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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