Chemistry 5343

1
Organic Reactions
Michael B. Smith Office (A-416) 486-2881
MW 2:30-3:20 pm (Chem. T215) + Fri. 1:25-3:15 (Chem. T215).
Introduction 1/3 lecture
Retrosynthesis and structure 1 lecture
Stereochemistry 2 lectures
Conformations 1-2 lectures
Undergrad reactions and Functional Group Exchanges 3 lectures
Oxidation 6 lectures
Reduction 6 lectures
Nucleophilic Carbon Reactions 9 lectures
Enolate anion reactions 7 lectures
Pericyclic Reactions 9 lectures
Anything else? C12 - perhaps some organometallic in C12 ? 4.7 lectures?
50 lectures
BOOKS
2
REQUIRED: "Organic Synthesis, 3
rd
Edition",
author, Michael B. Smith
MAKE SURE TO DOWNLOAD SpartanModel
with the book.
The Code is in the back of the book.
Order online:
http://store.elsevier.com/Organic-Synthesis/Michael-Smith/isbn-
9781890661403/
Imprint: Academic Press ISBN: 9781890661403
and download
"Student Solutions Manual to Accompany
Organic Synthesis" - online, author, Michael B. Smith - via SYLLABUS
see http://books.wavefun.com/organicsynthesis3rd
For SpartanModel. Follow instructions on last page of the book
Recommended, but not required.
"Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure", 6th Ed., by Michael B. Smith and Jerry
March
GRADES
3
Grades:
Three Exams: 09/27; 10/25; 11/22: 150 pts each
These will be in class. 2 hours
Quizzes: In class. From HW for the chapter under discussion.
Every Wed. and Fri. 5 min. 10 pts each.
Scaled to 100 points
Project: Written = 200 pts + Poster = 125 pts = 325 pts
Final Exam: 225 pts
Total Points = 150 x 3 + 100 + 325 + 225 = 1100 points
Online
4
syllabus (pdf)
In class notes
Solutions Manual, Chapters 1-7
Solutions Manual, Chapters 8-13
Answer Keys for Quizzes
http://orgchem.chem.uconn.edu/5343/5343home.html
http://orgchem.chem.uconn.edu/5343/53432013.html
If you need C1, C2 before book arrives - email me and
I will send them as pdf files.
The Project
5
The project will be either an assigned "special topic" or the task of writing a review of the
recent work of an individual researcher in Organic Chemistry. Your project is to write a
review of this topic, including only references since 2006. You may not use or cite reviews
of the work. Your paper should also include selected experiments which are taken directly
from the reference papers. The paper must be fully referenced (ACS style). The written
project will be given to me and graded. You will then choose the most important aspects of
your paper and present it in the form of a poster that will be hung in a classroom to be graded
by me, your classmates, and any faculty or senior graduate students who wish to attend. Each
of you will grade all the posters, including your own. Your Poster grade will be 50% for my
grade and 50% for the average of your colleagues' grades.
NOTE. SIMPLY COPYING THE PAPER AND POSTING IT WILL EARN A ZERO. NOTE. SIMPLY COPYING THE PAPER AND POSTING IT WILL EARN A ZERO.
You must make a poster of the paper - not tack up the pages of the paper You must make a poster of the paper - not tack up the pages of the paper
The paper is due Monday, December 2 - NO EXTENSIONS FOR ANY REASON .
The poster will be presented on Tuesday, November 19, at 4:30 PM.
Contact
6
I will be available in Chemistry A416 to answer questions.
My office hours are MWF from 10 am - 1 pm,
but I encourage you to stop in whenever you have questions. If there
are a lot of questions please set up an appointment.
My office phone is 486-2881.
michael.smith@uconn.edu
The internet site used for the course will include pdf files of the
lectures, and other information from this class will be posted at:
http://orgchem.chem.uconn.edu/5343/5343home.html
Suggested Homework Problems:
Chapter 1
2, 3, 5, 9, 13, 14, 17, 18
Functional Group Interchange Reactions
8
The largest number of actual chemical reactions that appear in a
synthesis do not make carbon-carbon bonds but rather manipulate
functional groups.
Changing one functional group into another is dened as a
functional group interchange (FGI).
Br
Br
NaCN
2 1
4 3
KOH , EtOH
DMF
CN
Carbon-Carbon Bond Forming Reactions
9
Building a carbon skeleton from simpler molecules requires
carbon-carbon bond forming reactions
H
3
C H :

Na
+
H
3
C
(S)
Br
5
6
(R)
CH
3
THF
Na
+
NH
2
THF

Note the use of an S
N
2 reaction using the alkyne anion
nucleophile, in a reaction that proceeds with 100%
inversion of configuration.
RETROSYNTHESIS: Disconnection and Transforms
1
0
Focus on C-C bonds and mentally disconnect key bonds to simplify the
structure, eventually leading back to a starting material
Disconnection of one bond leads to a transform.
A transform is dened as: "the exact reverse of a synthetic reaction to a
target structure".
The target structure is the nal molecule one is attempting to prepare.
:

Na
+
H
3
C
(S)
Br
(R)
CH
3
+
transform
:

Na
+
H
3
C
(S)
Br
(R)
CH
3
THF
synthesis
a
RETROSYNTHESIS
1
1
Disconnection gives an intermediate in the synthesis, and this process
is continued to bridge the target with a starting material
CO
2
H
C!N: Br OH
9 8
a

This denes a viable process based on known chemical reactions to
make each bond.
Working backward in this manner is termed retrosynthetic analysis or
retrosynthesis, dened by Corey as "a problem-solving technique for
transforming the structure of a synthetic target molecule to a sequence of
progressively simple materials along a pathway which ultimately leads to
a simple or commercially available starting material for chemical
synthesis".
SYNTHESIS
1
2
Disconnection gives an intermediate in the synthesis, and this process
is continued to bridge the target with a starting material
CO
2
H
C!N: Br OH
9 8
a

Reversing the retrosynthesis and providing reagents leads a synthetic
pathway.
Reagents are chosen based on known reactions, which were the basis
for each disconnection.
OH Br C!N:
CO
2
H
PBr
3
KCN
DMF
H
3
O
+
heat
Key Bonds. Donor and Acceptor Sites
13
Assume Assume bonds will be made by reactions bonds will be made by reactions
involving involving polarized or ionic intermediates. polarized or ionic intermediates.
Polarized bond notation such as C
!+
-Br
!-
and C
!-
-Li
!+
is
commonly used in describing the reactivity of such bonds.
The sites marked The sites marked d d in in 25 25 represent represent donor donor sites or sites or nucleophilic nucleophilic
atoms. atoms.
The sites marked The sites marked a a are are acceptor acceptor sites and correspond to sites and correspond to
electrophilic electrophilic atoms. atoms.
Assume bond polarization induced by the heteroatom extends
for 3 bonds from the electronegative source: due to inductive
effects that are a combination of through-space and through-
bond effects.
25
a
d
d
a
d
X
Donor and Acceptor Sites
14
Bond polarization (!+ and !-) is correlated with donor and
acceptor sites.
!+ correlates with a
!- correlates with d
As a practical matter, the effect is negligible beyond C4 As a practical matter, the effect is negligible beyond C4
and will be ignored. and will be ignored.
25
a
d
d
a
d
X
O
OH
N
H
!
!+
!
!
!
!
!
!
!
!+
!+
!+
!+
!+
!+
Disconnect Fragments
15
Natural bond polarization suggests d and a for
fragments as shown.
Use Use synthetic equivalents synthetic equivalents table to convert disconnect products table to convert disconnect products
into real fragments. into real fragments.
The point of this disconnect process is to show that The point of this disconnect process is to show that reactions are reactions are
related to structure and during the course, look for key structural related to structure and during the course, look for key structural
features to understand reactivity. features to understand reactivity.
25
a
d
d
a
d
X
CHO
HO

CHO

HO
a 5
6
transform
where
indicates a
disconnection
7
Synthetic Equivalents
16
R C
R
OH
R
C
R
O
H C
Cl
OR
R C
R
OR
R
C
R
CH
2
O
R
C
R
CH
2
O
H
R
C
R
C
O
H
C
R
R
C
O
R
R
C
R
C
H
OH
R
R
C
R
C
O

R
R
R
C
R
C
R
OH
R
R
O
C
R
R
R
C O
C R
R
R
C O
H
C R
R
R
C
S
S
Li
C
R
R
R
C
R
R
R
MgX C
R
R
R
Li C
R
R
R
CuLi C
R
R
R
PR
3
C
R
R
R
C
R
R
R
X
C R
R
R C
O
R
a
and
a
a a
and
(for the Wittig reaction)
a
(see abbreviations page)
or
and
d d
a
and
(enolate anion)
(acyl anion equivalent)
d
d
or or or
d
2
(X = Cl, Br, I, OTs, OMs, OTf, ...)
a
Reprinted with permission from Smith, M.B. and the Jour nal of Chemical Educ tation, Vol. 67, 1990, 848-856.
Copyright 1990, Divison of Chemica l Education, Inc.

Disconnect Fragments
17
Based on the table of synthetic equivalents
the d in 5 leads to an enolate anion
the a in 7 leads to an aldehyde
this analysis led to an aldol condensation to make 6
Note the correlation of bond polarization based on
structural position for predicting reactivity.
25
a
d
d
a
d
X
CHO
HO

CHO

HO
a 5
6
transform
where
indicates a
disconnection
7

CHO

O
d
a
H
Functional Group Exchanges
18
Functional group transformations involve changing
one group to another, but not necessarily making a C-C
bond.
OH
O
O
O
an alkene can be converted to an alcohol and then a ketone
an alcohol can be converted to an ester
The relationship between functional groups must be
recognized to utilize such transformations
Functional Group Exchanges
19
Functional group transformations are related
do not worry about the functional group per se, but
look at the bond and the structural changes
aldehydes, alcohols, halides are all related in that
simple reactions will change one into the other.
look at the bond being made, and think about the
interrelationships of one functional group to another
Later: think about acid-base properties of FG.
C=C and C=O are both electron donors: Brnsted-Lowry
bases with HX and Lewis bases with BF
3
.
Functional Group Relationships
20
C C
C
C
C O
C
C
C O
Cl
C
C
C
!"bond is a Bronsted-Lowry
and a Lewis base
Reacts with H
+
or BF
3
Not polarized. Does not
react with nucleophiles
no acyl addition
polarized with C(#+)
reacts with nucleophiles
acyl addition
No leaving group
on C
no acyl substitution
Cl is a leaving group.
acyl substitution
polarized with C(#+)
reacts with nucleophiles
acyl addition
!"bond is a Bronsted-Lowry
and a Lewis base
Reacts with H
+
or BF
3
!"bond is a Bronsted-Lowry
and a Lewis base
Reacts with H
+
or BF
3
Functional Group Manipulation
21
C O
C
C O
C OH
C C-X
C X
-CH
2
CH
2
-
C C
O
COOH
C-X
O
C=C
C CR
2
a. LiAlH
4
or NaBH
4
or H
2
/cat
c. NaOH/H
2
O or i. PPh
3
, RCO
2

,
MeO
2
C-N=N-CO
2
Me
(the Mitsunobu reaction)
e. HX
g. i. Br
2
ii. NaNH
2

i. NaNH
2
/NH
3

k. H
3
O
+

m. N
2
H
4
/KOH or Zn(Hg)/HCl
o. LiAlH
4
or H
2
/cat.
q. H
2
/cat
s. excess H
2
/cat.
u. Me
2
S
+
CH
2

w. i. B
2
H
6
ii. NaOH/H
2
O
2
or i. Hg(OAc)
2

ii. NaBH
4
x
w
n
o
p
q
r
s
m
v
e
f
g
h
i
j
d c
b
a
l
k
u
t
C!C
b. CrO
3
d. PCl
5
, SOCl
2
(X = Cl); PBr
3
(X = Br); i. NaH ii.
ii.

OH iii. H
3
O
+
RX (X = OR); i. PBr
3
or RSO
2
Cl
ii. K-phthalimide; hydrolysis or NaN
3
; H
2
/cat. (X = NH
2
)
f. NaOH/H
2
O or RO

/ROH
h. H
2
/cat or Na/NH
3
/EtOH
j. HX
l. PCl
5
n. i. RSO
2
Cl ii. LiAlH
4
(only one carbon reacts)
p. X
2
/h" or heat
r. 2 H
2
/cat
t. Ph
3
P=CR
2
v. RCO
3
H
x. i. O
3
ii. Me
2
S or H
2
O
2
Reprinted with permission from Smith, M.B. and the Journal of Chemical Eductation, Vol. 67, 1990, 848-856.
Copyright 1990, Divison of Chemical Education, Inc.

In a In a
disconnection, disconnection,
C=O is the C=O is the
same as CH- same as CH-
OH, which is OH, which is
related related
to C=C, etc. to C=C, etc.
Learn to think Learn to think
differently. differently.
You should You should
know ALL of know ALL of
these reactions these reactions
based on based on
undergrad undergrad orgo orgo