O O
O
O O
no cat.
NO L.A. +
H3C O CH3 required CH3
N N
H H
less reactive O
acylating agent

Reactions of Six-Membered Heterocycles

SN2: + H3C I N-methylpyridinium iodide

N N I
CH3

+ HO OH + H2O
N-Oxidation:
N N OH N
OH O
Pyridine-N-Oxide

Br
FeBr3 Preferential substitution @C3, why ??
EAS: + Br2
300 °C
N N High Temps required due to the fact that
30% electron withdrawing N-atom destablizes
carbocation intermediates.
B
Mechanism: Y Y
+ slow fast
Y+ H + HB+
N N N

23
 Electrophilic and Nucleophilic Substitutions on Pyridine

What about Nucleophilic Aromatic Substitutions ?

4
5 3
NaNH2
2
6
∆
N OCH3 N NH2
1
SNAr takes place ONLY at C2 and C4 positions
Br OMe
Why ???
NaOMe
∆
N N

Regiochemistry of SNAr
Regiochemistry of Nu Addition:

2-Different LG’s: If LG’s are different, Nu will preferentially substitute at LG which is weaker base
(better LG) better LG
Br- is weaker
Br NH2
base than CH3O-
NaNH2
∆
N OCH3 N OCH3

CH3 CH3

NaOMe
∆
N Cl N OMe

24
 Other Reactions of Pyridine

NBS
Benzylic Bromination
R ∆, ROOR R
N N
Br

Reactions of Pyridine Diazonium Salts

NaNO2 / HCl H2O

Cl
N NH2 0 °C N N N OH N O
N H
enolic form keto form (more stable)
α-pyridone

NH2 N OH O
N Cl-
NaNO2 / HCl H2O
N 0 °C N N
N H
enolic form keto form (more stable)
γ-pyridone

Summary Slide

• Aromatic compounds undergo electrophilic aromatic

substitution (EAS), (mechanistically related to alkene
additions) in which aromaticity is restored in the product
• Electron donating substituents activate benzene toward EAS,
and direct the electrophiles to the ortho and para positions
• Electron withdrawing substituents deactivate benzene toward
EAS, and direct electrophiles to the meta positions
• Halogens are deactivating (inductive effect) and ortho/para
directing (resonance)
• Nucleophiles can add to arenediazonium salts, strongly
activated aryl halides (SNAr), or benzyne intermediates
• 5-Membered heteroaromatics participate in EAS at C2-
position.
• 6-Membered heteroaromatics participate in EAS (C3-position)
and SNAr reactions (C2 and C4 positions)

25
 heterolytic cleavage Neutral Organic Reactions - Radicals
H H H H
H C C H + C
H C H formation of polar,
H H H H charged species
methyl anion methyl cation
homolytic cleavage
H H H H
H H +
C C C
H C H formation of non-polar,
H H H H neutral species
methyl radical methyl radical

both are Structure of radical is somewhere between a cation and anion,

electron-deficient half-filled p-orbital is a SOMO (Singly Occupied Molecular Orbital)

Thermodynamics
• Bond breaking is endothermic (∆H˚ is positive)
• Bond formation is exothermic (∆H˚ is negative)

H H H H
H H C +
C C C
H H ∆H˚ = 90 kcal/mol
H H H H

Energy of activation (∆G‡) = ∆H˚ when bonds are broken homolytically, but no bonds
are formed, IF no solvation is involved (in the gas phase)

formation of bond: cleavage of bond:

H H H
σ∗ sp3 C C sp3
H HH

H H H
C C energy 90 kcal/mol required
H H to break bond
sp3 sp3 H H H
H C C
σ H
H H ∆H˚ is positive
stabilization energy
= 90 kcal/mol reaction progress
∆H˚ is negative

26
 Bond Dissociation Energy (BDE)
X + Y

∆H˚ = ∆G≠ = BDE

energy

Bond Dissociation Energy

X Y (BDE) = energy required to
break a bond homolytically
reaction progress

Bond Dissociation Bond Dissociation

Bond Energy (kcal/mol) Bond Energy (kcal/mol)
Cl Cl 58 H H 104
Br Br 46 H3C H 105
I I 36 H3C CH3 88
RO OR 38 H2C CH2 67 (π bond only)
Cl H 103 H3C OH 92
Br H 87 H3C NH2 85
I H 71 H2N H 107
I CH3 84 CH3O H 104
Br CH3 70 HO H 119
Cl CH3 57 See Bruice Table 3.1, page 129

Two Factors Can Decrease the BDE (make the bond easier to
break)
1) Make bond less stable (raise the energy of the reagent)

H2 ∆H˚ =
C CH2
65 kcal/mol
H2C CH2 H2C CH2
CH2 ∆H˚ =
energy
H2 ∆H˚ = H2 C CH2 65 kcal/mol
C H3C
85 kcal/mol CH2 + CH3
H3C CH3
CH3CH2CH3 ∆H˚ =
85 kcal/mol
cyclopropane has strain energy that raises the energy reaction progress
of the C–C bond, therefore making it easier to break

2) Make radical more stable (lower the energy of the transition state)

BDE (kcal/mol) 85 85 96 99 101 104

-from cleavage 105
of a C–H bond,
with R = CH3

27
 Stability of Radicals: Just Like Carbocation Trends
1) Hyperconjugation: more substituted radicals are more stable

2) Conjugation/Resonance: more resonance, more stable radical

H
most C CH2 no
> > CH2 > CH2 resonance
resonance H3C

3) Hybridization: more s character of the SOMO, less stable radical

sp3-hybridized, H sp-hybridized,
CH2 > H > > R C C
least s character H3C most s character
H

Hyperconjugation in Carbocations and Radicals

Carbocation antibonding MO
stabilization:
A σ C–H bond donates
into the empty p-orbital to
stabilize the carbocation

σ C–H = donor (HOMO) bonding MO

empty p-orbital = acceptor (LUMO)
Cationic, 2-electron system

half-filled
Radical H p orbital
antibonding MO
stabilization:
A σ C–H bond donates H H
into the SOMO (singly C C
occupied molecular H H
orbital) to stabilize the
radical
σ C–H = donor (HOMO) bonding MO
SOMO = acceptor
Radical, neutral, 3-electron system
Hyperconjugation is less stabilizing for a radical because the one electron in the antibonding
MO has a destabilizing effect. (recall He2+ with a similar 3-electron system)

28
 Radical Reactions with Alkenes

reaction proceeds through a

carbocation intermediate,
rearrangements are possible

reaction proceeds through a

radical intermediate,
NO rearrangements are
hv or ∆ possible

Formation of bromine radical:

∆H˚ = 38 kcal/mol
Initiation steps
to create radicals

This is NOT a general reaction. The peroxide effect does NOT work with any other HX.

Mechanism: More Stable Radical Forms Faster

carbocation mechanism:

CH3
+ H Br H3C + Br- CH3
H3C H3C
δ+ δ-
Br
H+ adds to primary carbon to form a secondary carbocation, secondary
which is more stable than a primary carbocation alkyl bromide

radical mechanism:
H-abstraction and
formation of new radical
+ .Br H3C Br H3C Br + .Br
H3C H Br
primary
alkyl bromide
Br adds to primary carbon to form a secondary radical,
which is more stable than a primary radical

29
 Synthesis Using Primary Alkyl Bromides

A primary alkyl bromide is a good substrate for an SN2 reaction:

O
O
HBr, ROOR NaO CH3
H3C H3C Br H3C O CH3
hv
nucleophilic
substitution

Recall the previous general method that we used to convert an alkene to a primary SN2
substrate with a good leaving group:

1. BH3
2. NaOH, H2O2 1. TsCl/pyridine
H3C H3C OH H3C Nu
2. Nucleophile
hydroboration formation of good leaving group
and oxidation followed by nucleophilic substitution

Examples of nucleophiles = NaCN, NaOH, NaOMe, NaSMe, NaOAc, NaCl, NaBr

Radical Mechanism Sample Problem

HBr Br
Provide the mechanism for this reaction.
ROOR, hv

∆H˚ = 38 kcal/mol

Problem-solving strategy:
1. Draw a step that breaks the weak bond in the initiator
2. Draw a reaction of the initiator with one of the starting material (SM)
3. Draw a reaction of SM radical with another SM (repeat if needed)
4. Draw a termination step

30
 Radical Reactions with Alkanes

Major product because

Not practical or useful with F2 or I2 secondary radical is
more stable

Remember, rearrangements are not possible with radicals!!

Mechanism of Radical Reactions with Alkanes

H-abstraction

goes back to starting material

very minor by-product

desired product!!

The rate-determining step of the overall reaction is hydrogen abstraction

(Same mechanism for monobromination - practice at home…)

31
 Again, More Stable Radical Forms Faster

H-abstraction at benzylic
and allylic positions is easier
because benzyl and allyl
radicals are stabilized by
resonance

NBS as a Milder Brominating Reagent for Allylic Bromination

Advantage: the low

concentration of Br2 and
HBr present cannot be
added to the double bond

NBS provides a good source of HBr and Br2 in low concentration

O
Br
hv or ∆
+ N Br +
H3C H3C H3C Br
RO- OR
O (peroxide)

Unsymmetrical alkenes will form two different products because the allyl radical intermediate
has two resonance contributors that are not equivalent

H
+ .Br CH2
H3C H3C H3C + HBr

32
 Phenolic Compounds as Anti-Oxidants
• Radical reactions occur in the body, usually initiated by metal ions in enzymes.
Unwanted radicals cause damage to cells, leading to disease.
• Phenolic compounds, such as BHT, BHA and Vitamins A & E are “anti-oxidants” that act
as radical scavengers (inhibitors). They are typically used as food preservatives.
OH CH 3 CH 3 OH CH 3 CH3
CH 3 H 3C CH 3 HO
CH 3 H 3C CH 3 CH3
H3C O
CH3 CH3 CH3 CH3
OCH 3 CH 3 CH3
BHA BHT vitamin E
(butalyted hydroxyanisole) (butalyted hydroxytoluene) (α-tocopherol)

Radical scavenger mechanism:

H
O CH3 O CH3
R
CH3 CH3 Phenolic compounds
+ CH3 CH3 + donate an H to the
R H
unstable free radical to form
free radical
Reactive!! OCH3 OCH3 two stable unreactive
radical very stable radical (resonance) species
scavenger Unreactive!!!

Natural “anti-oxidants” that serve as radical scavengers in vitro can be found in chocolate,
green tea, wine, grape juice, fruits and vegetables, etc. Recent studies have shown that
dark chocolate has 2x as many phenolic compounds as milk chocolate, 2x as many as green
tea or wine, and 20x as many as in tomatoes.

Stereochemistry of Radical reactions

Br
Br2, hv
CH3 CH3 Racemic mixture of products
H3C H3C (a pair of enantiomers)

• Both enantiomers are formed because the radical

intermediate is planar, like a carbocation

• If there is already an asymmetric center present in the

molecule, then diastereomers will be formed.

Cl Br2, hv Cl Cl
CH3 CH3 + CH3 a pair of
H3C H3C H3C diastereomers
Br Br

33
 Summary of Radical Reactions
• Know practical information of which radical reactions work (see below)
• Know thermodynamics and effects of bond and radical stability on BDEs
• Know radical stability to identify which product will form and be able to explain why a
radical is stable - be able to draw resonance structures!!
• Know stereochemistry of radical reactions
Br
Br2, ∆ Br2 Br
CH3 CH3
hv or ∆

Br
HBr NBS, ∆
H3C CH3 Br
H3C
ROOR
secondary allyl bromide
alkyl bromide HBr
ROOR

Br primary alkyl bromide

H3C

1. Addition of H-Br to alkenes with peroxides

2. Halogenation (Cl2 or Br2) of alkanes
3. Substitution of benzylic hydrogens with Cl2 or Br2
4. Substitution of allylic hydrogens with NBS

Radicals: Sample Problems

1) Based on the BDEs given, explain why an acyl peroxide forms radicals more easily than an
alkyl peroxide? (include structures in your answer)
RO OR
alkyl peroxide ∆H˚ = 38 kcal/mol

CH3 CH3

O ∆H˚ = 29 kcal/mol
O O O
acyl peroxide

2) How many products are possible for the reaction of 3-methyl-1-cyclohexene with NBS?
Draw the structures of these products. (your answer does not need to include enantiomers)
CH3 O
hv or ∆
+ N Br
RO- OR
O (peroxide)

3) In order to demonstrate why BHA is such a good radical scavenger, draw the 5 major
resonance structures for the radical formed upon the reaction of BHA with a free radical.
OH CH3
CH3
CH3

BHA
OCH3

34
 Summary of Reactive Intermediates

Name Structure Stability Properties

R Electrophilic, electron-deficient,
strong acid, empty p-orbital
carbocation C 3˚ > 2˚ > 1˚ > Me
R (LUMO) is a good acceptor
R

R electron-deficient, singly occupied

MO (SOMO) is reactive, can be
radical C 3˚ > 2˚ > 1˚ > Me
R R either electrophilic or nucleophilic

R Nucleophilic, electron-rich,
carbanion Me > 1˚ > 2˚ > 3˚ strong base, lone pair (HOMO)
C
R R is a good donor

R Neutral divalent carbon, empty p-

orbital is a good acceptor and
carbene C all very reactive
lone pair is a good donor, so it is
R both electophilic AND nucleophilic

Carbene Formation
A carbene is a neutral species containing a divalent carbon
empty 2pz orbital
KO CH3 (carbocation)
Br
H3C CH3 Br
Br Br C 103˚
C Br C
Br H (or KOH)
Br
dibromocarbene
filled sp2 hybrid orbital
treatment with (lone pair/carbanion)
a strong base

Mechanism of formation:

Deprotonation
with strong base Br
α-elimination Br
Br Br Br
C C C
Br H Br Br

dibromocarbene
OH

35
 Formation of Carbenes from a Diazo-Compound
CH2N2 = diazomethane (a yellow gas) empty 2pz orbital
(carbocation)
H hv or ∆ H H
C N N C + N2 103˚
C
H H H
carbene and N2 gas filled sp2 hybrid orbital
(lone pair/carbanion)
resonance structures of diazomethane:

H H H
C N N C N N C N N
H H H
carbon has carbon has
cation character anion character

Examples of other diazo-compounds: (brightly colored, but dangerous!!)

H3C O
N2 N2 N2
H3C H3 C
O

4,4-dimethyldiazocyclohexa- diazocyclopentadiene methyl diazoacetate

2,5-diene (a purple liquid) (an iridescent orange liquid) (a yellow liquid)

Carbenes react with Alkenes to form Cyclopropanes

CH2N2 H
CH2
hv or ∆
H

H3C N2 H Stereochemistry of the

H H3C
alkene is retained in the
H CH3 hv or ∆ cyclopropane product
H CH3

H
CHBr3, KOH Br
C
Br
H

One-step stereospecific syn addition mechanism

36
 Carbenes: Molecular Orbital Interactions with Alkenes
Consider what orbitals are available to interact for bonding:

H H alkene π∗ = LUMO empty 2pz orbital = LUMO

(acceptor)
(acceptor)
H H H
C
H H alkene π = HOMO H filled sp2 hybrid
(donor) orbital = HOMO (donor)
H H

Two stabilizing (bond forming) interactions are possible:

Stabilizing Interaction #1: Stabilizing Interaction #2:
empty p orbital of
H carbene (acceptor) H lone pair of
carbene (donor)
C H C
H
empty p *
alkene π
H H orbital H H
alkene π sp2
H H H H
carbene
alkene π (donor) alkene π* (acceptor)

There are two destabilizing interactions that DO NOT occur:

1) interaction between alkene π and filled sp2 of carbene (because both are donors)
2) interaction between alkene π* and empty p orbital of carbene (because both are acceptors)

Carbenes: Sample Problems

1) Draw at least 5 of the major resonance structures for
4,4-dimethyldiazocyclohexa-2,5-diene (a purple liquid):
H3C CH3

N2

2) Fill in the products or reagents for these reactions:

H
H3C H3C Cl

Cl
H3C H3C H

O
N2
H3CO

hv

37
 Determining the Structures of Organic Molecules

How do you identify the products you synthesize?

1) BH3
OH H2O, H2SO4 2) NaOH, H2O2
OH
H3C H3C
H3C CH3

How can you tell which reagents give which products?

How can you tell if only one major product is formed?

CH3 CH3 CH3 Does the nitro group add once

HNO3 NO2 or twice?
-OR-
H2SO4 Is addition selective for the
NO2 NO2 ortho and para positions?

Chromatography - Good for separations,

but not for identification….

2.05 What is the structure

Chromatogram: min of this compound?

All we can tell here is

4.37
that the compound is
min
more polar

3.22
min

Time

Gas chromatography (GC) and Liquid chromatography (LC) only give information
about polarity (based on retention time), not the structure

(Recall, last semester in lab, you performed silica gel column chromatography to purify a
solid compound and you ran gas chromatography to check your SN2 reaction)

38
 4 Techniques to Identify Structures
of Organic Compounds (Analytical Chemistry)

1. UV/vis spectroscopy - information about conjugated π-systems

2. Mass spectroscopy - identify molecular mass of the compound and some

structural features (functional groups)

3. IR spectroscopy - tells you important functional groups present

4. NMR spectroscopy - tells you functional groups, connectivity of atoms

(framework), some stereochemistry, etc.

http://www.spectroscopynow.com

Spectroscopy and the Electromagnetic Spectrum

• Spectroscopy is the study of the interaction between matter and electromagnetic radiation

high frequency = short wavelength = high energy

• A visible spectrum is obtained if visible light is absorbed

• An ultraviolet (UV) spectrum is obtained if UV light is absorbed
• An infrared (IR) spectrum is obtained if infrared light is absorbed
• An nuclear magnetic resonance (NMR) spectrum is obtained if radiowaves
are absorbed

39
 UV/vis Spectroscopy: Background Info

LUMO (lowest unoccupied

molecular orbital)

HOMO (highest occupied

molecular orbital)

LUMO

Electronic Transitions hv

HOMO

• When a molecule absorbs light, an electron is promoted to a higher energy MO (from the
HOMO to the LUMO), and the molecule is in an “excited state”
• Although several electronic transitions exist between the MOs, only two transitions are low
enough in energy to occur with UV and Visible light.

electronic transition
with the lowest energy

Only organic compounds with π-electrons can produce UV/Vis spectra!!

40
 Effects of Conjugation

LUMO π∗
LUMO
LUMO

HOMO
HOMO

HOMO π

CH2 CH2
H2C CH2 H2C H2C
π orbitals π orbitals of π orbitals of
of ethene 1,3-butadiene 1,3,5-hexatriene
See table 8.3
λmax (nm) 165 217 256 Bruice p. 325

Conjugation raises the energy of the HOMO and lowers the energy of the LUMO
As conjugation increases, the HOMO-LUMO gap decreases

More conjugation = less energy required for electronic transition = longer wavelength

UV/Vis with Conjugated Carbonyl Compounds

Two peaks are observed in the

spectrum because two electronic
transitions can occur.

The HOMO-LUMO
gap decreases with
conjugation

41
 Functional group effects
Two structural features will show an increase in the wavelength of the chromophore:
1) Increased conjugation
2) A substituent with a lone pair attached to the chromophore (an auxochrome)

An auxochrome is a substituent in a chromphore that alters the λmax and

the intensity of the absorption

CH3
N
H3C
N
N

amine-substituted azobenzene - a yellow dye (approx. 400nm)

Sidenote #1: Polyenes and Vision or

“do carrots help you see better?”
• Vitamin A is a source of 11-cis-retinal
• Opsin, a vision protein, binds 11-cis-retinal to form the Rhodopsin complex (rods)
• When Rhodopson absorbs light, 11-cis-retinal isomerizes to 11-trans-retinal, causing it to be
released from opsin. Upon release, a nerve impulse is generated and perceived by our brain
as light in black or white vision
• Same mechanism exists with iodopsin, another vision protein, to give us color vision (cones)
• 1 carrot = 2000 mg of retinal equiv. (sweet potato and mango have 1200 and 800 mg each)

cis-alkene
H2N opsin
lysine side-chain

Rhodopsin H
H N
H O (500 nm)
11-cis-retinal opsin
hv

H
11-trans-retinal release
+ N opsin
opsin H

nerve impulse trans-alkene

= vision

42
 UV/Vis Spectroscopy: Sample Problems

1) Match the following UV absorption maxima with the corresponding compounds:

353 nm, 313 nm, 256 nm, 227nm, 180nm

CH3 CH3
CH3
H3C H3C

H3C
CH3

2) How can you use UV/Vis spectroscopy to identify if this reaction has consumed the
starting reagents and produced the desired cyclohexene structure shown?

O
O
∆ CH3
+ CH3

Mass Spectrometry
70 eV fragmentation
R X R X R + X
electron beam
dislodges electron molecular ion cation fragment radical fragment
radical cation observed in MS NOT observed in MS
observed in MS

A molecular ion (radical

cation) is recorded in a
mass spectrum.

High-Resolution Mass Spectrometry will

give you the exact molecular formula - useful
data for identifying an unknown structure.

43
 Fragmentation
70 eV
CH3CH2CH2CH2CH3
(electron beam
pentane
MW = 72

Only cations are recorded in

the mass spectrum

m/z = mass to charge ratio of the fragment

The base peak at m/z = 43 is the most abundant cation, which is not usually the
same as the molecular ion

Fragmentations Give the Most Stable Cations

Fragmentation of the molecular ion occurs one of two different ways to give the
most stable cations:
a) A C–X bond is cleaved heterolytically, where all electrons go to the more
electronegative atom (usually X)
b) A C–X bond is cleaved homolytically, at the α-position to give a stabilized cation
across the C–X bond

Examples of homolytic cleavage to give stable cations:

70 eV
H2C CH CH2 R H2C CH CH2 R H2C + R

m/z = 41

70 eV
R Z CH2 CH3 R Z CH2 CH3 R Z CH2 + CH3

Z = N, O, S
R can also be H

R 70 eV R
C O C O R C O + R
R R
acylium ion

44
 Fragmentations at Functional Groups

• The weakest bond is the C–Cl bond

heterolytic cleavage
• Both heterolytic and homolytic cleavage
of the C–Cl bond occur.

Cl isotope has 1/3

α-cleavage homolytic cleavage
the abundance

positive charge shared by C and Cl atoms

Fragmentations of
an Ether Group

45
 Fragmentations of an
Alcohol Group

γ-abstraction Formation of new radical cation by

formation of small neutral molecule
(such as H2O, ROH, NH3, H2, ethene, etc)

Fragmentations Occur to Give Stable Cations

acylium ions stabilized by resonance

γ-abstraction Formation of new radical cation

and a small neutral molecule

46
 Summary
• Fragmentations occur to give cations recorded in the mass spectrum; only
positively charged fragments are recorded.
• The base peak is the peak with the greatest intensity, due to its having the
greatest abundance
• Weak bonds break in preference to strong bonds
• Bonds that break to form more stable fragments break in preference to
those that form less stable fragments

1) Alkanes, alkenes and aromatics: cleave to give the most stable

carbocations
2) Alcohol: loss of water or α-cleavage to give stabilized cation
3) Ethers: loss of an alkyl group or α-cleavage to give stabilized cation
4) Ketones and aldehydes: loss of alkyl group to give stabilized acylium ion or
McLafferty rearrangement (γ-abstraction)

Be able to propose or identify favorable fragmentations for 2 or 3 of the largest peaks

in the spectrum. You DO NOT need to account for all of the peaks in a spectrum.

Mass Spectroscopy Sample Problems

CH3
1) Predict the cation structure and base peaks for toluene

2) Account for the peaks at m/z 87, 111 and 126 in the mass spectrum of
2,6-dimethyl-4-heptanol. CH3 OH CH3

H3C CH3

47
 Introduction to Infrared Spectroscopy
The covalent bonds in molecules are constantly vibrating

Stretching vibrations Bending vibrations

It takes more energy to stretch

a bond than to bend a bond

Each stretching and bending vibration of a bond occurs with a characteristic

frequency that gives a specific absorption band (peak) in the IR spectrum

An Infrared Spectrum
High frequency = short wavelengths (inversely proportional)

Wavelength (µm)

Wavenumber (cm-1)

Functional group region Fingerprint region

(4000-1400 cm-1) (1400-600 cm-1)
Peaks are similar for Pattern is unique for
each functional group each compound

High frequency = large wavenumbers (directly proportional) - high energy

48
 What Determines the Intensity of an IR peak?

Greater change in dipole moment = more intense absorption

A symmetrical bond will have no dipole moment and will therefore be infrared
inactive (have no absorption band)

H H
Cl Cl H3C C C CH3
H H unsymmetrical
unsymmetrical
symmetrical symmetrical symmetrical

Remember, you are looking only at each bond, not the entire molecule

What Determines the Position of an IR peak?

1) Smaller atomic mass = larger wavenumbers (higher frequency)

C H 3000 cm-1
C D 2200 cm-1
increasing wavenumber
C O 1100 cm-1
C Cl 700 cm-1

2) Stronger bonds = larger wavenumbers (higher frequency)

a) Higher bond order = stronger b) Hybridization:

more s character = stronger
triple bond C N 2200 cm-1 sp C C H 3300 cm-1
double bond C N -1
1600 cm 2
sp C C H 3050 cm-1
single bond C N -1
2900 cm-1
3
1100 cm sp C C H

c) Other factors: electron delocalization, the electronic effect of neighboring

substituents, and hydrogen bonding

Any effect that makes a bond stiffer and harder to stretch will increase the wavenumber

49
 Carbonyl Compounds: Resonance and Inductive effects
O O
stronger, less O weaker, more
flexible C=O flexible C=O
bond > > bond

C=O stretch 1788 cm-1 1718 cm-1 1691 cm-1

(ring strain) (resonance)

stronger C=O, O O O O weaker C=O,

more double R > > > R less double bond
R O R H R R R N character
bond character
H
ester aldehyde ketone amide
C=O stretch 1740 cm-1 1730 cm-1 1720 cm-1 1660cm-1
(approx.) (inductive (resonance)
withdrawl)

Stronger C=O because

Resonance No resonance to
weakens weaken C=O bond
C=O bond

Alcohol and Acid Characteristic Peaks

After a carbonyl peak, the broad O-H peak is the most characteristic peak to look for

O-H of alcohol O-H of acid

An O-H bond of an alcohol or acid are both
very broad and intense.

The O-H of an acid is even more broad,

usually covering the C-H peaks

Hydrogen-bonding effect: 3500-3200 cm-1 3300-2500 cm-1

An O–H bond is weaker and easier to stretch when it is hydrogen-bonded

Reality check: water contamination in your sample can make it look like there
is an OH present when there is not.

50
 Alcohol group
Broad
OH peak

Alcohol group +
carbonyl group
Broad
OH peak

Carboxylic
acid group
Super broad
OH peak

In addition to position,
identify type of carbonyl
by looking at secondary
peaks…

Ketone:
no secondary peaks

Aldehyde: C-H stretch

at 2720 and 2820 cm-1

Amide: N-H stretch in

3500-3300 cm-1 range,
and/or C-N stretch in
1200-1000 cm-1 range

(similar for an ester with a C-O stretch

and an acid with an O-H stretch)

51
 Do not confuse an alkene or alkyne with a carbonyl - the intensities are
much weaker than a carbonyl peak

Note the differences in

the sp, sp2 and sp3 C-H
stretches (both the
intensities and the
positions).

sp2 C-H stretch Also note the intensity

at 3080 cm-1 C=C stretch
and position difference
at 1650 cm-1
of the CC double and
sp3 C-H stretch triple bond.
at 2850-2950 cm-1

CC triple bond
Even when the intensity stretch at 1650 cm-1
is diminished, the shift of
the sp3 C-H is distinct
from the C-H of an
aldehyde because it is O-H C-H
sp3sp 3 C-H
stretch
stretch
higher frequency and no stretch at 2800-2950
at 2850-2950cmcm
-1 -1

carbonyl peak is present.

sp C-H stretch
at 3300 cm-1

Be able to identify compounds with benzene rings (sp2 vs. sp3 carbons)

52
 How to develop a “6th sense” for analysis of IR spectra:
Problem Solving Strategy
1. Look in 1800-1600 cm-1 range for strong sharp peak indicating a carbonyl,
consider its relative position.
2. Look for secondary peaks to distinguish between carbonyl compounds.
For example, a broad OH peak (3300-2500 cm-1) to indicate a carboxylic
acid.
3. Look in 3650-3200 cm-1 range for strong broad peak indicating alcohol or
amine.
4. Look for C-O and C-N peaks in 1250-1000 cm-1 range, indicating an ether
or tertiary amine.
5. Look in 2800-3100 cm-1 range for sp2 vs. sp3, indicating alkene or benzene
ring, look for C=C bond (1680-1600 cm-1) or triple bond (2100-2160 cm-1)
6. Do NOT confuse C=C bond or triple bond with a carbonyl - the carbonyl
has a strong intensity and the others have medium or small intensity
7. Consider symmetry that would account for “missing” absorption bands
8. Look in 1800-2800 cm-1 region - usually desolate, but has very
characteristic peaks for CN and CC triple bonds

Look in Appendix VI in your Bruice textbook to help with practice problems

IR Spectroscopy Sample Problems - Practice!!

Common Question Types:
1. Given an IR spectra for an unknown molecule, identify three functional
groups present in the molecule
2. Rank and/or explain which bond has a lower frequency (lower
wavenumber) for a series of bonds given
3. For several carbonyl compounds given, be able to identify which carbonyl
group exhibits the highest wavenumber.
4. Identify which compound has a vibration that is IR inactive
5. Know how to distinguish between a pair of compounds using IR data.
6. Use IR data, along with mass spectrometry and NMR data, to propose a
structure for an unknown organic molecule (in some cases, you will be
given a molecular formula)

Rank the relative frequencies of the following C=O bonds, where 1 = larger wavenumber
and 3 = smaller wavenumber
O O O
H3C H3C H3C
CH3 CH3 CH3
Cl F CH3

53
 Introduction to NMR Spectroscopy

NMR = Nuclear Magnetic Resonance

MRI = Magnetic Resonance Imaging

Nobel Prize (Physics) in 1954

Nobel Prize (Chemistry) in 1991
Nobel Prize (Chemistry) in 2002
Nobel Prize (Physiology and Medicine) in 2003 for MRI

NMR spectroscopy provides 4 pieces of data to identify the about

the carbon-hydrogen framework of an organic molecule:

1) Number of peaks: tells the number of different types of protons (or carbons)
2) Relative area of the peaks: tells the relative types of different protons
3) Position of the peaks: tells the chemical environment of the proton, ie. the
neighboring functional groups
4) Peak splitting pattern: tells the number of protons on adjacent atoms

NMR Theory
A nucleus must have a nuclear spin of +1/2 or -1/2 to be NMR active
Examples include: 1H, 13C, 19F, 29Si, 15N, and 31P

Any spinning charged particle generates a magnetic field; therefore, think of a

nucleus as a mini-magnet that can be affected by an applied magnetic field (Bo)

-
-

- - - - aligned against the field:

+

+
higher energy β nuclei
energy

+ + + +
-

aligned with the field:

+ + + +
-
-

lower energy α nuclei

+

- - - -
+
-

+ (slightly favored)

In the absence of an In the presence of an + pole

applied magnetic field Bo applied magnetic field Bo
Bo
- pole

54
 NMR Theory

Radiowaves supply enough energy to “flip the spin” of a nucleus

Higher energy - - - Energy - - - - Energy - - -

energy

β nuclei + + + supplied released + + +

+ + + +
+ + + + + + + + + + +
Lower energy - - - -
- - -
- - - -
α nuclei

+ pole
Absorption of energy Spin “relaxes” to equilibrium
Bo can “flip” the nuclear state through the magnetic
- pole spin - converts low field and energy is released,
energy to high energy which can be detected as a
signal

Signals in 1H NMR spectra - How many?

• Each set of chemically equivalent protons in a compound gives rise to a different
signal/peak in the 1H NMR spectrum - Look for symmetry!

propyl group ethyl group methyl group

+ methyl group
isopropyl group
tert-butyl group
+ methyl group

“vinyl” protons
“aryl or aromatic” protons

55
 NMR Time-scale
IR spectroscopy is like a fast camera - you get an instantaneous picture of all the
vibrations of a molecule (10-13 s)

NMR spectroscopy is like a slow camera - you get a blurry picture that is time-
averaged for the molecule (10-3 s)

Cyclohexane example:

H chair-chair
interconversion
H H
(ring flip)
(12.1 kcal/mol energy barrier) H

1 peak @ 25 ˚C (fast ring flip)

2 peaks @ –90 ˚C (slow ring flip)
the rate of chair–chair conversion
is temperature dependent

What Determines the Position of an NMR signal?

Less electron more electron

density = less density = more
shielded shielded

56
 NMR - Chemical Shifts

• The chemical shift is a measure of how far the peak/signal is from the reference signal (TMS)
• The common scale for chemical shifts = δ

Position of TMS =
Internal reference
signal (0 ppm)

CH3
H3C Si CH3
CH3
TMS = tetramethylsilane

distance downfield from TMS (Hz)

δ=
operating frequency of the spectrometer (MHz)

NMR - Chemical Shifts

1) Presence of an electronegative atom: more electronegative = less shielded

Electron withdrawing effects cause a proton to be deshielded and the NMR signals
appear at higher frequency (further downfield, at larger δ values)

2) Presence of an adjacent π-bond: C=C and C=O are also electron-withdrawing

CH3
CH3 CH3 CH3 CH3 CH3
O H3C

2.6 ppm 2.4 ppm 2.2 ppm 2.1 ppm 1.2 ppm

3) Hydrogens directly attached to a π-bond: sp2 carbon of alkene has high s character that is
electron-withdrawing, deshielding the hydrogen

7.5 ppm H R H 5.0 ppm but isn’t this a rather big effect
for just an sp2 carbon center?
R R Is there another effect?

57
 Diamagnetic Anisotropy - Effects of π-electrons
The π electrons are less tightly held by the nuclei than are σ electrons; they
are more free to move in response to a magnetic field. This creates an
induced magnetic field

Benzene Alkene
(5-6 ppm) Alkyne
(7-8 ppm) (2.5 ppm)
Bo - Binduced
Bo + Binduced
Protons are shielded
Protons are deshielded (at lower frequency)
(at higher frequency)
The induced magnetic field (Bo + Binduced) creates a unique environment for
hydrogens that are bonded directly to carbons that form π bonds

NMR - Chemical Shifts

Protons in more Protons in more

electron poor electron dense
environment environment
R C C H 2.4 ppm

What about protons attached directly to a triple-bonded carbon?

Proton on an alkyne experiences [Bo - Binduced], therefore, proton is shielded

58
 Chemical Shift Sample Problem
1) How many signals would you expect to see in the 1H NMR spectrum for each
of the following compounds?
2) For each molecule, indicate which protons are least shielded, ie. will give the
NMR signal with the highest chemical shift value (furthest downfield).

H2 H2 O Hb
H
F C Br O C N
C C H3C C C CH3 H3C CH3
H2 H2 H2 H2
Ha

3) The hydrogens attached directly to the carbon of an aldehyde are very distinct because
they occur at especially high chemical shift values, usually greater than 9 ppm. Explain
why this hydrogen is so deshielded?

NMR - Integration
• The area under each peak is proportional to the number of protons that give rise to
that signal
• The height of each integration step is proportional to the area under a specific signal
• The integration tells us the relative number of protons that give rise to each signal,
not the absolute number

59
 NMR - Splitting of the Signals

• The splitting of signals, caused by spin–spin coupling, occurs when different kinds
of protons are close to one another
• An 1H NMR signal is split into N + 1 peaks, where N is the number of equivalent
protons bonded to adjacent carbons
• The number of peaks in a signal is called the multiplicity of the signal

Splitting is observed if the protons are separated by three σ-bonds OR three σ-bonds
and a π-bond (alkene or alkyne)

What is the Theory Behind Splitting Patterns?

Splitting for a doublet (N = 1):

1:1 ratio

Splitting for a quartet (N = 3):

1:3:3:1 ratio

The ways in which the

magnetic fields of three
protons can be aligned

60
 NMR - Splitting of the Signals
An 1H NMR signal is split into N + 1 peaks,
where N is the number of equivalent protons
bonded to adjacent carbons

Singlet, N = 0
Doublet, N = 1 Quartet
Triplet, N = 2 (N = 3) Doublet
Quartet, N = 3 (N = 1)
Quintet, N = 4
Sextet, N = 5, etc

Triplet
(N = 2) Quintet
(N = 4)

NMR - Coupling Constants (J)

The coupling constant (J) is the distance between two adjacent peaks of a split
NMR signal in hertz

doublet
Coupled protons have the quartet
same coupling constant

The magnitude of the coupling constants is determined by the angle between the
two C-H bonds with the coupled protons – known as the Karplus relationship.

Why are coupling constants important?

1) They give you information about which protons are coupled to each other
2) They can help determine some stereochemical elements

61
 NMR - Coupling Constants with Alkenes

Coupling constants for alkenes can be used to identify the cis and trans
geometry of an alkene - trans coupling constant is always larger!!

In general….
You can always tell alkene stereochemistry by using NMR
You can almost always tell regioisomers apart by using NMR
You can usually tell diastereomers apart by using NMR
You can NEVER tell enantiomers apart by using NMR

NMR
Protons attached to benzene or an alkene are at relatively high frequency
because of diamagnetic anisotropy

The signals for the Hc, Hd, and He protons overlap

Notice benzene ring does not have “ideal” splitting pattern - all signals are
similar and overlap - multiplets

ethyl splitting
pattern

62
 NMR - Samples
The signals for the Ha, Hb, and Hc
protons do not overlap

Notice the difference in frequency for each proton signal - Look at resonance structures of
nitrobenzene to assign each hydrogen.

NMR - Protons Bonded to Oxygen and Nitrogen

Hydrogen-bonding and proton exchange cause O-H and N-H signals to be broad

without acid
No proton exchange,
splitting is observed

(ethyl pattern with

additional splitting)

with acid

proton exchange occurs,

splitting is NOT observed
(isolated ethyl
pattern with NO
additional splitting)

What happens if you add a drop of D2O to your NMR sample? The D exchanges for H
and the peak disappears
(this is a great experiment to test for an N-H or O-H peak)

63
 Carbon (13C) NMR Spectroscopy
• The number of signals reflects the number of different kinds of carbons in a compound
• Integration and signal splitting are typically not used
• The overall intensity of a 13C (an isotope of 12C) signal is about 6400 times less than the
intensity of an 1H signal
• The chemical shift ranges over 220 ppm
• The reference compound is TMS

Same resonance and electron withdrawing effects determine chemical shift :

O O
Electron deficient carbon of a carbonyl group is
shifted downfield to high frequency (165 – 220 ppm)
H
110 - 170 ppm
Diamagnetic anisotropy accounts for the
chemical shifts of aryl and vinyl carbons at
H
higher frequencies (downfield)
100 - 150 ppm

Z Electron-withdrawing effects of an electronegative

H3 C 40 - 80 ppm atom will cause smaller downfield shifts
(Z = OH, OR, NH2, NHR, Cl, Br, etc.)

Carbon NMR Spectroscopy

Proton-coupled 13C spectra – splitting is observed (uncommon)

Proton-decoupled 13C spectra – NO splitting is observed (very common)

Example of a proton-decoupled 13C spectra:

Each chemically equivalent carbon atom is a singlet

TMS

64
 1H and 13C NMR Shift Comparison

1H NMR shifts:

δ (ppm)

13C NMR shifts:

δ (ppm)

From Organic Chemistry Textbook by Wade

Types of NMR Questions

1) How many signals will be in an 1H NMR spectra for a given molecule (how
many protons are chemically equivalent)?
2) How many signals will be in an 13C NMR spectra for a given molecule (how
many carbons are chemically equivalent)?
3) Relative chemical shift values, for example, identify which proton will give a
signal with the highest chemical shift value (farthest downfield) for a given
molecule.
4) Assign a spectra - which proton accounts for which peak, and what is the
splitting pattern
5) Identify an unknown compound using NMR and IR data (see examples in
the practice problems handed out in class)

Do lots of practice problems!!!

65
 NMR Sample Problems
1) Label the splitting pattern that will be observed in the 1H NMR spectrum for each of the
indicated hydrogens.

H2
C CH3
C
H2

3) An unknown compound C4H8Br2, gave the following 1H NMR data. What is the compound?

Singlet at 1.97 ppm (6H integration)

Singlet at 3.89 ppm (2H integration)

NMR Sample Problems

How would you use NMR data to determine which is the major product in each
of the following reactions?

CH3 H3C X
X2, hv X
-OR-
1)
X = Br or Cl

H3C Cl CH3 CH2

KOH, EtOH
2) -OR-

CH3
H3C Cl CH3
HCl Cl
3) -OR-

66
 “One C=O bond to Rule them All”
nucleophilic
Carbonyl structure O O
and reactivity: C
electrophilic

Substitutent (Z) on
carbonyl determines
reactivity:

O O O O O O O O
R R
R Cl
> R H > R R > R O R > R O > R N > R O
acid ester H carboxylate
chloride aldehyde ketone anhydride or acid amide ion
Most Most
electrophilic nucleophilic
increasing reactivity
carbon oxygen
with nucleophiles
Most inductive
electron-withdrawing Most resonance

Introduction to Carbonyl Compounds

H3C CH3 1. O3 H3C CH3 Ketone or aldehyde synthesis

O + O using ozonolysis
H3C H 2. H2O2 H3C H

H2O, H2SO4
O Ketone synthesis from
H3C C C CH3 H3C an internal alkyne
1. disiamylborane CH3

2. H2O2, NaOH
O
H2O, H2SO4
H3C CH3
HgSO4 Ketone or aldehyde synthesis
H3C C C H O from a terminal alkyne
1. disiamylborane
H3C
2. H2O2, NaOH H

O
O Synthesis of an aromatic ketone
AlCl3 CH3 using Friedel-Crafts acylation
H3C Cl +
with an acid chloride

67
 Introduction to Carbonyl Compounds

O O O O O O O O
N
R R C
R H R R R OH R O R N R Cl R O R R
carboxylic H acid or acyl
aldehyde ketone acid ester amide chloride anhydride nitrile

carbonyl oxygen
O O
O
Cyclic ester = lactone
R' O NH Cyclic amide = lactam
R O
lactone lactam
carboxyl oxygen

Systematic nomenclature is rarely used for carbonyl compounds, but common names are
somewhat consistent for a series of carbonyl compounds:

O O O O O O
N
C
H3C H H3C OH H3C Cl H3C O CH3 H3C NH2 H3C
acetaldehyde acetic acid acetyl chloride acetic anhydride acetamide acetonitrile

Carbonyl Structure and Bonding

C=O bond (1.23 Å) is shorter and

stronger than a C=C bond (1.33 Å) C O
δ+ δ-
Large dipole moment

O O O
C C
major minor high energy structure,
contributor contributor do not ever draw this!!!

Carbon is an electrophile (has Lewis acid character)

Oxygen is a nucleophile (has Lewis base character)

O O O O O O O O
R R
R Cl
> R H > R R > R O R > R O > R N > R O
acid ester H carboxylate
chloride aldehyde ketone anhydride or acid amide ion
Most Most
electrophilic increasing reactivity nucleophilic
carbon with nucleophiles oxygen

68
 Molecular Orbitals of C=O Double Bond

Compare the molecular orbitals of alkene π* C=O π*

the C=C and C=O double bond: (LUMO) (LUMO)

The C=O bond is unsymmetrical!! alkene π C=O π

(HOMO) (HOMO)

π* C O

The 2p orbital of oxygen is lower

energy

C 2p energy (because oxygen is more

electronegative) and contributes
O 2p more to the π molecular orbital.
The higher energy 2p orbital of
carbon contributes more to the π∗
π C O molecular orbital.

Resonance vs. Inductive Effects

O Most inductive electron
withdrawing effects
R Cl

Resonance structure shows

that carbonyl oxygen is more
Lewis basic than the carboxyl
oxygen (OCH3 or OH)

Most resonance donation

Most Lewis basic oxygen

High double bond character in amide (as seen in resonance structures)

causes trigonal planar geometry of nitrogen, indicating sp2-hybridization

Recall relative IR stretch frequencies based on resonance and inductive effects…

69
 General Comments About Acid-Catalyzed Reactions of
Carbonyl Compounds
H Protonation of the carbonyl oxygen makes any carbonyl
O H+ O
a better electrophile (more susceptible to nucleophilic
R X R X attack) because the C=O LUMO is lowered

aldehydes
ketones
esters
amides

Complexation of a carbonyl oxygen (a lewis base) with a Lewis acid will also make the
carbonyl a better electrophile by lowering the LUMO

BF3 BF3
O O
Lewis acids = BF3, AlCl3, ZnCl2, FeBr3
R X R X

The proton and Lewis acid both have an electron-withdrawing effect. Any electron-
withdrawing effect will lower the LUMO and increase the electrophilicity of the C=O.

Physical Properties: High Boiling Points

intermolecular hydrogen-bonds and dipole-dipole interactions

Hydrogen-bonding
accounts for the super
broad OH peak in the IR
spectra of an acid

Amides have the

highest boiling points

N-H of an amide is also

broad in the IR spectra,
but not as much

70
 Reactivity of Carbonyl Compounds
Recall order of reactivity of carbonyls with nucleophiles:
O O O O O O O O
R R
R Cl
> R H > R R > R O R > R O > R N > R O
acid ester H carboxylate
chloride aldehyde ketone anhydride or acid amide ion

Increasing reactivity
with a nucleophile

Nucleophilic Acyl addition elimination

Substitution:
Y = good leaving
groups
carbonyl
product
Z = oxygen, nitrogen, hydride and carbon nucleophiles

Nucleophilic Addition: addition

Z = oxygen, nitrogen,
hydride and carbon protonation
nucleophiles a tetrahedral tetrahedral
intermediate product

Nucleophilic Acyl Substitution Reactions

General mechanism: Y:- must be a

good leaving
addition elimination group

RDS is elimination

RDS is addition

(a) the nucleophile (Z:–) is a weaker base (k–1 >> k2)

(b) the nucleophile (Z:–) is a stronger base (k2 >> k–1)
(c) the nucleophile (Z:–) and the leaving group have similar basicities

71
 Nucleophilic Acyl Substitution
For nucleophilic acyl substitution, a carbonyl compound must have a good leaving group
(a weak base) that can be replaced by a nucleophile

in nucleophilic acyl substitution reactions:

O
A weaker base is
Cl < O R < OR ~ OH < NH2 easier to eliminate
weakest base strongest base
best leaving group poor leaving group

See Bruice Table 17.1 on page 672

O O Ketones and aldehydes DO NOT undergo nucleophilic acyl

substitution because there is not a good leaving group that
R H R R' can eliminate.
(However, remember that they are great electrophiles and we will
(R’ = alkyl or aryl group)
discuss other addition reactions with them soon.)

MO diagram of Nuclelophilic Acyl Substitution

acceptor

Donor
(on nucleophile)

Examples of nucleophiles (Lewis bases) for acyl substitution reaction:

OH O
H 2O CH3OH NH2CH3 H
N
H3C CH3 O CH3

72
 Reactions of Acid Chlorides

esters

acids

O O O O
+ anhydrides
H3C Cl O CH3 H3C O CH3

amides

Reactions of Acid Chlorides with Amines

Not a good
nucleophile

• Requires 2 equivalents of amine because HCl is formed and amine will be

protonated and no longer be a good nucleophile for the reaction

• Only primary and secondary amines can be used to synthesize an amide

O H3C CH3
+ N No reaction to give amide products
H3C Cl CH3
(2 equivalents)

But a tertiary amine still has a lone pair to serve as a donor, why doesn’t it react ?

73
 Tertiary Amines Still Promote the Reaction

O H
O N
+ + N Cl-
H3C NH2 +
H3C Cl H3C N CH3
H
(1 equiv)
(1 equiv)

A tertiary amine will still add to a carbonyl, but since NO O

deprotonation can occur, it will always be the best leaving group
H3C Cl

Cl-

O O
O N
+ + +
H3C NH2 H3C N CH3 N CH3
H3C Cl
H Cl-
(1 equiv)
(1 equiv)

H3C NH2

H H
O O+
N Cl- N OH
+
+
H3C N CH3 H3C N CH3 N
N CH3
H H H2
Cl- H3C

Sample Problem: Mechanism

Provide a mechanism for the following conversion of an acid chloride to an ester:
O O
+ CH3OH
H3C Cl H3C OCH3

Problem solving When nucleophile is neutral: When nucleophile is an anion:

strategy: Step 1 = addition Step 1 = addition
Step 2 = deprotonation Step 3 = elimination
Step 3 = elimination

Must draw three steps and show tetrahedral intermediate!!

74
 Reactions of Anhydrides

ester + acid

acid (2 equivalents)

amide

Anhydrides are still reactive enough to synthesize esters, amides and acids;
however, they are actually more stable than an acid chloride making them
more practical to use.

Reactions of Esters
1) Amidolysis

2) Hydrolysis
Reaction is reversible and both
acid and ester will be present
at equilibrium

3)Trans-esterification
Reaction is reversible and
both esters will be present
at equilibrium

75
 Acid-catalyzed Hydrolysis of an Ester

No negatively charged species

Several of proton-transfer steps

Need to drive equilibrium by adding excess

water or removing the alcohol product

Acid catalyzed Hydrolysis of an Ester

Esters with tertiary alkyl groups undergo faster hydroylsis by SN1-related mechanism

H CH3 OH
CH3 O H H3C +O SN1
+
H3C H3C H3C + CH3 O R
H3C O R H3C O R
tertiary
H2O carbocation

Provides both an
acid and an alcohol
product CH3 B:
CH3
H3C
H3C
H3C O H
H3C OH
H

Once the carbonyl oxygen is protonated, the carboxylic acid is an

excellent leaving group for an SN1 reaction

76
 Hydroxide Ion-Promoted Hydrolysis of an Ester:
Saponification

Hydroxide ion increases the rate of formation of the tetrahedral intermediate

This reaction is
NOT reversible

Under basic conditions, the carboxylic acid will be deprotonated. The

carboxylate ion is NOT electrophilic and the reverse addition will not occur

Hydrolysis of an Amide Requires Harsh Conditions

Amides are very stable and hydrolysis conditions require acid or base, with heat

• Requires both heat and acid to hydrolyze an amide

• Nitrogen must be protonated to become a good leaving group
O H O H+
H3C NHCH2CH3 + HNCH2CH3 H2NCH2CH3
HO H3C OH

HCl, H2O O O
H+
N
H2N OH H3N OH
O H
β-lactam
A cyclic amide (a lactam) will be easier to hydrolyze if there is ring strain

77
 Sidenote: Importance of the Amide Bond in Biological
Systems

amide H
bond
N R5
H
O R1 O R3 O R5
H H H H R4 O
N N N N
N N N N
H O
H H H
O R2 O R4 O R3 O R2
N H
amino acids linked by amide bonds: Linear Structure N
H
O O
N R1
Amide bonds are difficult
O
to hydrolyze, making
them perfect for proteins. alpha helix
with hydrogen-bonds
Of course, there are
enzymes that can
hydrolyze the amide bond
quite readily!!
protein structure

Reactions of Carboxylic Acids

1) Acid-base reactions (recall pKa’s)

O O No amides will
H CH3 CH3
+ N + H2N form because
H3C OH
CH3
H3C O CH3 the amine will
be deprotonated

2) Activated by converting to an acid chloride

Converts carboxylic acid to a

very electrophilic (activated)
carbonyl to use in nucleophilic
acyl substitition reactions

Mechanism:

78
 Reactions of Carboxylic Acids cont’d

3) Lactonization with Br2 or I2

OH
I2
O + H I
O CH2Cl2 O
I
I
I

OH
O+
O O H
I+ I
I- I-

The carbonyl oxygen is more nucleophilic than the carboxyl OH and will add to to
the halonium intermediate (electrophile)

Sidenote: Activated Carboxylic Acid Derivatives for Biosynthesis

Similar to anhydrides,
great leaving groups
for synthesis:

ATP is a great energy storage device: thermodynamically reactive and kinetically unreactive

Good sterics, good

leaving group, not
as much energy

OK sterics, good
leaving group,
gives more energy

AMP
Reactions are determined by sterics, leaving group ability and “energy requirements”
of the biochemical pathway. Enzymes play a big role!

79
 Reactions of Nitriles
O
Br NaCN CN HCl/H2O
H3C H3C H3C OH
S N2 ∆
butanenitrile Butanoic acid
(propyl cyanide) (butyric acid)

Acid-catalyzed hydrolysis to a carboxylic acid is even more difficult than an amide hydrolysis

H2, Pd/C
Reduction of a nitrile to give an amine: CN H3C NH2
H3C

(2 equiv of H2 is required for reaction, but since H2 is added in the gas form, excess is always added)

Sample Problems
1) Rank the reactivity of the following esters towards hydrolysis, where 1 = most reactive
and 3 = least reactive.
Cl OCH3
O O O
Hint: Since the carbonyl is the
electrophile, the rate is CH3 O CH3 O CH3 O
increased by anything electron-
withdrawing and decreased by
anything electron-donating

H
O O CH2
2) Rank the relative energy level of the
LUMO for the following C=C and C=O R OCH3 R OCH3 H3C CH3
bonds, where 1 = lowest LUMO (most
electrophilic) and 3 = highest LUMO

3) Show three ways to prepare an amide from N,N-dimethylamine

80
 Lidocaine Synthesis: Nucleophilic Acyl Substitution vs. SN2
Nucleophilic O
O R NH2 H
acyl subsitution N
Cl R
Cl N R
(excess H
amine)

SN2
If only one equivalent of amine is used, nucleophilic acyl substitution will be faster than
an SN2 because acyl halides are better electrophiles (more reactive) than alkyl halides

CH3 CH3 O
Step 1: O NaOAc Cl
NH2 + Cl N
Cl H
CH3 CH3
1 equivalent amine

Step 2: CH3 O CH3 O

CH3
NaI, Et2NH
Cl N CH3
N N
H H
Lidocaine
CH3 CH3

Synthesis of Aspirin
An experiment from Chem E2a lab: Acyl transfer with acetic anhydride

O O O CH3

OH H3C O CH3 O O
+ H
OH H3PO4 OH H3C O

O O
Salicyclic acid Aspirin™
• Active ingredient in wart (acetylsalicylic acid)
removal medicine (40 %)
• Active ingredient in some acne
treatment medicine (1.5%)

How to get rid of excess acetic anhydride in a reaction?

hydrolysis gives acetic acid:

O O H2O O O
+
H H
H3C O CH3 H3C O O CH3

Acetic anhydride Acetic acid

81
 Sidenote: Aspirin Mechanism of Action
The reverse acyl transfer from Chem E2a lab:

Cyclooxygenase
O CH3
Ser Cyclooxygenase
O OH OH
+ Ser
OH enzyme-mediated OH O

O O H3C O
Aspirin™ salicylic acid

Aspirin is a nonsteroidal anti-inflamatory drug (NSAID) that inhibits the

biosynthesis of prostaglandins (which cause inflammation) by PGH2 synthase.
Specifically, Aspirin inactivates the cyclooxygenase (Cox) activity of PGH2
synthase by an irreversible covalent modification mechanism: acylation of the
Ser530 amino acid, a strategic location which blocks entry of the enzyme
substrate into the binding site

Ibuprofen is an NSAID that also inactivates cyclooxygenase activity of PGH2

synthase, but inactivation with Ibuprofen occurs by competitive substrate
binding (a non-covalent, reversible mechanism)

β-Lactam Antibiotics: Medicine and Molecular Orbitals

Penicillin mechanism of action: Inhibits Transpeptidase to prevent cross-linking of small
peptide chains (petidoglycan strands) in the cell wall of gram+ bacteria.

But how is penicillin reactive if amides are so unreactive to hydrolysis?

Planar structure allows good

C N overlap between lone pair on N (in
N N O
O H O H
H p-orbital) and the C=O π bond to
give good resonance stabilization
β-lactam
3-D picture = planar

CH 3
H H H S
N
S CH 3 CH 3 Ring constraints of fused β-lactam
O CO 2 H structure force lone pair to be almost
N C N
O
CH 3 O perpendicular to the C=O π bond
OH and resonance stabilization is lost
O
penicillin G 3-D picture = bent

82
 Sample Problems
General 1) Provide reagents or products in a reaction scheme (or short syntheses)
question 2) Know mechanisms and relative reactivity trends for Nucleophilic Acyl Substitution
types: 3) Remember IR and NMR data relating to the C=O bond
4) Be able to draw resonance structures and understand how they influence reactivity

1) The β-lactam of penicillan G is fairly labile in your stomach (acidic conditions). Provide
a curved-arrow mechanism showing how it is rendered inactive in your stomach.

R H
S CH3
N CH3
O
CO2H
penicillin G

β-Lactam Antibiotics: Medicine and Sterics

Bacteria become resistant to penicillan G by producing an enzyme (penicillanase) that

catalyzes the hydrolysis of the amide bond. However, simple structural modifications of
penicillan G can make a drug that is effective against penicillan G-resistant bacteria.

CH3
H H
N H H
S CH3 N
S CH3
O N CH3 CH3 O N
O CH3
O
OH
O OH
O
penicillin G methicillin
More bulky
aryl group

Methicillan is effective in treating patients infected with penicillan G-resistant bacteria

because the bulky aryl group prevents it from binding in the active site of the penicillinase.
It does not, however, prevent it from inhibiting the transpeptidase target.

83
 Sample Problem

2) Provide a synthesis of methyl butyrate from bromopropane: O

Br
H3C H3C OCH3
starting material desired product

Reactivity of Aldehydes and Ketones

Recall order of reactivity of carbonyls with nucleophiles:

O O O O O O O O
R R
R Cl
> R H > R R > R O R > R O > R N > R O
acid ester H carboxylate
chloride aldehyde ketone anhydride or acid amide ion

Increasing reactivity
with a nucleophile

O O O
> >
H H R H R R
formaldehyde an aldehyde a ketone

An aldehyde is more electrophilic because an H atom is electron-withdrawing

compared to an alkyl group: more electron-withdrawing effect = greater
positive charge on carbon (less stable)

84
 Two Factors: Electronic and Sterics

O O O O O
Very > > > > H3C CH3
Less
CH3
reactive H H H3C H H3C CH3 H3C reactive
CH3 CH3 CH3

Reactivity based on stability

and sterics: stability more Reactivity determined by sterics:
important than sterics more sterics = less reactive

Electronic effect (stability):

A hydrogen is more electron-withdrawing than an alkyl group.
EWG = Greater positive charge = more electrophilic = Lower LUMO
(Remember, Electron-withdrawing groups always lower the LUMO)

Sterics has two effects:

1) The carbonyl carbon of an aldehyde is more accessible to the nucleophile
2) Ketones have greater steric crowding in their transition states, so they
have less stable transition states

Aldehydes and Ketones - Nomenclature

Aldehydes - remove “e” from hydrocarbon name and add “al”

Ketones - remove “e” from hydrocarbon name and add “one”

85
 Nucleophilic Addition Reactions

Recall Nucleophilic Acyl Substitution:

addition elimination

carbonyl
product

Nucleophilic Addition:

addition

protonation
a tetrahedral tetrahedral
intermediate product

(Both general reactions can also be acid-catalyzed)

Addition of Carbon Nucleophiles: Grignard Reagents

Grignard reagents react with aldehydes, ketones, and carboxylic acid derivatives
to form new C–C bonds

Recall: Synthesis of a
Grignard reagent from Very polar
an alkyl bromide: C–Mg bond!

Grignard reactions with aldehydes give secondary alcohols:

Grignard reactions with ketones give tertiary alcohols:

86
 Grignard Reactions with an Ester - Double Addition

MgBr

O 1) OH
Methyl OCH3 2.5 equivalents Triphenylmethanol
benzoate
2) H2O

Nucleophilic PhMgBr
(1st equiv) H2O
acyl substitution

O PhMgBr OMgBr
(2nd equiv)

Nucleophilic
addition

Addition of the first equivalent of Grignard reagent will form a ketone

Addition of the second equivalent of Grignard reagent will form an alcohol

Grignard Addition to CO2: Synthesis of a Carboxylic Acid

O
Br Mg, Et2O MgBr 1. CO2
OH
2. HCl, H2O

bromobenzene benzoic acid

Useful synthetic methods to recall:

Two methods
1. BH3 to synthesize
H3C OH Hydroboration/oxidation
H3C a carboxylic
2. H2O2, NaOH
acid
PBr3 Alkyl bromide formation
OH Br
H3C H3C
O SN2 and
NaCN HCl, H2O Nitrile
Br CN
H3C H3C H3C OH hydrolysis

Br2, hv CH3 Br2 CH3

Br
(or NBS) FeBr3
Br

Radical Electrophilic aromatic

bromination substitution: bromination

87
 Synthesis Sample Problem

1) How would you synthesize the following compound from any carbonyl compound and
any alkyl bromide? You may use any inorganic reagents.

OH
H3C CH3

2) Provide a synthesis of this carboxylic acid from benzene:

H3C
CO2H
CH3

Other Carbon Nucleophiles: Acetylide anion

Recall: Previous reactions of acetylide anion with electrophiles:

H 1) NaNH2 (or nBuLi) SN2 with

CH3
H3C H3C
alkyl halides
2)
H3C Br

H 1) NaNH2 (or nBuLi) OH

Epoxide
H3C 2) O H3C
opening

88
 Hydride Ion as a Nucleophile
General mechanism: reduction of ketone to secondary alcohol by addition of a
hydride ion, followed by protonation

Tetrahedral products

CH3
What are sources of hydride ion “H:–”?
NaBH4 = sodium borohydride - four “H:–” equivalents CH3 CH3
Dibal-H = diisobutylaluminum hydride - one “H:–” equivalent Al
H3C H
LiAlH4 = lithium aluminum hydride (LAH) - four “H:–” equivalents
Dibal-H

Relative ease of reduction:

Most O O O O O Least
reactive > > > > reactive
R H R R R OR R NR2 R O

NaBH4

LiAlH4 - most reactive

H
NaBH4 Reductions Na H B H
H
• Only works with aldehydes and ketones
• Each molecule of NaBH4 provides 4 hydride equivalents (therefore, you only need
one molecule of NaBH4 for every four molecules of carbonyl compound)

Aldehydes give
primary alcohols

Ketones give
secondary alcohols

Because NaBH4 is less reactive, it can be very selective. You can selectively reduce
a ketone and the ester will remain untouched.

Only the ketone will be reduced!!

89
 H
LiAlH4 reductions Li H Al H
H
1) LiAlH4 is a stronger reducing agent than NaBH4
2) LiAlH4 is used to reduce compounds that are nonreactive toward NaBH4
(basically, LiAlH4 will reduce any carbonyl compound)
3) Double hydride addition will occur to give the completely reduced product

Amine substitution
depends on what
amide substitution
started as

An ester is reduced to a primary alcohol (double hydride addition)

A carboxylic acid is reduced to a primary alcohol (double hydride addition)
An amide is reduced to an amine (double hydride addition)

LiAlH4 Double Addition Mechanism with an Ester

elimination

addition

addition

protonation

The first hydride addition is a nucleophilic acyl substitution and a carbonyl

product is obtained. The second hydride addition, a nucleophilic addition
reaction, follows immediately because the aldehyde is even more reactive.

90
 Dibal-H Reductions
Dibal-H allows the addition of only one equivalent of hydride to an ester
because it is less reactive than LiAlH4

LiAlH4 reduction gives alcohol (double hydride addition):

Dibal-H reduction gives aldehyde (single hydride addition):

CH3
Why is Dibal-H less reactive than LiAlH4?
Dibal-H CH3 CH3 1) As a neutral species, it is less nucleophilic than
Al the anionic aluminum species
H3C H 2) It is more sterically hindered

Reduction Sample Problems

Provide products for each of the following reactions:

1. NaBH4 O O 1. LiAlH4
2. HCl, H2O H CH3 2. HCl, H2O

1. NaBH4 O O 1. LiAlH4
2. HCl, H2O H OCH3 2. HCl, H2O

1. Dibal-H O O 1. LiAlH4
2. H2O CH3
H3CO N 2. HCl, H2O
CH3

O
1. LiAlH4
O
2. HCl, H2O

91
 Alcohols Can be Oxidized to Carbonyl Compounds

[O]
Reduction: Oxygen Oxidation: Oxygen
content decreases Oxidation O content increases
OH R
and/or hydrogen R and/or hydrogen
Reduction H
content increases content decreases
[H]

Oxidation with chromic

acid reagents:

Secondary alcohols can

be oxidized to ketones

Aldehydes and ketones

can be oxidized to
carboxylic acids

Oxidation Mechanism with Chromic Acid

What are the different Chromium reagents?

All three are variations of the same reagent, (chromic acid):

H2CrO4 = Chromic acid O

CrO3/H2SO4 = H2CrO4 HO Cr OH
Na2Cr2O7/H2SO4 = H2CrO4 O

Mechanism:

Proceeds by substitution
and an E2 elimination

92
 PCC Oxidation of Alcohol to an Aldehyde
Chromic acid will oxidize a primary alcohol all the way to a carboxylic acid:

H2CrO4 O H+ OH H2CrO4
OH H3C H3C O
OH H3C
H3C H2O
H2O H H OH
Primary aldehyde hydrate Carboxylic acid
alcohol

The oxidation of a primary alcohol can be stopped at the aldehyde if

pyridinium chlorochromate (PCC) is used as the oxidizing agent
H
N N
CrO3 + HCl + CrO3ClŠ

PCC

The oxidation with PCC stops at the aldehyde because PCC can be used in a non-aqueous solvent
to avoid formation of the hydrate. The hydrate is what oxidizes further to the carboxylic acid

Swern Oxidation
Swern is also a useful method to oxidize a primary alcohol to an aldehyde because
over-oxidation can be avoided….. And less toxic than chromium reagents

Mechanism:
Me
O O Cl
O O S Me O Cl
Cl
Cl S Cl O Me S
Me Me Cl Cl S Me Me
O
O O
oxalyl DMSO Me dimethylchlorosulfonium
chloride ion
R
Cl H
Cl H O
O R O R O H
S NEt3 R H
R OH Me Me S S H S
Me Me Me triethyl- Me CH2
SN2 amine E2 aldehyde

+ S
Me Me

dimethyl-
Proceeds by substitution sulfide
and an E2 elimination
Dimethylsulfide is:
Note: also converts secondary alcohols to Ketones 1) A great leaving group
2) Super Stinky!!!

93
 Sidenote: Analysis of Blood Alcohol Content

H2SO4
H3C OH + Na2Cr2O7 H3C O + H2Cr2O3

OH

The ethanol from your lungs (in equilibrium with your blood) will be oxidized by
chromic acid. The chromate ion produced can either be detected by the a
simple color change that indicates if any alcohol is present, or a quantitative
Breathalyzer™ can be used for a more accurate reading of the alcohol content.
However, a direct blood test is the most accurate measurement.

H2SO4
Na2Cr2O7 reduced chromate ion
ROH
Red-orange green color
color

Synthesis Sample Problems

1) Provide a synthesis of Ibuprofen from the starting matieral provided:
H3C CH3
H3C CH3
O

OH
CH3
Starting material Ibuprofen (AdvilTM)

2) Provide a synthesis of the ketone below, starting with any alcohol that is 4 carbons or
less, and using any inorganic reagents.

CH3 O
CH3
H3C
CH3
Desired product

94
 Reactions of Aldehydes and Ketones with Nitrogen
Nucleophiles: Imines from 1° amines
H H
R R
R O H2N H2O + R N
"Imines"
aldehyde 1° amine aldimine
-OR-
R R
R "Schiff
H2O + R
R O H2N R N Bases"

ketone 1° amine ketimine

Bonding in an imine:

CH3 CH3
C N
CH3

sp2-hybridized carbon
sp2-hybridized nitrogen

Reactions of Aldehydes and Ketones with Nitrogen

Nucleophiles: Enamines from 2° Amines
R R R
HN
R R R
O R H2 O + N
aldehyde 2° amine R
or ketone enamine

recall...

R R
R R
O OH
"keto" tautomer "enol" tautomer

95
Mechanism of Imine Formation

protonation deprotonation
addition

protonation

deprotonation
elimination

Mechanism of Enamine Formation

96
 Carbonyl Group Removal via Imine (hydrazone) Formation:
The Wolf-Kischner Reduction
NH2
Me H2N Me Me
Works with hydrazine NaOH H
O N NH2
any ketone ∆ H

ketone hydrazone alkane

Mechanism to form hydrazone is EXACTLY as with imines

Reduction mechanism:

This ketone reduction is more general than the H2 with Pd/C

reduction conditions that ONLY work with benzylic ketones

Reactions of Aldehydes and Ketones with Oxygen

Nucleophiles: Gem-Diols (Hydrates) from Water
O
HO OH
R R H2O
R R
ketone or Water gem-diol or
aldehyde "hydrate"

Recall... OH
OsO4/H2O2
R R
R R
OH
vic-diol

gem, geminal => gemini, "twins"...attached to same carbon

vic, vicinal => vicinity, "neighbors"...attached to neighboring carbons

97
 Carbonyl Reactivity Predicts the Amount of Hydrate
Present

most stable,
least reactive

least stable,
most reactive
most stable

Acetals and Ketals

O
OH H+ RO OR
R H R H2O +
R H
aldehyde alcohol acetal

O
H+ RO OR
OH
R R R H2O + R R
ketone alcohol ketal

Examples of “H+”acids = HCl, H2SO4, p-TsOH

SO3H
p-TsOH =
H3C

98
Mechanism is Similar to Hydrate Formation, conditions are
Similar to Imine Formation (dehydrating)

This reaction does not happen unless you get rid of the water!

The Dean-Stark Apparatus

H O

5g OH
condenser HO

cold water
MeO O

Dean-Stark
pTsOH benzene
Trap (reflux)

water
level O O

reaction flask
6.4g + H2O (0.54 mL)

MeO O

99
 Applications of Ketals in Synthesis

OH O O O
LiAlH4 ??
Me OH Me OMe Me OH
BOTH
carbonyl groups LESS REACTIVE
reduced NaBH4 carbonyl group
reduced?

OH O

Me OMe

MORE REACTIVE
carbonyl group
reduced

Ketals are Useful as “Protecting Groups”

O O O
??
Me OMe Me OH

pTsOH
OH H2O, more reactive
D/S trap
HO
benzene HCl carbonyl group
de-protected

LiAlH4
O O O O O
Me OMe Me OH

more reactive LESS reactive

carbonyl group carbonyl group
protected reduced

100
 Applications of Protecting Groups with Alcohols

Re-call from E2a: TMS ethers are useful protecting groups for alcohols

OMe OH OMe
Me MeI/NaH Me ?? Me
OMe OH OH
Me (excess) Me Me
BOTH
Alcohols converted MeI/NaH LESS REACTIVE
to methyl ethers alcohol converted
to methyl ether
OH
Me OMe
Me

MORE REACTIVE
alcohol converted
to methyl ether

Protecting Groups Are Important for Organic Synthesis

Protecting groups are often necessary, but remember, each protecting group
adds 2 steps to your synthesis, so they should be minimized or avoided.

101
 Sidenote: Acetals in Aesthetic Chemistry: The Nanoputians…

Addition of Sulfur Nucleophiles to Aldehydes and Ketones:

Formation of Thioketals

+ H2O

Thioketals Offer a Milder Alternative to the Wolf-Kischner Reduction

102
The Wittig Reaction: Conversion of Aldehydes and Ketones
to Alkenes

O O-
X Y +X Y- S S+
ylide resonance Me Me Me Me
contributor DMSO

Ph H
Ph P -
Ph CH3

Ylide Formation and the Mechanism of the Wittig

Reaction

103
 Wittig Reaction and Alkene Stereochemistry

stabilized ylide UNstabilized ylide

-
O O
+ + +
Ph3P Ph3P Ph3P Me
OMe OMe
- -

O
O
+ H
Ph3P OMe
OMe E-alkene predominates
-
O R H

R H Me

H
+ Z-alkene predominates
Ph3P Me
- R H

Sample Problem
Propose a synthesis of the following product from the indicated starting material

Ph OH Ph OH

104
Nucleophilic Addition to α,β-Unsaturated Aldehydes and
Ketones

Mechanism of Conjugate Addition

105
Nucleophiles That are Weak Bases Will Generally Form
Conjugate Addition Products
O Nu OH
Carbonyl C=O bond broken
Nu H

O O

H Br R SH R
Br S
O

R Carbonyl C=O
NH H CN left intact
R
O O

R
N C
N
R

Grignard Reagents Prefer 1,2-addition (direct),

Cuprates Prefer 1,4-addition (conjugate)

O O HO R
1) R2CuLi 1) RMgBr

R 2) H3O+ 2) H3O+

106
 Summary

• Amine nucleophiles add to aldehydes and ketones to form imines and

enamines
• Alcohols and thiols (diols and dithiols) add to aldehydes and ketones to
form acetals and thioacetals
• Acetals are useful as protecting groups so that chemistry can take place
on less reactive carbonyl groups
• Thioacetals are useful for two-step reduction of carbonyls to alkanes as
a mild alternative to the Wolf-Kischner reduction
• Unsaturated carbonyl compounds can undergo direct (1,2) or conjugate
(1,4) addition
• 1,4 addition is preferred for weak nucleophiles, 1,2 addition is
preferred by very strong (eg Grignard) nucleophiles. Cuprates allow
1,4 addition of carbon nucleophiles to predominate

Carbonyl Compounds Part III: Reactions at the α-

Carbon
So far, carbonyl groups have only served as electrophiles at the carbon
bound to oxygen, or the terminal carbon of an unsaturated carbonyl.
We will now see that the α-carbon of a carbonyl compound can act as a
nucleophile.

alcohol: pKa = 16 carboxylic acid: pKa = 5

O O
H H
H3C O H3C O- + H+ H3C O H3C O- + H+

alkane: pKa = 50 ketone: pKa = 20!!

O O
H H H H
H3C H3C - + H+ H3C H3C - + H+
H H
H H H H

107
 Electron-Withdrawing Groups Stabilize α-Anions

For a more
extensive table see: http://daecr1.harvard.edu/pdf/evans_pKa_table.pdf

The Effect of Stabilization is Additive: More Groups, More

Stability

108
 Enols and Enolates are Nucleophiles

Enols are like very reactive alkenes...

OH
O
+ Br Br H Br
H3C Br
H3C

Enolates are carbon nucleophiles

O
O
+
H3C R X + X
H3C R

O
O O OH
+
H3C
H R H3C R

Keto-Enol Tautomerization

109
 Enol-Keto Interconversion is Catalyzed by Base or Acid

Halogenation of Ketones: Acid Catalysis

Only 1 α-hydrogen is replaced by a halogen

110
 Halogenation of Ketones: Base Promotion

Stoichiometric Formation of an Enolate With Lithium

Diisopropylamide (LDA)
Preparation of LDA from diisopropylamine and n-butyllithium

Me Me Me Me
+ + CH3
Me N Me H3C Li Me N Me H3C
H Li
DIA LDA

111
 Alkylation of Ketones, Esters, and Nitriles

Note Similarity to…

R n-BuLi R H3C Br R
H Li
CH3

Sample Problem: Ketone Alkylation

Propose a synthesis of the following branched ketone from a linear ketone starting
material:
O
H3C
CH3
CH3

112
 Enolates of Unsymetrical Ketones: Regiochemistry
Problem with α-Branched Ketones

Thermodynamic and Kinetic Enolates

'kinetic' 'thermodynamic'
enolate enolate
CH3 CH3
O OLi OLi
H H
H3C N CH3 CH3 LDA CH3 CH3
Li H +
LDA
1.1 equiv LDA: major minor
(Low Temperature)
0.95 equiv LDA:
minor major
Mechanism of Equilibration: (Higher Temperature)
CH3I CH3I
O OLi
H H O O
CH3 CH3
H3C CH3 CH3
H +
CH3
OLi O
CH3 CH3
+

The kinetic enolate is formed more quickly because of reduced steric hindrance, and when
there is no excess ketone around, it cannot equilibrate. When there is excess ketone, the
kinetic enolate can deprotonate the ketone and form more of the thermodynamic enolate.

113
 Hydrazones Give Alkylation Products That Would Result
from the Kinetic Enolate

+Li

Bu-

Ketone Alkylation Can Be Problematic: Polyalkylation,

Regiochemistry, and O-Alkylation are Possible

Enamines are monoalkylated, and are a good alternative when over-alkylation

is a problem, especially in the case of methylation.

114
 Carbonyl Alkylation: Stereochemistry and the Evans
Asymmetric Alkylation
New Stereocenter Formed (product is racemic)
products cannot easily be separated!
O O O
CH3 LDA CH3 CH3
MeO MeO + MeO
PhCH2Br
H H
Ph Ph

Ph O O O O
O O Li
O O CH3 CH3
CH3 LDA Br N N
O N CH3 O O
CH3I O N H H
Ph Ph
CH3 H i-Pr i-Pr
i-Pr major minor
H3C (diastereomeric proiducts can be easily separated)
single enantiomer:
chiral auxilliary Sm(OTf)3/MeOH
derived from valine O
O O
Me
Cl H CH3
O N + MeO
Et3N H
i-Pr Ph
single enantiomer

Synthesis of Evans Auxilliaries

O phosgene
(1 equiv)
O
CH3 O CH3 Cl Cl + Et3N
LAH H
O N
H3C OH H3C OH
OR: Cl O Cl
NH2 NH2 Cl Cl
i-Pr
occurs in nature as one Cl O O Cl
enantiomer. "triphosgene" (0.33 equiv)

O
Synthesis of the other enantiomer Me
of chiral ester would require the Ph O N
H
enantiomeric chiral auxilliary... OH
NH2
norephedrine Ph Me

• Chiral auxilliaries are useful for making enantiomerically pure products by a variety of
reactions, not just alkylation.
• Since the two products are diastereomers, purification can be used to increase the purity
of the product, and thus the final enantiomeric purity once the auxilliary is cleaved.
• The auxilliary can be recovered by purification and used in subsequent reactions.

115
 The Aldol Addition

• It was first observed as a dimerization

of aldehydes to produce a molecule that
was named “aldol” because it was a β-
hydroxy aldehyde
• These two examples represent
homoaldol reactions, or reactions
where both the electrophile and
nucleophile are derived from the same
molecule.

The Cross Aldol Addition: The Nucleophile and

Electrophile Emanate from Two Different Carbonyl
Compounds

A-A

A-B

B-A

B-B

116
 The Cross Aldol Reaction

• While the dimerization of aldehydes and ketones through the aldol reaction is not terribly
useful, the cross aldol reaction is very useful.
• The cross aldol reaction involves an electrophile and nucleophile derived from different
carbonyl compounds.
• In the cross aldol reaction, the enolate nucleophile usually comes from an ester or a ketone,
and the electrophile is usually an aldehyde.
• Because the carbonyl that supplies the nucleophile and the electrophile are both acidic, the
nucleophile must be generated in the absence of the electrophile.

Intramolecular Aldol Addition: 5- and 6-Membered Rings

are Favored.

117
 Stereochemistry of the Aldol Reaction: The Acetate and
Propionate Aldol Addition Reactions
O OLi O OH
LDA RCHO
CH3O CH3 CH3O CH3O R
one new stereocenter created
("acetate" aldol product)

OLi
O OH
CH3O
CH3 MeO R
O E(O)-enolate RCHO CH3
LDA
anti-aldol product
CH3O CH3 OR
OLi O OH
CH3
CH3O MeO R
Z(O)-enolate CH3
syn-aldol product
two new stereocenters created
("propionate" aldol product)

Polyketide Natural Products are Synthesized by

Successive Aldol Additions
O
H3C CH3

H3C CH3 O OH OH O OH OH
OH
OH CH3
H3C Me HO
O OH H3C H3C H3C OH CH3 CH3 CH3
O OH
CH3
7 "propionate" units make up the skeleton of erythronolide
Erythronolide B

O
Me
H O OH O OP O OH OP
O
CH3 CH3 CH3
Me RO H RO
RO
CH3 CH3 CH3 CH3

118
Update: The Aldol Reaction is Nothing More than a
Special Case of Carbonyl Addition…

"Carbonyl Addition"
RMgBr H-
O Nu OH
Nu = Li
R H R Nu
R

The Aldol Reaction

OLi
O Nu =
R OH O
R H R R

Sample Problem

119
 The Aldol Condensation: Elimination of Aldol Products to
α,β-Unsaturated Carbonyl Compounds

Condensation reactions involve the loss of water or an alcohol so that the molecular
weight of the product is less than the sum of the two starting materials.

Aldol Addition vs Condensation

O O OH O
LDA HCl/H2O
R
RCHO R NaOH/H2O R
Me ∆ Me

aldol addition aldol condensation

NaOH/RHCO
∆ HEAT
∆

• Use of LDA to form an enolate, followed by addition of an aldehyde will produce the aldol
addition product
• If the aldol addition product is then treated with either aqueous acid OR base, the
condensation product will be formed
• If the aldol components are combined with base, it is likely that the condensation product will
predominate

120
 The Aldol Condensation Produces “Wittig-like”
Products…when is it useful?
O O
O O O
Ph Ph Ph Ph O O
Ph Ph
Ph Ph Ph3P PPh3 Ph Ph
Ph Ph
Wittig Aldol

The aldol condensation is one step, not two (like the Wittig), so in cases where
control of alkene geometry is not important, aldol condensation is OK
In many cases, such as cyclizations, only one product is possible from aldol
condensation, so it is the way to go…
K O
O O O
KOH + Ph H
Ph Ph Ph Ph Ph Ph Ph
O
O
K EtOH Ph
O O O
O H K Ph
Ph Ph Ph Ph
Ph Ph EtOK

O O
O Ph Ph
Ph O O
Ph H Ph
Ph H

The Michael Reaction: Conjugate Addition of an

Enolate

When an enolate nucleophile reacts with a conjugated carbonyl compound,

it is called the Michael Reaction.
This reaction works well with very stable enolates, ie those derived from β-
carbonyl compounds

121
 The Michael Reaction: Conjugate Addition of an
Enolate
If one reactant in the Michael reaction (or other reaction involving an alkoxide base) is
an ester, it is important to match your alkoxide base with the ester component.

If the enolate component in a Michael Reaction is an unstabilized ketone, it works better if you
use the corresponding enamine, which is called the Stork Modification after Gilbert Stork.

The Claisen Condensation: Reaction of Enolates with

Esters
When an enolate nucleophile reacts with an ester to give the product of nucleophilic
acyl substitution, it’s called the Claisen Condensation.

O O O
2 H3C NaOCH3 H3C + CH3OH
OCH3 OCH3
CH3

122
 The Driving Force for the Claisen Condensation is the
Formation of a Stable Anion

A full equivalent of base is employed, and the product is the dicarbonyl

anion and alcohol from which the alkoxide is derived.

Mixed (Cross) Claisen Condensation and the Dieckman

Condensation
O O
O O
CH3 NaOEt
H3C O H3C O
H H H3C O
Me

α-proton removed NO α-protons!

to form enolate

O O O O
H
CH3 NaOEt CH3
H H3C O
H H

α-protons of ketone are more acidic...

the enolate of the ketone will be formed preferentially

The intramolecular Claisen condensation is called the Dieckman condensation

123
 Update: The Claisen Condensation is Nothing More
than a Special Case of Nucleophilic Acyl Substitution…

"Nucleophile Acyl Substitution"

O Nu O R
Nu = NH R H2O
OH
R X R Nu R

The Claisen condensation

ONa
O Nu =
R O O
R X R R

Sample Problem

124
 Michael + Aldol = Robinson Annulation

Decarboxylation of Dicarbonyl Compounds

β-carbonyl acids will lose CO2, or “decarboxylate,” when heated…

H CO2
O O O O OH O O
C
R OH R O R R CH3
O

Recall... O O
HCl/H2O
R OMe R OH

Hydrolysis of a β-keto ester results in decarboxylation…

CO2
O O O O O
HCl/H2O
R OMe R OH R CH3

125
 Malonic Ester Synthesis: Alkylation of a Dicarbonyl
followed by Decarboxylation

" X O "
+
R H3C OH

O X O
Base
+
H3C OH R H3C O R

Malonic Ester Synthesis: Can be Used Iteratively to

Incorporate Two Electrophiles

126
Acetoacetic Ester Synthesis is Analogous to the Malonic Ester
Synthesis

O O O
2 H3C NaOCH3 H3C
OCH3 OCH3
CH3

Sample Problem

127
 Sample Problem

Biosynthesis of Polyketide Natural Products by Claisen

Condensations and Decarboxylations

O O O O O
AT
H3C SCoA -O S H3C S NADPH
Acyl Transferase
ACP ACP

acyl carrier protein Keto-

reductase KR

O OH O
DH NAD+
NADPH H3C S H3C S
Dehydrogenase
ACP ACP
Enoyl- ER
reductase
O

H3C S
NAD+
ACP

128
 Carbonyl Chemistry on One Slide

O O O
R1 R1 R1
R OMe R H R R N N
R
[H-] [O] R R R
[H-] [O]
R1
O OH OH R1O OR1

R OH R R R R R R R

OM

O Nu O R1 O O
Claisen
R Nu R X R R1
OM
OH Nu O OH O
R1 Aldol
R Nu R R R R1
R R
OM
O
Nu O Nu O
R1 1 Michael
R O
R R R R
R R

Sample Problem

129
 Sample Problem

The Diels-Alder Reaction

• Conjugated dienes react with alkenes in a process known as the Diels-Alder Reaction.
• The product is a substituted cyclohexene
• The mechanism is concerted and pericyclic (concerted = bond formation and bond breakage
occurs simultaneously in the same step)
• The hydroboration reaction is the other concerted, pericyclic reaction that we have seen
previously.

diene dienophile

1 1
2 CH2 6 2 6
CH2 ∆
3 CH2 CH2 3 5
4 5
4

3 π-bonds 1 π-bond
4 σ-bonds 6 σ-bonds

2 π-bonds were "traded" for 2 σ-bonds

∆= heat: in this case temperatures of 30-250 °C are generally necessary

130
 Molecular Orbitals of the DA Transition State

The Diels-Alder reaction is a [4π + 2π] cycloaddition

reaction.

Diene=
4π component

Dienophile=
2π component

The Diels Alder Reaction is Accelerated by Lowering the

LUMO of the Dienophile

LUMO

LUMO is lowered by the

electron-withdrawing group
Energy

(CO2Me)

lower ∆G(HOMO/LUMO) =
lower ∆G‡(reaction)
HOMO

ethene
H O
methyl
H OMe
acrylate
1,3- H
butadiene

Dienophiles with EWGs (electron withdrawing groups) are good dienophiles.

EWGs = cyano, ester, aldehyde, ketone, etc

131
 The Diels-Alder Reaction is a Stereospecific Syn Addition:
Dienophile Stereochemistry
O
H H
H CO2Me CO2Me
OMe ∆

H Me Me Me
H H
cis-dienophile cis Diels-Alder products
(Z-alkene) (enantiomers)

O
H H
H CO2Me CO2Me
OMe ∆

Me H H H
Me Me

trans-dienophile trans Diels-Alder

(E-alkene) products
(enantiomers)

Diene Stereochemistry/Syn Addition Transition States: Top Face or

Bottom face Addition gives Enantiomers

H
H
H MeO2C H
H CO2Me
H
MeO2C H H
Me H Me
H
H
Me H
H CO2Me H
H
H
H Me
H

H
MeO2C H MeO2C H
CO2Me
Me H H
H H
Me
H
H Me H
H H

132
 The Diels-Alder Reaction is a Syn Addition:
Diene Stereochemistry
Me Me Me
CO2Me
H CO2Me CO2Me
H
H
H CO2Me CO2Me
CO2Me
Me Me Me
E-E-diene cis Diels-Alder products
(enantiomers)

Me Me
Me CO2Me CO2Me CO2Me
H
H
Me CO2Me CO2Me
H CO2Me Me Me
H
trans Diels-Alder products
E-Z-diene (enantiomers)

Note: Alkynes can serve as dienophiles, but a double bond is produced, so no new
stereocenters are formed from the dienophile

The Diels Alder Reaction is Accelerated by Raising the

HOMO of the Diene

LUMO
Energy

HOMO is RAISED by adding an

Electron Donating Group (OMe)

HOMO
lower ∆G(HOMO/LUMO) =
lower ∆G‡(reaction)

ethene
H H
1-methoxy-1,3- H
butadiene
1,3- MeO H
butadiene H

133
 Regiochemistry of the Diels-Alder Reaction is Predicted by the
Substituents of the Diene and Dienophile

1. Draw out resonance contributors

OMe +
OMe OMe O -
O O
H H H H
H H + H OMe H H -
OMe OMe
H H H
H H H H H
- - H + H H + H
H H H

2. Match up charges (opposites attract) OMe O OMe

+ -
OMe CO2Me

OMe O - +
H H
H OMe
H H H OMe
H OMe
+
H X +
- X -
OMe
CO2Me
O

Diene Conformation: “s-cis” Required for the Diels-Alder Reaction

H H
H H
H H
H free rotation H Diels Alder Reaction
H H
H H
s-trans conformation s-cis conformation

NO Diels-Alder REACTION

diene is locked in s-trans conformation

(no free rotation around σ-bond)

FAST DIELS-ALDER REACTION

diene is locked in s-cis conformation

More s-cis conformer of diene results in a faster Diels-Alder reaction

134
The “Endo” Rule: Endo and Exo Transition States Produce the Endo
and Exo Diastereomers of Product

H
H H CO2Me "exo" (substituent of dienophile is
oriented away from double bond)
H
H CO2Me H
CO2Me
H Me H Me CO2Me
H H
O H
H H
H
H
OMe

H H
H
CO2Me
H
H H H
MeO2C H Me
H CO2Me
H H
MeO2C H
"endo" (substituent of dienophile
Me H
Me H is oriented toward double bond)
H
endo transition state, and thus
the endo product, is favored

Sample Problem
For the following three reaction, draw the DA product that results, including
RELATIVE stereochemistry. Circle the reaction that proceeds fastest.

CO2Me
+

CO2Me
+

CO2Me
O +

135
 Introduction to Pericyclic Reactions
1) Polar/Ionic Reactions: Heterolytic bond cleavage, formation of anionic or cationic
intermediates
O Aldol
O O OH
reaction
H3C H CH3 H3C CH3

2) Radical Reactions: Homolytic bond cleavage, formation of radical intermediates

H H H
H Cl
Cl 2Cl HCl + Cl
Cl H H H

3) Pericyclic Reactions: Cyclic transition structures where all bond-breaking and bond
forming occurs at the same time (in concert), reorganization of electrons in the reactants,
without formation of an intermediate

O H O
H H
BH2
O O H3C H3C BH2

O H O
Hydroboration
Diels- Alder reaction

transition
state Pericyclic Reactions
A concerted, single barrier,
one-transition state reaction

starting A B (intramolecular)
material(s) A + C B (intermolecular)
energy

product

progress of reaction

• Cyclic transition structures (therefore, SN2 is not a pericyclic reaction)

• Can be thermal or photochemical reactions

- A photochemical reaction takes place when a reactant absorbs light
- A thermal reaction takes place without the absorption of light
- In a thermal reaction the reactant is in its ground state; in a photochemical reaction,
the reactant is in its excited state

• Orbitals MUST have the same symmetry (be in-phase) to overlap and form products
(“conservation of orbital symmetry” theory)

• Can have suprafacial or antarafacial orbital interactions (bond formation or

rearrangements); always suprafacial for 6 atoms or less in transition state

136
 3 Types of Pericyclic Reactions

1) Cycloaddition Reaction

Usually intermolecular

diene dienophile
(Note: look for conjugated alkenes)

2) Electrocyclic Reaction

Always intramolecular

(Note: look for conjugated alkenes)

3) Sigmatropic Rearrangement

Always intramolecular

Molecular Orbitals: Thermal vs. Photochemical

(LUMO) (HOMO)

Thermal HOMO and

photochemical
HOMO are different!
(HOMO)

energy levels
(ground state) (excited)
thermal photochemical

• The normal electronic state of a molecule is known as its ground state

• The ground state electron can be promoted from its HOMO to its LUMO by
absorption of light (excited state)
• In a thermal reaction the reactant is in its ground state; in a photochemical
reaction, the reactant is in its excited state

137
 Molecular Orbitals of 1,3-Butadiene: Thermal vs. Photochemical

(LUMO)

(LUMO) (HOMO)

(HOMO)

The ground state HOMO

and the excited HOMO
have opposite symmetry

Pericyclic Type 1: Cycloaddition Reactions

Two π-bonds are converted into two σ-bonds and a new ring is formed
(usually intermolecular)

thermal
∆ reaction

forms new cyclohexene ring

photochemical
reaction (doesn’t
work with thermal
conditions)

forms new cyclobutane ring

[# + #] refers to the number of π-electrons in the cycloaddition reaction:

[4 + 2] = [4π + 2π] = 4π electrons + 2π electrons
[2 + 2] = [2π + 2π] = 2π electrons + 2π electrons

138
 Review of Diels Alder Reaction
(Bruice chapter 8: pages 313-321)

•Conjugated dienes react with alkenes (dienophiles) in a process known as the Diels
Alder Reaction. The product is a substituted cyclohexene
• The mechanism is concerted and pericyclic - proceeds through a cyclic transition state
• The reaction is stereospecific: stereochemistry of the starting materials is conserved in
the products

CH3
CH3
∆ CH3
+

dieneophile diene cyclohexene

transition state product
O O

H3CO ∆ H3CO
+
CH3 H3C
trans-dieneophile diene trans-cyclohexene
product

A dienophile with an electron-withdrawing group (carbonyl or CN), will make the

Diels-Alder reaction faster because the LUMO of the dienophile is lowered to have
better overlap with HOMO of the diene

Molecular Orbitals for [4 + 2] Cycloaddition (Diels-Alder)

Consider the HOMO and LUMO (frontier molecular orbitals) of both reactants:

(This orbital
interaction is Suprafacial bond formation =
most common) formation of both bonds on the
same face (side) of the π-system

You can consider EITHER combination of HOMO and LUMO interactions,

as long as the overlapping orbitals are in-phase

139
 Antarafacial vs. Suprafacial

• Only suprafacial orbital interactions

will occur if the transition state has six
or fewer atoms in the ring

Migrating group = C, H or other atoms

[2 +2] Cycloaddition Reactions

H3C CH3 H3C CH3

H3C CH3 Two π-bonds are
hv
+ H3C CH3 converted to two
σ-bonds

Must be a photochemical reaction for in-phase orbital overlap

[2+2] cycloaddition/dimerization reactions of your DNA:

DNA
photolyase

• Ultraviolet light (hv) can cause skin cancer by promoting thymine dimerization, a
structural modification of DNA that can lead to mutations
• DNA photolyase is an enzyme that repairs damaged DNA by reversing the [2+2]
cycloaddition reaction to regenerate the original thymine residues

Note: you will not be responsible for stereo- and regiochemistry for [2+2] cycloadditions

140
 MO Analysis of the [2 + 2] Cycloaddition Reaction

Orbitals are NOT in-phase = NO reaction

X

Orbitals ARE in-phase = cycloaddition

Pericyclic Type 2: Electrocyclic Reactions

• Electrocyclic reactions are reversible: ring closing or opening

• Look for conjugation in reagents and/or products
Ring closing:

An intramolecular reaction in which

a new σ bond is formed between the
ends of a conjugated π system to give
a cyclic ring product

Ring opening:

An intramolecular reaction in which a

σ bond of a ring breaks and a
conjugated π system is formed in an
acyclic product

141
 Electrocyclic Reactions: Conrotatory vs Disrotatory Ring Closure
The symmetry of the HOMO of the compounds undergoing ring closure determines
the stereochemical outcome of the electrocyclization.

HOMO (ground state)

H CH3
H Me Me H3C H
∆

HOMO (excited state)

H H
H3C CH3H
H Me Me

The ground state HOMO is symmetric, so disrotatory closure occurs

The excited state HOMO is asymmetric, so conrotatory closure occurs

Woodward-Hoffman Rules Relate the Number of π-Bonds

to the Mode of Cyclization

For systems with an EVEN # of π-bonds, the ground state undergoes conrotatory closure

Me
Me ∆

Fortunately, a set of selection rules prevents the need to draw out the HOMO for
each specific case: These are known as the Woodward-Hoffman Rules

142
 Pericyclic Type 3: [m,n] Sigmatropic Rearrangements

4 4 (note: do not worry

a [1,5] sigmatropic rearrangement
(a 1,5-hydrogen shift)
3 5 3 about the 1,3 shifts in
5
the book or previous
lecture note copy, the
2
1 2 book has an error and
the 1,3-shifts are less
1 useful so we will not
discuss them.)

2 2
1 3 1 3

1 3 1 3
2 2

Suprafacial rearrangement =
migrating group remains on the
same face (side) of the π-system

• Sigmatropic rearrangements have cyclic

transition states
• Rearrangement must be suprafacial if the
transition state has six or fewer atoms in the ring

[3,3] sigmatropic reactions

Count Carbons:
1) Count Carbons (1,2,3-3,2,1) in
the starting material to see where
alkenes will shift, and what the
product will look like

2) Count carbons in the product

(1,2,3,4,5) to help identify IF a [3,3]
sigmatropic rearrangment can be
used to synthesize the product

What is the driving force for these rearrangements?

More substituted double bonds in Cope rearrangement (usually)
Stronger bonds formed (C=O vs. C=C) in Claisen rearrangement

143
 Ireland-Claisen Rearrangement
General Claisen reaction forms an alkene and an aldehyde:

Ireland-Claisen rearrangement forms an alkene and a carboxylic acid:

O O

H3C O CH3 CH3 1. LDA

OH
HO acetylation of O O 2. H3O+
alcohol with workup O
acetic anhydride Ireland-Claisen
forms ester Rearrangement

Mechanism:
O O O
Claisen OH
Rearrangement H3O+
O CH3 LDA O CH2 workup
O O
enolate
formation

[1, n] Hydrogen Shifts (H starts at C-1 and

ends up on C-n)

4 4
1,5-hydrogen shift 5 5
3 3

2 2
1
1 One C–H σ bond
broken, one C–H
σ bond formed

1,7-hydrogen shift 3 2 3 2
1 4
4 1

5 5

6 7 6 7

144
 Vitamin D Synthesis

Sunlight (hv) converts a cholesterol steroid to vitamin D using two

pericyclic reactions:

(Precursor to vitamin D)

Summary: How to Identify Different Pericyclic

Reactions
Are two molecules coming together to form a new ring?
That’s a cycloaddition

Is a ring opening or closing in an intramolecular fashion?

That’s an electrocyclic process

Is something shifting from one point in the molecule to another? Sometimes

products do not look like starting materials?
That’s a sigmatropic rearrangement (Hardest to identify - count carbons)

- Be able to identify different pericylic reaction types, (especially specific [1,5] and
[3,3] sigmatropic rearrangments)
- Know thermal vs. photochemical HOMO
- Be able to provide products from given starting materials
- you do NOT need to know how to draw the cyclic transition state, but you should
be familiar with the mechanistic details of the process

Vocabulary: Concerted, Pericyclic, Electrocyclic, Suprafacial , Antarafacial

Conservation of orbital symmetry

145
 Sample Problems

1. a) What kind of pericyclic reaction is this?

120°C
b) What is the driving force of this reaction?

2. a) What is the product of this reaction?

b) Describe, as specifically as possible, what type pf pericyclic reaction this is.

O 170°C

H3C CH3

3. Provide products and indicate what type of pericyclic reaction occurs.

O
170°C CH2 hv
+ O
CH2

Introduction to Carbohydrates: Polyfunctional Compounds

general molecular formula = Cn(H2O)n

Carbohydrates (saccharides) are named based on their molecular formula,
which make them appear to be “hydrates of carbon”

Monosaccharide: the simplest carbohydrate unit or “single sugar”, classified by its

number of carbons (trioses, tetroses, pentoses and hexoses)
α- and β-notations: relative stereochemical designation at the anomeric center
D- or L-notations: the stereochemical designations for the configuration of a
sugar, based on glyceraldehyde (instead of R- and S-designations)
Reducing Sugars: have an aldehyde or hemiacetal group that can be oxidized

146
 Classification by Carbonyl Type and # of Carbons

Aldoses: polyhydroxy aldehydes (an aldehyde sugar)

Ketoses: polyhydroxy ketones (a ketone sugar)
# of Carbons: triose, tetrose, pentose, and hexose

1
CHO
2
CHOH
3
CH2OH
an aldotriose

Nomenclature and Structure: Glyceraldehyde H OH

OH
Glyceraldehyde (an aldotriose) has a single stereogenic center and can exist in two
enantiomeric forms:

Fischer projections:
Horizontal lines are taken as
H O CHO coming forward and vertical
D-notation:
H OH hydroxy is on lines are going backward
H
CH2OH CH2OH the right side
HO
(R)-glyceraldehyde D-glyceraldehyde
(Fischer projection)

H O CHO
HO H
L-notation:
H
CH2OH hydroxy is on
HO CH2OH
the left side
(S)-glyceraldehyde L-glyceraldehyde
(Fischer projection)

Note: “CHO” is a common shorthand for drawing an aldehyde group

147
 Nomenclature and Structure: Enantiomers and Epimers
• Same D- and L-notation for aldoses with more carbons - look at lowest OH group
• Aldehyde group is always written at the top of the fischer projection and the
primary alcohol is at the bottom.

enantiomers

“D-series” “L-series”
of sugars of sugars

Epimers = diastereomers that differ in configuration at only one stereogenic

carbon center; epimers are NOT enantiomers (C-1 epimers are called anomers)

Hydroxy-Aldehydes Form Cyclic Hemiacetals

Intramolecular 5- and 6-membered ring (cyclic) hemiacetals are easily

formed, and are usually more stable than the open (acyclic) form.

a “pyran” ring a new stereocenter

H is formed in the
H H 2O O hemiacetal product
OH
HO O
hydroxy-aldehyde cyclic hemiacetal
Cyclic product is the
(open form) (favored) predominant form

H 2O
O OH
H H
H H 2O H derived from derived from
O O the alcohol the aldehyde
O OH

Equilibrium exists in aqueous solution, or with catalytic acid

148
 The Hemiacetal (cyclic) Form Predominates with Aldoses

β-glucose is favored because the anomeric

OH is in an equatorial position beta = hydroxy up, equatorial
OH
(more favored)
O
CHO HO β-D-glucopyranose
HO OH
H OH OH OH
H
HO H
HO
OH β−D-glucose
H OH HO O (64%)
H OH OH anomeric center at C1
H OH
CH2OH (0.02%)
D-glucose O
HO H
open/acyclic form HO
OH α-D-glucopyranose
OH
α-D-glucose alpha = hydroxy down, axial
(36%) (more steric strain)

The new chiral stereocenter of a hemiacetal is called the anomeric center (carbon-1).
Therefore, the two resulting α- and β-stereoisomers are called anomers
(anomers are specifically a C-1 epimers at an hemiacetal or acetal center)
Equilibrium (open-close-open) between the two anomers is called mutarotation - this
is NOT simply a chair flip - acetals can NOT mutarotate, only hemiacetals
Ketoses also exist predominantly in cyclic forms

Same Structures, Different Representations:

How to Draw Cyclic Monosaccharides

• hemiacetal (cyclic)
form is predominant

• β-anomer is more
favored

(α-D-glucopyranose) (β-D-glucopyranose)

• Six-membered rings are called pyranoses

• Five-membered rings are called furanoses

149
 Anomeric Effect

HO mutarotation HO If the α-anomer (axial) is

O O
HO H HO OH disfavored because of
HO HO
OH OH steric interactions, why do
OH H we even see any of it??
α-anomer, β-anomer,
OH axial (34%) OH equatorial (64%)

We see even more α-anomer (axial) for more electron withdrawing groups:
increasing
e- withdrawing
X %axial ability
HO HO
HO O O
HO H HO
HO X OH 34
OH OH OMe 67
X H OAc 86
Cl 94

Reason? Although an equitorial position is favored for steric reasons,

the axial position is favored for molecular orbital reasons

Anomeric Effect: Molecular Orbitals

axial lone pair

equatorial lone pair

O O
H X
good overlap between X no overlap
σ* C-X H
axial lone pair of O and with equatorial
axial σ* C-X bond C-X bond!

Look at σ* C–X bond in H X σ* C–X

Newman projections:
must have antiperiplanar X H
orientation between lone σ* C–X No overlap!!
pair and σ* C–X bond good overlap!!

• The lone pair of oxygen stabilizes the axial anomer through donation of electron
density into the empty anti bonding orbital (σ* C-X)
• This effect is strongest for the most electronegative substituents (X) because
there is better overlap between the orbitals
(This alignment is similar to the conformation that is necessary for E2 elimination)

150
 Reactions of Carbohydrates: Reductions
Reduction of a cyclic hemiacetal proceeds through a small amount of open (acyclic)
form. As long as an equilibrium exists between the cyclic and acylic form, the reduction
will take place and more open form will be regenerated until the reaction is complete

Reduction of an aldose:
CHO CH2OH
OH OH
H OH H OH
O OH HO H 1. NaBH4
HO HO HO H
HO OH HO O H OH
OH 2. H2O H OH
OH
H H H OH H OH
β−D-glucose (0.02%)
CH2OH CH2OH
D-glucitol
Reduction of a ketose:
CH2OH CH2OH CH2OH
HO O H OH HO H
CH2OH
O HO H NaBH4 HO H HO H
HO +
H OH H OH H OH
H OH
HO H OH H OH H OH
CH2OH CH2OH
α-D-fructofuranose CH2OH
D-glucitol D-mannitol
open chain
ketone A mixture of sugar alcohols (alditols)

More Reductions of Carbohydrates

(H2/Ni can
also be used)

CHO CH3
H OH H OH
H2NNH2 Reduces the aldehyde
HO H HO H group all the way to a
H OH NaOH, heat H OH methyl group
H OH H OH
CH2OH CH2OH

Wolff-Kishner reduction (via hydrazone)

151
 Oxidations of Carbohydrates

Oxidation to gluconic acids:

Only the aldehyde

will be oxidized

This method will NOT

oxidize an alcohol or a
ketose, therefore, it is a
useful test to distinguish
between aldoses and
ketoses
Oxidation to glucaric acids:

BOTH the aldehyde AND

the primary alcohol will be
oxidized with HNO3

Oxidations of Carbohydrates: Reducing Sugars

A sugar with an aldehyde, a hemiacetal, a ketone or a hemiketal group is
considered a reducing sugar and can be oxidized. Hemiacetals and
hemiketals MUST be in equilibrium with the open form for oxidation.
Benedict’s and Tollen’s reagent will oxidize BOTH aldoses and ketoses, therefore,
they are good tests for reducing sugars

Oxidation to gluconic acids: Benedict’s reagents = Na2CO3,

CuSO4, and sodium citrate
Cu(OH)2
+ Cu2O
(Benedict’s
A red solid
solution)
Look for color change or
mirror to show proof of an
aldehyde (a positive test).
these will NOT oxidize the
1. Ag2O, NH3 primary alcohol
2. H3O+ workup + Ago
Silver mirror
(Tollen’s test)

Tollen’s reagent = Ag(NH3)2+ -OH

152
 Base-Catalyzed Enediol Rearrangments

How is a ketose a reducing sugar? How can a ketone be oxidized?

In a basic solution, ketoses are converted into aldoses (an enediol

rearrangement).

This rearrangement explains why a ketose (and a hemiketal) can be a reducing

sugar - the ketose can still provide an aldehyde for oxidation.

The conditions for the Benedict’s and Tollen’s test are basic enough to
promote the endiol rearrangement.

Enediol Rearrangement Mechanism

A “must know” mechanism

153
 Base-Catalyzed Epimerization of an Aldose

This is known as the “Lobry de Bruijin-Alberda van Ekenstein reaction”

resonance stabilized enolate

Deprotonation of the alpha-proton will give an achiral enolate. Now,
reprotonation can occur from either face to give a mixture of epimers.

(must know mechanism)

Reactions of Carbohydrates: Alcohols

The OH groups of monosaccharides show the chemistry of typical alcohols.

For example, the OH groups can be acylated or alkylated:

Ester formation: acylation with acetic anhydride

Ether formation: alkylation with an alkyl iodide and Ag2O

Ag2O is a milder method to alkylate instead of using a base (NaH) to deprotonate the OH.
Ag2O associates with the iodide to make the CH3I a better electrophile.

154
 Kiliani-Fischer Synthesis
The carbon chain of an aldose can be increased
by one carbon in a Kiliani–Fischer synthesis

Addition of the cyano group is not selective

and it will make two epimers. This means that
a mixture of aldose products will result in this
synthesis

O- and N-Glycoside Formation

A glycoside is an acetal or ketal, which do not equilibrate with the open form.
Therefore, glycosides cannot be oxidized and they are NON-reducing sugars

Acetal (O-glycoside) formation with glucose and ethanol:

Reducing sugar NON-Reducing sugars

N-glycoside formation with ribofuranose and phenylamine:

A mixture of α- and β-
glycosides will form

155
 Mechanism of Glycoside Formation

Step 1: Protonation of
anomeric OH at C-1

Step 2: Elimination of water

to form oxygen-stabilized
cation (electrophile)

Step 3: Nucleophile (O, N

or other) can attack from
either the top or the
bottom face.

Step 4: Deprotonation

A mixture of anomers will

be produced - acetals DO
NOT mutarotate
A “must know” mechanism

O-Glycoside Formation to make a Disaccharide

A disaccharide is composed of two monosaccharide subunits hooked together by an
acetal linkage
OH α-1,4'-glycosidic linkage
OH 6
4
4 6 5 O
5 O H+ HO
HO 1 OH
HO 2 H
1 6'
HO 2 H 3 OH 4'
3 OH 5' O
O
1'
α-D-glucose HO HO 2' H
3' OH
(two equivalents)
HO
β-1,4’-glycosidic linkage
OH OH OH
HO HO 6 OH
4 6
O 5 O H+ 4 5 O
+ HO 4 6
1
1
5 O
HO OH HO 2 OH HO O
2 1
OH 3 OH 3 OH HO 2 OH
H H H 3 OH
β-D-galactose β-D-glucose H
(a C-4 epimer of glucose) lactose

1,2’- and 1,6’-glycosidic linkages are also possible

If a disaccharide glycoside still has an end with a hemiacetal group, then it is
still a reducing sugar - both maltose and lactose are reducing sugars.

156
 Polysaccharides: Biopolymers

Amylose (a linear structure)

is a component of starch

Amylopectin is another polysaccharide component of starch that has a branched structure

Carbohydrate Summary

• Sugars (carbohydrates) are polyfunctional compounds that have similar reactivity to

their alcohol, aldehyde and ketone components (such as reductions, oxidations,
acetal reactions, ether and ester formation)
• Reducing Sugars (aldoses and ketoses) are hemiacetals (since they exist
predominantly in their cyclic form) and can mutarotate
• Non-reducing sugars (glycosides) are acetals (which do not equilibrate with an open
chain form) and they do not mutarotate
• Tollens’s and Bendedict’s test will distinguish between a reducing and non-reducing
sugar. The Br2/H2O oxidation will distinguish between aldoses and ketoses.

1) Be able to draw the cyclic hemiacetal form from a Fischer projection

2) Be able to identify and draw anomers and epimers; identify D- and L-sugars
3) Be able to fill-in products or reagents for a given reaction
4) Mechanisms you need to know: hemiacetal formation, mutarotation, enediol
rearrangement, epimerization and glycoside formation
5) Know molecular orbital interactions for anomeric effect

Vocabulary: Epimers, Anomers, Anomeric center, Ketose, Aldose, Mutarotation, D- and

L-notations, alpha- and beta-notations, glycosides, glycosidic linkage

157
 Summary of Reducing and Non-reducing Sugars

(Reducing gives positive test with Tollen’s or Benedict’s reagent)

Reducing sugars:
Look for an aldehyde, hemi-acetal, ketone or hemiketal. Hemiketal MUST be able to access
the open form for enediol rearrangement of the ketone to an aldehyde
OH
HO OH
CH2OH O
O HO
HO O
HO HO H OH
H HO OH OH
OH OH O
O
HO H HO OH
α-D-fructofuranose β−D-glucose maltose
OH
H
If a disaccharide glycoside still has a
hemiacetal, then it is still a reducing sugar
Non-Reducing sugars:
Alcohols and acetals are non-reducing and ketals cannot access the open form for enediol
rearrangement of the ketone to an aldehyde.
CH2OH
OH HO CH2OH H OH
O
O HO HO H
HO
HO OCH3 H OCH2CH3
OH H OH
H HO
H OH
methyl β−D-glucopyranoside ethyl α-D-fructofuranoside
CH2OH
All monosaccharide glycosides are NON-reducing sugars Sucrose D-glucitol

Amino Acids, Peptides, and Proteins

α-amino acid residue
(amino acid -H2O)

O R O R
H
H2N α N OH
OH H2N N
H
R O R O
α-amino acid oligo/poly-peptide:
(prominant in nature) amino acids linked
by amide bonds

H2N O

R β α OH
β-amino acid
(uncommon in nature,
studied by synthetic chemists)

protein
(large peptide)

158
 Amino Acids are Chiral and Charged

O
Most amino acids have one stereocenter
H2N
OH All “natural” amino acids are L-configuration,
R most have the absolute configuration S

Amino acids have at least one basic and one acidic functional group, so as a
result they are always charged...positively at low pH (in acid) and negatively at
high pH (in base). At neutral pH, amino acids are net neutral, with one negative
and one positive charge (zwitterionic)

net charge = +1 net charge = +0 net charge = -1

Amino Acids 1: Hydrocarbon, Alcohol, Thiol, Acid and

Amide side chains

O O O O O
H2N H2N H2N H2N H2N
OH OH OH OH OH
CH3 H3C H3C
H3C CH3 CH3
glycine alanine valine CH3 leucine isoleucine
(Gly/G) (Ala/A) (Val/V) (Leu/L) (Ile/I)

O O O O
H2N H2N H2N H2N
OH OH OH OH
S
HO HO CH3 HS H3C
serine threonine cysteine methionine
(Ser/S) (Thr/T) (Cys/C) (Met/M)

O O O O
H2N H2N H2N H2N
OH OH OH OH
HO H2N

O O
HO O H2N O
aspartic acid glutamic acid asparagine Glutamine
(Asp/D) (Glu/E) (Asn/N)) (Gln/Q)

159
 Amino Acids 2: Basic, Aromatic, and Heterocyclic
Sidechains

O O O O
H2N H2N H2N H2N
OH OH OH OH

HN HO
H2N
H2N NH phenylalanine tyrosine
lysine arginine (Phe/F) (Tyr/Y)
(Lys/K) (Arg/R)

O O
H O H2N H2N
OH OH
N
OH
N HN
NH

proline histidine tryptophan

(Pro/P) (His/H) (trp/W)

The Acid-Base Properties of Amino Acids are

Important in Many Circumstances

160
 The Isoelectric Point (pI)

• When the AA has no ionizable

sidechain (no acidic or basic groups)
the pI is calculated by averaging the
pKas of the amino and acid groups.

• In the case of alanine, when the pH

is below 2.34, both groups are
mostly protonated. When the pH is
above 9.69, both groups are largely
deprotonated.

The Isoelectric Point (pI)

161
 Isoelectric Point (pI) for Amino Acids with
Ionizable Sidechains

For groups with ionizable sidechains, the pI is the point at which the two groups
with similar pKas share one charge, which is then balanced with the charge of
the third group.
For lysine (basic side chain), at pH 9.87, the two amino groups are 50%
protonated [2 x (+0.5)], and the carboxylic acid is 100% deprotonated (-1), so the
net charge is 0.

For glutamic acid (acidic side chain), at pH 3.22, the two carboxylic acid groups
are 50% deprotonated [2 x (-0.5)], and the amino group is 100% protonated (+1),
so the net charge is 0.

Electrophoresis Separates Amino Acids and

Peptides Based on their pI Values
Amino acids will migrate toward electrodes when applied to a stationary surface that
is held at constant pH with a buffer. Amino acids with pIs higher than the buffer pH
migrate toward the cathode (- electrode), and amino acids with pIs lower than the
buffer pH move toward the anode (+ electrode).
The bigger the difference between pI and pH, the faster the amino acids will migrate.

A few drops of a mixture of

amino acids was placed here

Arginine, alanine, and aspartic acid separated by electrophoresis at pH 5.

162
 Amino Acids are visualized in Electrophoresis with Ninhydrin

Ninhydrin is also a useful stain for distinguishing primary (purple), secondary

(yellow), and tertiary (no color) amines in TLC experiments

Analysis of Amino Acids and Peptides

By Ion Exchange Chromatography
•Charged resins are used to separate amino acids based on charge, in analogy to
silica gel chromatography separating organic molecules based on polarity
•Cation exhange resin (eg Dowex 50, shown below) has a negatively charged
group bound to the resin and an “exchangeable” cation (Na+).
•Anionic amino acids and peptides (low pI) flow through quickly, while cationic
amino acids and peptides (high pI) flow through slowly.

163
Automated Ion Exchange Chromatography: Determination of Relative
Amounts of Individual Amino Acids

Analysis of Amino Acid Content is Useful for Structure Determination

(based on the known structures of these amino acids)

A typical chromatogram obtained from the separation of amino acids using an

automated amino acid analyzer.

Determination of the Structure of Peptide Natural Products

O H O O
H2N N H2N
OH OH OH
CH3
HO CH3 2 proline
threonine (Pro/P) alanine
(Thr/T) (Ala/A)
Hydrolysis
O O
(6N HCl/reflux) H2N H2N
OH OH

HO HN
2 tyrosine arginine
(Tyr/Y)
H2N NH (Arg/R)

O
O
H2N
OH H2N
OH
HO
OR H2N

Cyclonellin D O
O
aspartic acid asparagine
(a cyclic peptide (Asp/D) (Asn/N))
natural product)
Readout from Amino Acid Analyzer

164
 Synthesis of Amines: Reduction of Amides

H H
H primary amines
O R N
(R1=R2=H)
H
R OH

SOCl2
H
O N O H H
R2 LiAlH4
1
R R2 R2 secondary amines
R Cl R N R N (R1=H)
Et3N H
R1

H H
R2 tertiary amines
R N
R1

Ammonia Cannot be used to Synthesize Amines

from Alkyl Halides

NH3 H3C Br
H3C Br H3C NH2 H3C NH
(n-BuBr)
H3C
Br-
+
H3C N CH3 H3C N CH3

H3C CH3 H3C

O O O
phthalimide; an "NH3" synthon,
R NH2 R N R
or synthetic equivalent H
amide imide

O
1) KOH
2) n-BuBr
NH H3C NH2
1) H+/H2O
2) NaOH
O

165
 The Gabriel Amine Synthesis of Primary Amines

Synthesis of Primary Amines with Azide and Cyanide

Azide is also an NH3 Synthon (replaces Br with NH2)…

NaN3 H2; Pd/C

H3C Br H3C N3 H3C NH2

Cyanide is a CH2NH2 Synthon (replaces Br with CH2NH2)…

NaCN H2; Pd/C NH2

H3C Br H3C H3C
N

166
Reductive Amination: Conversion of Aldehydes and Ketones
to Amines
O H
NaHB(OAc)3 N CH3
H + H2N CH3

"H-"
N CH3

imine intermediate

NaHB(OAc)3 CH3
+ H3C N CH3
N
H CH3

H3C N CH3 "H-"

enamine intermediate

Synthesis of Amino Acids: From Acids and α-Keto Acids

O O O
1) Br2/PBr3 NH3
OH OH O-
2) H2O Br NH3+

(+/-)-phenylalanine

O O O
NH3 H2; Pd/C
OH OH O-
O NH NH3+

(+/-)-phenylalanine

Note: these syntheses will give racemic products

167
Synthesis of Amino Acids 2: From Aldehydes…The
Strecker Reaction

O
H 1) NH3/HCN
O-
O 2) H+/H2O NH3+

Imine (+/-)-phenylalanine
NH3
formation
H H+/H2O

N H N
H
H-CN
N
H H H
-CN
N+
H H
Nucleophilic
addition

Synthesis of Amino Acids 3: Amino Malonic Ester

Alkylation
O O O
1) KOEt/BnBr
EtO OEt O-
O N 2)H+/H2O NH3+ CO2
O
(+/-)-phenylalanine

O O

HO OEt
KOEt H2N Ph
Br
O OK EtOH
O O
EtO OEt O O
EtO OEt
O N O H+/H2O
O N Ph EtO OEt
O Ph
H2N

phthalic acid

168
 Preparation of Enantiomerically Pure Amino Acids:
Kinetic Resolution
•All of the amino acid syntheses discussed are racemic, but generally, enantiomerically
pure amino acids are desired.
•While they can sometimes be resolved (Bruice 5.14), or prepared using a chiral auxilliary
, a kinetic resolution can also be effective.
•A kinetic resolution is a reaction in which a catalyst (synthetic or enzyme) reacts more
quickly with one enantiomer than the other. Unlike a normal resolution, where a full
equivalent of a chiral reagent is required, a kinetic resolution uses only a small amount of
catalyst or enzyme.

Peptide Bond Synthesis: Regiochemical Problem

Normally, making amides from acids and amines is easy…

O O R2 O
SOCl2 H2N
1 1 1
R2
R OH R Cl Et3N R N
H

Since amino acids are bifunctional, there is a problem with regiochemistry…

which amine group reacts with which acid?

169
 Peptide Synthesis Step 1: N-Protection

One standard protecting group for peptide synthesis is the t-butoxy carbonyl
group, also called a t-Boc or Boc group:

Peptide Synthesis Step 2: C-Activation

The imidate intermediate is an

activated ester “equivalent,” similar
to an acid chloride, but produced
under milder, more selective
conditions

170
 Peptide Synthesis Step 3: Amide bond Formation

Peptide Coupling Agents Accomplish a Net Dehydration

O H O O CH3
BocNH N BocNH OH + H2O
OH H OH N
H
CH3 CH3 CH3 O

N O
C
N + H2O N N
H H

DCC is one of many different coupling reagents, but in all cases they work
by basically the same mechanism…activation of the carboxylic acid so that
a nucleophilic acyl substitution can take place. In all cases, the peptide
coupling agents produce a product that results from the addition of one
equivalent of water.

171
 Peptide Coupling Reactions Can Be Repeated to Make
Long Chains

Peptide Couplings Are NOT Well-Suited to Large Peptide

Synthesis
Problems with peptide synthesis:
• Low yields from incomplete reactions
•Difficult separation of product, unreacted starting materials, and DCU
•Difficulty of purification. Chromatography is difficult with very polar molecules and
crystallization is limited to large scale
Bruce Merrifield received the Nobel Prize for solving all of these problems with a new
synthetic technique known as “solid phase synthesis” which is still widely used today.

The first step involves attaching the first amino acid to the resin:

172
 Solid Phase Peptide Synthesis

In the next step, the N-protecting group is removed, and the amine is coupled to a
protected amino acid.

reaction
Solution
resin beads
(90 µM)

fritted glass
filter
stopcock

The incoming acid and DCC can

be used in gross excess to ensure
complete reaction;
The excess acid, and DCU are
washed away!

Primary Structure of Peptides: Sequence

Determination by Edman Degradation

Edman degradation removes one amino

acid residue from the N-terminus

R O
R' H O
R O H
+
S + N
H+ N H3N+
H H
N
N N O R''
H H
S peptide without the original
thiazolinone N-terminal amino acid
PTH-amino acid
derivative
The Edman degradation can be performed a maximum of 50 times, so it is suitable
only for short peptides

173
 Longer Peptides are Sequenced by Partial Hydrolysis

Dilute acid is used to perform a random partial hydrolysis, but various reagents and
enzymes can used to perform site-specific cleavage reactions:

Partial Hydrolyses Lead to Fragments Which are Lined

up to Determine the Complete Structure

Ala-Lys-Phe-Gly-Asp-Trp-Ser-Arg-Met-Val-Arg-Tyr-Leu-His

Trypsin: Ala-Lys Phe-Gly-Asp-Trp-Ser-Arg Met-Val-Arg Tyr-Leu-His

Chymotrypsin: Ala-Lys-Phe Gly-Asp-Trp Ser-Arg-Met-Val-Arg-Tyr Leu-His

Elastase: Ala Lys-Phe-Gly Asp-Trp-Ser-Arg-Met-Val-Arg-Tyr-Leu-His

Cyanogen
Bromide: Ala-Lys-Phe-Gly-Asp-Trp-Ser-Arg-Met Val-Arg-Tyr-Leu-His

Modern peptide sequencing is largely done by Mass Spectroscopy. New

advances in MS have fueled many discoveries in Proteomics, or the study of
the protein products of gene expression.

174
Secondary Structure of Proteins: Amide Bond Rotation

The peptide chains that make up proteins might look like they are very
flexible, but in reality many factors contribute to their rigid structure

Cysteine Residues Form Disulfide Bonds

(Br2)

175
 Disulfide Bonds Contribute to Secondary Structure

Hydrogen Bonding is an Important Secondary Structural

Element: The α-Helix

176
Hydrogen Bonding is an Important Secondary Structural
Element : The β-Pleated Sheet

Coil/Loop Conformation: >50% of Most Globular

Peptide Secondary Structure

177
Tertiary Structure: The 3-D Structure That results From
the Composition of various Secondary Structural
Elements

Summary of Protein Structure

178
 Enzyme Active Site

Nucleic Acids Make up DNA and RNA

A nucleic acid is a polymer

of ribofuranoside rings,
phosphate ester groups
and nucleobases

NH2
7 6
N 5 N1
8
2
N 4 N
5' 9
a ribose- HO O
3

phosphate 4' 1'

backbone 3' 2'

OH

A nucleoside

179
 Ribofuranoside Rings from Ribose

nitrogen base
CHO R R
HO R R HO
H OH OH N N
O O
H
H OH
H glycosidic H H
H OH H
HO OH bond formation
HO OH
CH2OH
β-D-ribofuranose a ribonucleotide
D-ribose

nitrogen base
CHO R R
HO R R HO
H H OH N N
O O
H
H OH
H glycosidic H H
H OH H
HO bond formation
HO
CH2OH
β-D-2-deoxyribofuranose a deoxyribonucleotide
D-2-deoxyribose

Phosphoester and Nucleobase Structures

180
 Aromatic Amines and Basicity: 6-membered Rings
piperidine

+ H+
pyridine pKa=11.2
N+ N
H H H sp3
+ H+
+
N N morpholine
H sp2 O O
pKa 5.2 + H+
+
N N pKa=9.3
H H H

The lone pair of pyridine is NOT part of the π-system of

N the aromatic ring. The nitrogen is sp2 hybridized, and therefore less
basic. Basicity = piperidine > morpholine > pyridine

nb: do not confuse acidity, basicity, low pKa, and stability of the conjugate
base…they are all ways of asking the same question!
Whenever ranking acidity or basicity, consider 4 effects: aromaticity,
resonance, hybridization, and induction (EWGs).

Nitrogen Atoms are Electron-Withdrawing in an

Aromatic Ring

pyridine pyrimidine
N
+
N N+
H 2
sp H sp2
pKa 5.2 1.0

Pyrimidine is significantly less basic

than pyridine due to the electron
withdrawing effect of the added nitrogen

181
 Aromatic Amines and Basicity: 5-Membered Rings
Recall: EAS of 5-membered heterocycles (E+ = H+)

H
+ H+ + H+
N H N+ N N+ N
H+ H H 2 H H
H sp H sp2
pKa -3.8 11.3

The lone pair of pyrrole IS part of the π-system of

N H the aromatic ring. Protonation destroys aromaticity,
and is therefore highly disfavored.

pyrrole pyrrolidine

N N DEprotonation of pyrrole to
sp3
H sp2 H form an anion is facile. The
resultant anion is very stable.
pKa 17 36

Imidazole is Aromatic, and Behaves like a

hybrid of Pyridine AND Pyrrole

pyridinium protonated protonated

pyrrole imidazole H
N N+
Aromaticity
+
N N+ N+ N Retained
H H H H H H
pKa = 5.16 pKa = -3.8 pKa = 6.8

pyrrole imidazole Imidazole can serve as a weak

N acid or as a moderate
base/nucleophile. It is
N N responsible for many important
H biological functions.
H
pKa = 17 pKa = 14.4 O
H2N
OH
histidine
N (His/H)

NH

182
 The Nucleosides of RNA and DNA

Nucleoside = ribofuranoside + nucleobase

NucleoTIDE = Nucleobase + Ribofuranoside +

Phosphate

183
 Monomeric Nucleotides are Important Biological
Molecules

The Phosphate Linkage is Reactive…Kind of Like

an Anhydride
O
OH -O P O
O
O -O
HO HO P O-
O + H2O ∆G = + 3.3
HO HO
-O HO kcal/mol
OH
OH OH
OH
Not a favorable reaction

O O O
P P P A O O
-O O O O
O P P ∆G = - 7.3
-O -O -O A O
+ H2O O O O kcal/mol
-O -O O
OH + HO P O-
-O
ATP OH
ADP

Reaction becomes O
favorable: OH
O -O P O
HO -O ∆G = - 4.0
HO + ATP O + ADP kcal/mol
OH HO
OH HO
OH
OH

184
 ATP is Thermodynamically Unstable (reactive), but
KINETICALLY Quite Stable (UNreactive)

Enzymes are necessary for the phosphoryl transfer reactions of ATP

Without ATP, No Phosphorylation Would Take Place

This phenomenon is reminiscent of alcohol activation by conversion to a

tosylate…you must have a good leaving group!

Nu: R OH x OH- R Nu

TsCl/ Unstable leaving group

Pyr

Nu: TsO- R Nu
R OTs

Stable leaving group

185
 ATP’s Function in Biosynthesis

The following reaction is impossible in the absence of ATP…

Activation with ATP allows thioester formation to take place

Kinases are an Important Class of Enzymes that

Mediate Phosphoryl Transfer Reactions

Kinase +
P
ATP

Inactive Protein Active Protein

Amino acids with alcohol groups in their side-chains are subject to

phosphorylation by kinases…
O O O
H2N H2N H2N
OH OH OH
HO HO CH3
serine threonine
(Ser/S) (Thr/T) HO

tyrosine
(Tyr/Y)

186
 Inhibition of Kinases Could lead to Cures for Many
Diseases, including some kinds of Cancer

Molecules that “look”

like ATP can occupy the
binding site and prevent
phosphorylation

The problem is
specificity: all
kinases (and many
other enzymes) have
ATP binding sites, so
most kinase inhibitors
are non-specific

GleevecTM (Novartis) is the one of the first SPECIFIC

Kinase Inhibitors Approved for the Treatment of Cancer

187
Several Other Nucleotides Play Important Biological Roles

Oligomerization of Nucleotide Triphosphates gives DNA

188
 Hydrogen Bonding of Nucleobases

N O N OH N NH N NH2
H H
keto enol imine amine

H-Bond d a
H H H H a
donor, d N N N
X a Hd a
N N N
H
a a d
N O N O N OH
B R R R
H-Bond cytosine
acceptor, a

Keto-enol and imine-amine tautomerization of the nucleobase

determines the type of hydrogen-bonding that can occur

Base Pairing in DNA Occurs through Hydrogen Bonding

189
Complimentary Strands are Anti-parallel; π-Stacking
Interactions are Important

The attractive force between two proximal

aromatic rings is referred to as "π-stacking"

The Double Helical Structure of DNA

190
 DNA Structural Unit: Chromatin
Histones combine with DNA to form nucleosomes,
the fundamental structural units of chromatin. All of
this points to the conclusion that chromatin in intact
nuclei is highly dynamic, with different folding
conformations that reflect its activity.

(Figure from Biology: Concepts and Connections by

Campell, Mitchell, and Reece. Text from Introduction
to Cell and Molecular Biology by Stephen L. Wolfe)

How Can Drugs React with DNA if it is Packed in a Nucleosome?

1) Outer surface of DNA is still

accessible to small molecules

2) Nucleosomes are in dynamic

equilibrium with uncoiled DNA so that the
drug can bind after uncoiling, which also
interferes with the binding of the DNA to
the histone

3 Types of DNA binders:

1) Reversible DNA binders
- External electrostatic binding
- Groove binding
- Intercalation
2) Irreversible covalent reactions with DNA binders by Alkylation
3) Irreversible DNA strand breakers by radical reactions

191
Reversible DNA Binders
1) External electrostatic binding:
cationic complexes, usually metals,
bind the negatively charged
phosphate backbone and lead to
disruption of the DNA structure
2) Groove binding: interactions with
minor groove by electrostatic and
hydrogen bonding
3) Intercalation: flat, aromatic
molecules insert in between base
pairs, stabilized by π-stacking and
charge transfer interactions

(anti-tumor agent)

Intercalation: Ethidium Bromide

Ethidium bromide is a
common fluorescent stain
used with double-stranded
DNA. Ethidium intercalates
between DNA bases. In the
intercalated state, ethidium
exposed to short-wave UV
light (302nm) will fluoresce
bright orange (595nm). The
intercalation of ethidium into
double-stranded DNA
causes the helix to extend
and unwind.

192
 DNA as a Nucleophile: Alkylation
most nucleophilic
site in DNA
double helix
O
H3C O
N NH N NH
N N NH2 N N NH2
O O H3C I O O
H H
O H alkylation H H
O H
O P O-
O P O-
O
O

Most reactive nucleophilic sites of DNA:

N-7 of guanine > N-3 of adenine > N-7 of adenine > N-3 of guanine > N-1 of adenine
> N-1 of cytosine. The amine on C-2, the O-6 of guanine and phosphate groups can
also be alkylated.

This reactivity is strongly controlled by a combination of steric, electronic and

hydrogen-bonding effects. For example, nucleophilicity is diminished by hydrogen-
bonding and nucleophilic sites on the interior of the DNA double helix are sterically
less accessible.

Recall: DNA Damage with other electrophiles

epoxide
p450 hydrolase

HO
O
benzo[a]pyrene OH
O p450
N NH O

O N N NH2
O P O HO
O
O- OH
O diol epoxide
O
N NH HO
Cytochrome O
N p450
O N N
H
O P O O
O- benzene benzene
covalently modified, oxide
O damaged DNA

193
 Recall: Nitrogen Mustards as bis-Alkylating Agents that
Crosslink DNA
CH3
S N
Cl Cl Cl Cl
sulfur mustard mechlorethamine
toxic nerve gas used treatment of advanced
Two methods: in World War II Hodgkin's disease

Nu: Nu:
CH3
CH3 SN2 CH3 SN2
N N N
Cl Cl Cl Nu Nu Nu
intermolecular intermolecular

intramolecular Nu:
H3C H3C CH3
substitution (SN1)
N N N
Cl Cl Cl Cl Nu

aziridinium ion is Nu:

a great electrophile!!
CH3
N
Nu Nu

bis-alkylation product

Recall: Bis-Alkylation of DNA = Crosslinking

DNA
Nu:
intramolecular CH3
H3C substitution (SN1) H3C
N N N
Cl Cl Cl Cl DNA

aziridinium ion
intramolecular
substitution (SN1)
O DNA
-O P O Nu: CH3
H O N
H H DNA
-O
O CH3 O O P O
N
HN N O
N N N
H2N
N NH2
O N N
O P O O H
O
O-
H H Crosslinked G-G residues of DNA double-helix
O H
O P O-
O

194
DNA is Transcribed into RNA, Which is Used in the
Template Synthesis of Peptides

The DNA code: Each amino Acid is Described

by a 3-letter Codon

195
 DNA is Very Stable (encyclopedia),
RNA is hydrolyzed very readily (post-itTM note)

Cell Biology Experiments Involve the Ability to Control

Gene Expression

DNA Genetics (mutation/deletion)

Block Transcription (eg triple

RNA helix)
Block Translation
(Antisense/siRNA)
Peptide
Chemical Genetics (small
molecules/drugs)
Function/Phenotype

196
 Antisense Oligomers and siRNA bind to RNA and
Prevent Translation into a Protein

DNA-like strand still

around
5'-T-A-C-G-T-A-T-T-5'
U C T A
A G A A RNAse (recognizes RNA-
DNA duplex, destroys the
Antisense RNA strand)
Oligonucleotide 5'-T-A-C-G-T-A-T-T-5'
(DNA-like)
3'-A-U-G-C-A-U-A-A-5'
3'-A-U-G-C-A-T-A-A-5'
Ribosome,
tRNA, etc Ribosome

X
Protein

Chemically Modified RNA Analogs Are not Hydrolyzed, and are

More Effective at Blocking RNA Translation

O O O O
base base base
O O O
O base

O O H N
O O S
P O- P S- C H O P
O O O O
Me N
base base base O base
O O O Me

N
O O O

Phosphodiester- Phosphothioate- Thioformacetal- Morpholino-

linked DNA linked DNA linked DNA linked “DNA”

197
 RNA Was Probably the First Biological Molecule:
Ribozymes

The Ribozymes are oligomers of RNA that can catalyze reactions…Tom

Czech received the Nobel Prize for this discovery.

X-ray crystal structure of the

Tetrahymena ribozyme. The secondary
structure is highly pre-organized for
substrate binding, much like an enzyme.
(T. Czech, et al, Sciene 282, p282, 1998)

RNA Was Probably the First Biological Molecule:

The Ribosome
The Ribosome is made up of mostly RNA, unlike most enzymes which are
made of amino acids. Gray=RNA, Yellow=Peptide

198
 How, then, Did Life Begin, Chemically Speaking?

The Miller experiment demonstrated that simple organic molecules would

spontaneously form amino acids with the help of lightning
O O O

H OH H2N HO
OH OH
O
O O
H2N H3C O
OH OH
CH3 OH H3C OH
O O
H3 C O
H2N OH OH
H2N
O O OH
H O
N CH3
HO N OH H3C OH
H
O O O
HO H3C
OH N NH2 H2N NH2
H
CH3
O O
H2N H2N
OH OH

CO2H
CO2H

The Oro Experiment Demonstrated That Prebiotic

Nucleobase Synthesis was Possible

In the presence of UV light, HCN forms adenine…

NH2
N N
HCN
N N
H
Adenine;
C5H5N5 or 5 x
HCN!

The conditions can be varied to produce other heterocycles, including other

nucleobases

199
 The Formose Reaction Provides Ribose
O O O-
Base
HO HO
H H H H

Formaldehyde Glycoaldehyde O
(the simplest
carbohydrate) H H
O-
OH O HO O
H
HO H HO H
HO OH HO Ribozymes

Ribose Threose
NH2
NH2
N N
N N
N N
HO N N HO
OH H
O O

OH OH OH OH

The yield of ribose is quite low, and many other sugars are formed at the
same time. The addition of borate to the reactions greatly increases the
selectivity for ribose formation (Science, 303, 196, 2004).

How Did we End Up as Single Enantiomers?

This is a raging origin of life debate, but the answer is probably not through the
influence of magnetic fields…

O OH
New Stereocenter Created...
RMgBr racemic (no magnetic field)
H R
up to 90% ee (magnetic field)

Angew. Chem. Int. Ed. Engl. 1994, 33, 454; (original paper); Angew. Chem. Int. Ed. Engl. 1994, 33, 1458;
(results not reproducible); Angew. Chem. Int. Ed. Engl. 1994, 33, 1459; (results not reproducible) ;
Angew. Chem. Int. Ed. Engl. 1994, 33, 1376; (paper withdrawn); Angew. Chem. Int. Ed. Engl. 1994, 33,
1457; (paper withdrawn); Angew. Chem. Int. Ed. Engl. 2004, 43, 2194. (Ph.D. revoked)

“On February 7, 1996, as recommended by the commission, the

committee of the Faculty of Mathematics and Natural Sciences decided
to strip Guido Zadel of his doctorate because of grave deception during
(and after) his doctoral studies.”
“The doctoral certificate must be withdrawn and Guido Zadel is no
longer allowed to use the title of Doctor.”

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 Biosynthesis, Natural Products and Drug Action

Basic organic chemistry concepts can be applied to biological systems in two

main topics of discussion:

1) Biosynthesis of natural products: How does nature synthesize all

of her molecules? Recall ATP…but there are also other methods.

Paul M. Dewick (2002) Medicinal Natural Products: A Biosynthetic Approach

John Wiley and Sons, New York, NY.

2) Drug design and drug action: How do small molecules have such a
huge impact on biological systems? Recall aspirin…

Richard B. Silverman (2004) The Organic Chemistry of Drug Design and

Drug Action Elsevier Academic Press, Burlington, MA.

Sample Problem: Aflatoxin

Aflatoxin is formed in peanuts as a result of a mold that can grow inside the
shell. One mode of toxicity involves covalent modification of DNA by a
metabolite of aflatoxin, namely aflatoxin epoxide.
O O
O O

O O
H cytochrome H
p450 O

O O O O
H H

O aflatoxin aflatoxin

O
a) Enzyme-mediated oxidation generally take place on
O electron-rich alkenes. In the case of aflatoxin, why is only
H one of the 3 possible alkenes epoxidized?

O O
H

201
 Sample Problem, continued
b) Aflatoxin epoxide damages DNA by covalent modification of N7 of adenine.
Draw the product.
NH2
N N

N N
HO O

O
O P O-
O-
c) N7 of adenine is not the most nucleophilic nitrogen. What binding property
might aflatoxin have that would cause it to interact more selectively with DNA?

Chlorismate Mutase: Biosynthesis of Phenylalanine

and Tyrosine Using a Claisen Rearrangement

CO2H
decarboxylative
aromatization and NH2
transamination

L-Phe
O OH O O OH
O
chorismate
chlorismate HO OH
mutase HO CO2H
mutase O
OH O
O NH2
Claisen
OH O rearrangement OH
OH acid
prephenic L-Tyr
chlorismic acid
decarboxylative
Count carbons to see which alkenes are OH
aromatization,
involved in the [3,3]-sigmatropic rearrangement oxidation, then
transamination

[3,3] sigmatropic rearrangements such as the Claisen rearrangment normally occur

under thermal reaction conditions. The rate of the Claisen rearrangment is increased
106-fold in the presence of the enzyme due to stabilization of the transition state.

202
 Synthesis of Vitamin C from D-glucose

OH
HO2C
O O
HO OH NAD+ HO OH
HO HO
OH OH NADH
D-glucuronic acid
D-glucose
HO2C
OH
NAD+ = oxidant; NADH = reductant HO OH
HO
OH
OH OH OH L-gluconic acid
HO HO HO
O EKT HO O [O] HO O OH
O O O
CH2OH
HO OH O L-gluconolactone H OH
Ascorbic Acid 2-oxogluconolactone HO H
(Vitamin C)
H OH
Plants and most animals can convert glucose into ascorbic acid H OH
(vitamin C) by the pathway shown. Humans and primates are deficient CO2H
in the enzyme oxidizing gluconolactone to the ketolactone, and are thus
dependent on a dietary source of Vitamin C.

Sample Problem: Ascorbic Acid’s Acidity

OH Ascorbic Acid (Vitamin C) is not a carboxylic acid, yet

HO it is acidic enough to get “acid” in it’s name. Which
O
O proton is most acidic and why?

HO OH
Ascorbic Acid
(Vitamin C)

203