CHEM 333:
University of Illinois
at Chicago
Advanced Synthetic Laboratory
UIC
Advanced Synthetic
Laboratory (CHEM 333)
Lecture 1
Instructor: Dr. Chad Landrie
Lecture CRN: 17449
TR, 2:00-2:50 pm
June 12, 2012
Project 1: Preparation of Benzocaine, Lidocaine
and DEET through Fischer Esterification
Project 1: Preparation of Benzocaine, Lidocaine and
DEET through Fischer Esterification and Nucleophilic
Acyl Substitution of Carboxylic Acid Derivatives
NH2
CH3
EtO
O
Benzocaine
H
N
O
CH3
Lidocaine
O
N
Et
N
Et
Et
Et
CH3
N,N-Diethyl-m-toluamide
(DEET)
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 2
Lecture 1: June 12
Preparation of Three Synthetic Targets Through
Nucleophilic Acyl Substitution
O
O
OH
Fisher Esterification
CH3CH2OH, H3O+
H2N
OCH2CH3
H2N
Benzocaine
O
Cl
Addition/Elimination
Acyl Transfer
Nucleophilic Acyl Substitution
H3CH2C
CH3
CH3
NH2
CH3
H
N
CH2CH3
Addition/Elimination
Acyl Transfer
Nucleophilic Acyl Substitution
Cl
Cl
O
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
O
CH2CH3
N
CH2CH3
CH3
CH3
DEET
H
N
O
CH3
CH2CH3
N
CH2CH3
Lidocaine
Slide 3
Lecture 1: June 12
CHEM 333:
University of Illinois
at Chicago
Advanced Synthetic Laboratory
UIC
The Essentials:
Bonding and Acidity
pKa Scale
acid
pKa
HCl
hydrochloric
-3.9
H3O+
hydronium
-1.7
acetic acid
4.7
O
H3C
OH
NH3
HA
anilinium
5.2
OH
phenol
10
H2O
water
15.7
CH3CH2O H
ethanol
16
NH3
ammonia
36
CH3CH3
ethane
62
University of
Illinois at Chicago
UIC
Take home message:
the larger the Ka value, the
smaller the pKa value,
the stronger the acid.
acid
dissociation
H
+
A–
conjugate
base
[H+][A-]
pKa = -log10 [HA]
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
-log10(1/100) = 2
-log10(1/10) = 1
-log10(1) = 0
-log10(10) = -1
-log10(100) = -2
Slide 5
Lecture 1: June 12
Structural Effects on the Strengths of Acids
•
•
•
1. Electronegativity:
Dominant effect for atoms in the same period (row).
More electronegative conjugate base = more stable conjugate base
= Ka lies further to right
Alternate reasoning: H of conjugate acid (HA) becomes more
positive with increasing electronegativity of A–.
H–A ⇌ H+ + A–
more electronegative
= stabilizes negative charge
= more stable (lower NRG)
= larger Ka
University of
Illinois at Chicago
UIC
[H+ ][A – ]
Ka =
[HA]
A system at equilibrium lies furthest
toward the side that is the most stable
(lowest in energy). This is a major topic
in CHEM 114.
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 6
Lecture 1: June 12
Structural Effects on the Strengths of Acids
Increasing electronegativity of atom in bold.
H
Acid
C
H
N
H
H
H
O
H
H
pKa = 60
pKa = 36
H
F
H
pKa = 16
H
pKa = 3
Increasing acid strength.
Conjugate
base
C
H
N
H
H
H
O
H
F
H
Increasing stability (lower NRG) of conjugate base.
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 7
Lecture 1: June 12
Structural Effects on the Strengths of Acids
Inductive effect: polarization of a bond by an electron
withdrawing atom (electronegative) through two or more bonds.
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 8
Lecture 1: June 12
Structural Effects on the Strengths of Acids
1. Electronegativity (cont.):
H H
H C C O H
H H
H H
H C C O
H H
F H
F C C O H
F H
F H
F C C O
F H
University of
Illinois at Chicago
UIC
+
+
H
Ka = 1 x 10-16
pKa = 16
H
Ka = 5 x 10-12
pKa = 11.3
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 9
Lecture 1: June 12
i>Clicker Question
Rank the carboxylic acids below in order of
increasing acid strength (decreasing pKa).
A.
B.
C.
D.
E.
O
R
O
carboxylate anion
(conjugate base)
a
University of
Illinois at Chicago
b
UIC
c
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
c<a<d<b
b<d<a<c
b<a<c<d
c<a<d<c
none of the above
d
Slide 10
Lecture 1: June 12
Structural Effects on the Strengths of Acids
•
•
•
2. Bond Strength:
Dominant effect for atoms in the same group (column).
Bond strength for H–A decreases as A moves down a column.
Size of A increases as it moves down a column; bigger A = less
overlap between orbitals of H–A = weaker bond.
4
3
2
1
2
3
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 11
Lecture 1: June 12
Structural Effects on the Strengths of Acids
•
•
•
2. Bond Strength:
Dominant effect for atoms in the same group (column).
Bond strength for H–A decreases as A moves down a column.
Size of A increases as it moves down a column; bigger A = less
overlap between orbitals of H–A = weaker bond.
•
Covalent bonds are formed when two
electrons are shared between two
atoms.
•
Electrons are shared when the orbitals
(electron cloud) that contain the
electron for each atom overlap.
•
The closer in size the orbitals are, the
better (stronger) the overlap. Better
orbital overlap = stronger bond.
University of
Illinois at Chicago
UIC
2
3
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 12
Lecture 1: June 12
Structural Effects on the Strengths of Acids
Similar Size = Better Overlap = Strong Bond
The shared electrons spend a larger percentage
of the time in between the two atoms.
University of
Illinois at Chicago
UIC
Dissimilar Size = Poorer Overlap = Weaker Bond
The shared electrons spend a smaller percentage
of the time in between the two atoms.
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 13
Lecture 1: June 12
Structural Effects on the Strengths of Acids
•
•
•
2. Bond Strength:
Dominant effect for atoms in the same group (column).
Bond strength for H–A decreases as A moves down a column.
Size of A increases as it moves down a column; bigger A = less
overlap between orbitals of H–A = weaker bond.
HF
HCl
HBr
HI
pKa = 3
pKa = –4
pKa = –6
pKa = –10
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 14
Lecture 1: June 12
Structural Effects on the Strengths of Acids
•
•
•
2. Bond Strength:
Dominant effect for atoms in the same group (column).
Bond strength for H–A decreases as A moves down a column.
Size of A increases as it moves down a column; bigger A = less
overlap between orbitals of H–A = weaker bond.
pKa = 15.9
pKa = 10.6
pKa = 5.2
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 15
Lecture 1: June 12
i>Clicker Question
Which of the following is the strongest
acid?
A. H2O
O
B. H2S
S
C. H3N
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 16
Lecture 1: June 12
Structural Effects on the Strengths of Acids
•
•
3. Resonance (Electron Delocalization):
Delocalization of electrons in the conjugate base = increased stability
(lower NRG) of conjugate base
More stable (lower energy) conjugate base = larger Ka = smaller pKa =
stronger acid.
H2SO4 ⇌ H+ + HSO4–
[H+ ][HSO 4– ]
Ka =
= 1,000
[H2SO 4 ]
H2SO3 ⇌ H+ + HSO3–
[H+ ][HSO 3– ]
Ka =
= 0.0150
[H2SO 3 ]
For oxyacids, the greater the number of oxygen
atoms, the more resonance structures can be drawn.
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 17
Lecture 1: June 12
Structural Effects on the Strengths of Acids
Resonance structures are formed by “pushing” electrons
into different allowed arrangements.
O
O
O
S
OH
O
University of
Illinois at Chicago
OH
O
O
O
O
S
O
O
O
S
S
OH
UIC
O
S
OH
O
OH
more resonance structures =
more charge delocalization =
more stable conjugate base =
equilibrium lies further to the
right (larger Ka) =
stronger acid
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 18
Lecture 1: June 12
Structure Affects Acid Strength
•
•
3. Resonance (Electron Delocalization):
Delocalization of electrons in the conjugate base = increased stability
(lower NRG) of conjugate base
More stable (lower energy) conjugate base = larger Ka = smaller pKa =
stronger acid.
H H
C
H
H3C
O
H3C
O
C
O
H
H H
C
H3C
O
H3C
H3C
University of
Illinois at Chicago
UIC
O
C
O
C
O
O
+
+
H
Ka = 1 x 10-16
pKa = 16
H
Ka = 2.0 x 10-5
pKa = 4.7
H3C
O
C
O
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 19
Lecture 1: June 12
Acid-Base Equilibria: Determining the Direction
of Acid-Base Reactions
You must identify the ACID on each side of the equilibrium:
pKeq = pKa (acid left) - pKa (acid right)
Keq = 10
-[pKa (acid left) - pKa (acid right)]
• remember: p = -log10
• this equation works for any acidbase reaction; doesn’t matter which
way equilibrium is written
Example:
O
H
+
phenol
(pKa = 10)
acid
HO
O
C
O
Keq
+
O
hydrogen carbonate
(pKa = 10.2)
base
phenoxide anion
(pKa = NA)
base
HO
O
C
OH
carbonic acid
(pKa = 6.4)
acid
-[10 - 6.4]
-[3.6]
Keq = 10
= 10
= 2.5 x 10-4
since Keq <1, then equilibrium lies to the left
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 20
Lecture 1: June 12
Acid-Base Equilibria: Determining the Direction
of Acid-Base Reactions
You must identify the ACID on each side of the equilibrium:
pKeq = pKa (acid left) - pKa (acid right)
Keq = 10
-[pKa (acid left) - pKa (acid right)]
• remember: p = -log10
• this equation works for any acidbase reaction; doesn’t matter which
way equilibrium is written
Example:
O
H
+
phenol
(pKa = 10)
acid
Keq = 10
HO
O
C
O
Keq
+
O
hydrogen carbonate
(pKa = 10.2)
base
phenoxide anion
(pKa = NA)
base
-[10 - 6.4]
-[3.6]
= 10
HO
O
C
OH
carbonic acid
(pKa = 6.4)
acid
= 2.5 x 10-4
Acid-base equilibria always lie to the side
with weaker conjugate acids and bases.
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 21
Lecture 1: June 12
Finally, What About Strengths of Bases?
Question: Is
ammonia or pyridine
a stronger base?
Solution:
1. Determine which conjugate
acid of each base is the weakest.
2. The weaker the conjugate acid,
the stronger the conjugate base.
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 22
Lecture 1: June 12
i>Clicker Question
What is the Keq for the
following acid-base reaction?
OH
pKa = 17
10
University of
Illinois at Chicago
UIC
+
OH2 +
HCN
pKa = 9.0
acid
–(9.0 – -3.0)
pKa = -3.0
acid
CN
pKa = NA
A. 1 x 10-20
B. 1 x 10-6
C. 1 x 10-12
D. 1 x 1020
E. 1 x 1012
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 23
Lecture 1: June 12
CHEM 333:
University of Illinois
at Chicago
Advanced Synthetic Laboratory
UIC
Reactivity of
Carboxylic Acids
Derivatives
O
R
Cl
acid chloride
O
O
R
O
R'
anhydride
O
R
SR'
thioester
O
R
OR'
ester
O
NR'2
R
amide
O
R
OH
carboxylic acid
Review: Carboxylic Acid Derivatives
Other Mechanisms
path a = thionyl chloride (SOCl2)
path b = Fischer (H3O+ / HOR')
O
R
Cl
acid chloride
O
O
O
R
O
R'
anhydride
R
SR'
thioester
O
O
R
NR'2
R
amide
OR'
ester
O
R
OH
carboxylic acid
Increasing Reactivity
path e = add amine (NR'3)
path c = add alcohol (HOR')
path d = add hydroxide (OH-)
"saponification"
Nucleophilic Acyl Substitution
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 25
Lecture 1: June 12
Structure Determines Reactivity
O
R
Cl
acid chloride
O
O
R
O
R'
anhydride
O
R
SR'
thioester
O
O
R
Acyl Halides & Anhydrides = Most Reactive
Because:
NR'2
R
amide
OR'
ester
O
R
O
R
OH
carboxylic acid
Nuc
O
Cl
Cl
R Nuc
• Chloride and acetate are good leaving groups
(tetrahedral intermediate)
tetrahedral
intermediate
• Inductive effect of halogen or acetate group
(increase electrophilicity of carbonyl carbon)
• Little resonance contribution
University of
Illinois at Chicago
UIC
Cl
O
+
R
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Nuc
Slide 26
Lecture 1: June 12
Leaving Group Ability
Generally, lower pKa = better leaving group
O
Ph
O
Cl
Ph
O
CH3
O
OH
Ph
+
-3.9
University of
Illinois at Chicago
O
UIC
H
CH3
4.7
Ph
O
S
CH3
Ph
ester
H2O/H3O+
OH
CH3
10.7
Ph
OH
Ph
CH3
H
N
H
15.2
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
OH
carboxylic acid
H2O/H3O+
O
O
+
O
CH3
H2O/H3O+
Ph
H
O
N
H
amide
O
+
O
pKa
Ph
+
H
CH3
thioester
O
O
O
S
H2O/H3O+
OH
H Cl
Ph
H2O/H3O+
O
Ph
O
anhydride
acid chloride
H2O/H3O+
O
OH
Ph
OH
+
+
CH3
OH
H
~36
15.7
Slide 27
Lecture 1: June 12
Resonance Contribution & Inductive Effect
Resonance Contribution
N > O > S > Cl
O
H3C
O
X
R
H3C
O
X
R
H3C
X
R
• 3rd row elements (S & Cl) less able to donate sp3 lone pair to
π-system of C=O; poor orbital overlap; primarily inductive effect
• amide resonance is a powerful stabilizing force (18-20 kcal/mol)
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 28
Lecture 1: June 12
Practice: Acyl Hydrolysis
Place the following molecules in order of increasing rate
of hydrolysis to their respective carboxylic acids
(5=fastest, 1=slowest).
O
O
hydrolysis
X
OH
HX
+
H2O
O
O
OCH3
University of
Illinois at Chicago
Cl
5
2
UIC
O
O
N
H
CH3
1
O
O
O
4
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
SCH3
3
Slide 29
Lecture 1: June 12
Extending Concepts
Place the following molecules in order of increasing rate
of hydrolysis to their respective carboxylic acids
(5=fastest, 1=slowest).
O
O
hydrolysis
OCH3
O
O
OCH3
O
OCH3
Cl
1
+
CH3OH
H2O
X
H2N
OH
OCH3
MeO
4
O
O
OCH3
AcO
2
OCH3
O2N
3
5
C.L. Liotta, E.M. Perdue, H.P. Hopkins, J. Am. Chem. Soc., 95, 2439 (1973).
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 30
Lecture 1: June 12
CHEM 333:
University of Illinois
at Chicago
Advanced Synthetic Laboratory
UIC
Biological Activity
and Synthesis of
Benzocaine
O
O
OH
H2N
p-aminobenzoic acid (PABA)
H3C
OH
H2SO4
O
H2N
benzocaine
CH3
Preparation of Benzocaine: Fischer Esterification
O
O
H3C
OH
OH
O
H2SO4
H2N
CH3
H2N
p-aminobenzoic acid (PABA)
benzocaine
Bacteria produce folic acid from PABA
Sulfonamides (sulfa drugs) =
generally, antibacterial by
inhibiting folic acid synthesis
Me
O
OH
N
N
H2N
N
O
N
H
N
H
OH
OH
O
O
H
N
N
O S O
N
F3C
N
NH2NH
folic acid
University of
Illinois at Chicago
UIC
CH3
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
O
S NH2
O
Celecoxib (Celebrex)
Slide 32
Lecture 1: June 12
Preparation of Benzocaine: Fischer Esterification
O
O
H3C
OH
OH
H2SO4
H2N
O
H2N
p-aminobenzoic acid (PABA)
•
•
•
•
•
•
nerve is stimulated
some sodium (Na+) gates
(transmembrane proteins) open
Na+ rushes into the cell
more Na+ gates induced to open as
threshold potential is released
polarization is reversed
hypothesis: benzocaine binds to
Na+ gates, preventing depolarization
of nerve cell and propagation of
action potential
University of
Illinois at Chicago
UIC
CH3
benzocaine
Sodium Gate
Sodium Pump
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 33
Lecture 1: June 12
Preparation of Benzocaine: Fischer Esterification
O
O
H3C
OH
OH
H2SO4
H2N
O
CH3
H2N
p-aminobenzoic acid (PABA)
benzocaine
Sodium Gate
•
benzocaine is poorly water soluble
•
generally, nontoxic since not readily
absorbed
•
site specific
•
few other biological activities
Sodium Pump
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 34
Lecture 1: June 12
Source of Esters
H3C
O
O
O
O
O
CH3
O
CH3
O
OH
methyl salicylate
(oil of wintergreen)
3-methylbutyl acetate
(bananas)
OH
aspirin
(analgesic)
O
H3C
N
OMe
O
O
N
O
O
cocaine
(analgesic)
University of
Illinois at Chicago
UIC
procaine, "Novocaine"
(analgesic)
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 35
Lecture 1: June 12
Mechanism of Fisher Esterification?
O
O
H3C
OH
OH
H2SO4
H2N
O
UIC
+
H2O
H2N
p-aminobenzoic acid (PABA)
University of
Illinois at Chicago
CH3
benzocaine
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 36
Lecture 1: June 12
Effecting Completion of Reversible Reaction?
O
O
H3C
OH
OH
H2SO4
H2N
O
CH3
+
H2O
H2N
p-aminobenzoic acid (PABA)
benzocaine
Take Advantage of LeChatlier Principle:
University of
Illinois at Chicago
•
Use excess alcohol (maybe as solvent)
•
Remove water (molecular sieves, azeotropic
distillation, Dean Stark apparatus → CHEM 232
Lecture 27, etc.)
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 37
Lecture 1: June 12
Homework: Synthesis
Design a reasonable synthesis of
benzocaine beginning with benzene.
I will distribute a homework set in the
next two weeks. This is due with your
first project 1 report.
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 38
Lecture 1: June 12
Upcoming . . .
Next Week in lab:
Complete benzocaine synthesis (page 655).
Have your intended procedure (Pre-Lab) written in your lab
notebook.
Before Thursday’s Lecture:
Review infrared spectroscopy–any source.
Project I Reading Assignment:
Pages 237-281; 651-657; 669-687; 703-704; 747-757
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 39
Lecture 1: June 12
Website
www.chadlandrie.com
University of
Illinois at Chicago
UIC
© 2012, Dr. Chad Landrie
CHEM 333: Advanced Synthetic Chemistry
Slide 40
Lecture 1: June 12