A Research Project in the
Second Semester Organic
Chemistry Laboratory
Timm A. Knoerzer
Nazareth College
NERM 2004
Rochester, NY
The Problem

Students are usually not engaged in problem
solving or critical thinking while in the
laboratory
 No connection of work from week to week
(does not simulate the real world; the “one
and done” scenario)
 Chemistry not done in context (scientifically
relevant)
 Student do not always learn about modern
chemical techniques and reactions
 Limited integration of technology
 Little exposure to structurally sophisticated
molecules
The Objectives
Provide students with an opportunity to:

Do what real organic chemists do (perform a
multi-step, multi-week project that requires
students to plan, adapt, modify, improvise)
 Learn modern/advanced chemical techniques
 Use technology to support and explain
experimental outcomes
 Learn relevant chemistry (connected to what
students are learning in class and are
interested in)
 Summarize and communicate the work
(report and poster)
Synopsis of The Project

Objective: To generate a diverse small
molecule library of benzothiazine/amino
acid/isothiocyanate hybrids
 Context: Students are active participants in
generating new compounds and in rehearsing
critical synthetic transformations
 Novelty: Synthesize a heterocycle that has
limited precedence in the chemical literature
(unknown utility)
 Relevance: To ultimately explore the binding
potential of these compounds toward various
molecular recognition targets (receptors,
enzymes, and other proteins) = bioorganic
chemistry
Synopsis of The Project

Strategy: Combinatorial chemistry in
conjunction with the synthesis of key
nitrocinnamic acid starting materials
 Schedule: Spring semester -- Begins in week
5; ends in week 14 (total of 9 weeks)
 Topics: carbonyl addition, NAcS, SN2
(Mitsunobu), peptide synthesis, NArS,
synthesis of ethers, enolates, use of
protecting groups, spectroscopy, molecular
modeling, scientific communication –
parallels the chemistry introduced in class
Our target
diversification #2: nitrocinnamic acids
diversification #1: amino acids
O H
*
N *N
H R1 O S
H2N
linker
R2
R3
N
HN
R4
diversification #3: phenyl isothiocyanates
Combinatorial strategy
T1
Solid-phase parallel synthesis
OH
SCN1
AA1
attach linker split #1
NCA1
AA2
AA3
I1
split #2
I2
I3
split #3
SCN2
NCA2
Total AA = 3, total NCA = 2, total SCN = 2
3 x 2 x 2 = 12 total compounds in this library
Synthesis
H2N
OH
O
O
N
Wang Resin
(1.1mmol/gram)
N
N
O
O
NH 2
N
H
NH 2
N
HO
NH O
R1 O
HOBt, HBTU, Hunig's base
DMF
(CDI)
O
O
O
O
N
H
N
H
H
N
HO
20% piperidine
fmoc
DMF
R1
O2N
DCC, HOBt, Et3N
DMF
R2
O
O
O
N
H
N
H
H
N
R3
SnCl2
DMF
R1
O
NO 2
R2
R3
Synthesis
R2
O
O
O
N
H
N
H
H
N
R1
R
R3
O
NCS
DMF
NH 2
R2
O
O
O
N
H
N
H
H
N
R1
R3
50% TFA, CH2Cl2
O
S
NH
HN
O
H2N
N
H
R4
R2
H
N
R1
R3
O
S
N
HN
R4
Nitrocinnamic Acid Synthesis
O
H3CO
H
H3CO
NO 2
HO
HO OH
pTSA, toluene
reflux
O
H3CO
NO 2
OH
20% aq. KOH
dioxane
reflux
NO 2
O
RO
PPh3, DIAD
R
O
H
O
H
H3CO
O
H3CO
O
H
H3CO
NO 2
10% aq. HCl
acetone, heat
O
O
RO
H3CO
H
NO 2
HO 2C
piperidine,
CO2H
pyridine
RO
H3CO
OH
NO 2
We have used this scheme to construct 13 novel substituted 2-nitrocinnamic acids
McDonald, E; Suksamrarn, A. J. Chem. Soc., Perkin Trans. 1 1978, 440-446.
Project Design

PowerPoint introduction to project
 Students select synthetic units:





(2-3) amino acids
(2) nitrocinnamic acids
(1-2) phenyl isothiocyanates
may also select linker
Students are responsible for generating enough
synthetic material to complete project (need ~20
mg of the final compound)
 Students are responsible for using analytical and
spectroscopic methods to confirm products
 Students must decide if synthetic products are
pure enough to continue – if not they must purify
(e.g. chromatography)
Technology Connection #1
1. Is this pathway SN2 or NArS?
2. Why does the conversion occur para to the nitro group
rather than meta upon exposure of the starting 4,5dimethoxy compound to 20% KOH (aq)?
H3CO
H3CO
O
O
H
NO 2
20% aq. KOH
dioxane
reflux
HO
H3CO
O
O
H
NO 2
Molecular Modeling (Spartan)
The red line represents the energy of the transition state (kcal/mol)
and the green line represents the charge on the incoming OH
nucleophile.
More Modeling Results
Here surface value = +20 in range of –60 to +26
Here surface value = +13 in range of –60 to +26
Technology Connection #2
How can you confirm the identity/purity of your products?
NMR
Mass Spec
LC
O
Example
NMR data
O
O
O
NO2
CH3
5
.
6
0
3
2
.
9
2
1
1
8
1
.
.
0
2
0
7
3
0
.
9
.
1
9
5
.
.
9
2
3
2
9
6
5
4
3
2
1
p
p
m
NMR Expansions
b
O
f
b
d
O
e
O
a
O
NO2
CH3
c
4
.
3
4
.
2
4
.
1
4
.
0
3
.
9
3
.
8
3
.
7
3
p.
p
6
m
2
.
0
1
.
8
1
.
6
1
.
4
1
.
2
1
.
0
p
p
m
Example Mass Spec and LC data
M+1 at 478.4 amu
O
O
H2N
N
H
H2N
OMe
H
N
O
NH2
More Mass Spec and LC data
M+1 at 483.2 amu
O
H N
2
“391” = loss of NH-Ph
“348” = leftover starting material (incomplete rxn)
N
H
H2N
H
N
O
S
N
HN
Ph
Further Study and Extensions

Design TLC system to monitor the course of
the Mitsunobu reaction and to perform
subsequent column chromatographic
purification
 Determine how to obtain solid products that
are free of solvent
 Further confirmation of products by 13C-NMR,
13C-DEPT, and 1H-1H-COSY
 Adjust # of equivalents and observe changes
 MECHANISMS
 Must determine how much analysis is to be
completed for “publication”
Communicating results
Poster
Formal Report
Questions to Ponder
Pictures
Pictures
Acknowledgements

Dr. Benjamin Miller (U of R Medical School
Center for Future Health)
 Dr. Paula Satterly-Childs
 Nazareth College summer research students
(Jessica Goodman, Jennifer Cahoon,
Christina Gallis, Ed O’Neil, Ashanti Tolbert)
 Graduate students in the the Miller group
 Terry O’Connell
 Organic chemistry students 2002-2004