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332L Final Project-Spring 2018
Deadlines for Spring 2018
Project Proposal: March 25th at 11:59 PM
Project ELN: Three days after you complete your project lab work
General Timeline
Approximately Mid Semester
• Form a project team of two or three members (not larger).
• Read the scientific paper included at the end of this document for background information.
• Plan the detailed procedure for replicating the synthesis of the following compound described in the scientific
paper (compound 4l) and one variation of the original compound using available reagents (listed in this
document).
Compound 4l
•
•
Ask your TAs (or other 332L TAs, head TA, or course instructor) questions to clarify your understanding of the
project.
Look at the Project Proposal Guidelines included in this document and write a Project Proposal.
Approximately Two Weeks Before Project Work Begins
• Submit your project proposal. All team members may submit the same proposal. Your TA will grade and
provide feedback within a week.
During Project Lab Periods
• Perform the work outlined in your proposal. Be sure to implement TA feedback. Record data in your ELN. .
Please see guidelines included in this document for details about expectations so that you record all necessary
information while you are in the lab.
• Please plan to run simultaneous syntheses the first day so the second day can be spent primarily on obtaining 1H
NMR as well as spectral interpretation. Your TAs will run samples for you during your second project class
period.
Third Day After Project Work is Completed
• Submit your project ELN by 11:59 PM on the third day after project work is completed. This must be
independent work. Please see ELN Guidelines and Rubric included in this document for details about
expectations.
Grading
•
•
Project Proposal: 40 pts
o Submitted as a team
ELN for project work: 40 pts
o Submitted individually
Overview
For the past few semesters, 332L students have been participating in a research project involving synthesis of
compounds to be tested for antibacterial properties. For your final project you also will be synthesizing multi-ring
compounds with the potential to be potent anti-bacterial agents. You will be synthesizing two related compounds. The
first compound, 3-[(4-chlorophenyl)-piperidin-1-yl-methyl]-4-hydroxy-chromen-2-one or compound 4l (see structure
above), has been synthesized by Mukhopadhyay, et. al. and you are going to try to replicate the synthesis. The second
synthesis will be much like the first, except you will vary one of the reactants in order to get a new compound.
Introduction
The surfacing of bacteria resistant to available antibiotics is causing disturbing public health issues. As such, design and
synthesis of organic compounds effective in treatment of these resistant bacteria is of vital importance. Much effort is
focused on synthesis of coumarin derivatives. This is due to the prevalence of naturally occurring coumarin derviatives
with many medicinal uses as well as the ready availability of coumarin and its reactive tendencies.
The type of reaction you will be performing is a multicomponent, one-pot, Mannich reaction. In general, a Mannich
reaction involves the condensation of a nonenolizable aldehyde, a primary or secondary amine and an enolizable
carbonyl compound:
For your first synthesis, you will be using 4-chlorobenzaldehyde for your nonenolizable aldehyde, piperidine for your
amine and 4-hydroxycoumarin which has an enol moiety.
For your second synthesis, you will again use 4-hyroxycourmarin, but you will choose a different aldehyde and/or amine.
Project Planning
Your team will need to plan two syntheses:
1. For the first synthesis you must repeat the synthesis of compound 4l from the scientific paper included in this
document. The procedure is described in the paper included in this document. You must monitor the reaction
as it progresses and you must characterize your product using whatever methods are available in the lab. You
will also submit your product for proton spectra using high field NMR.
2. The second synthesis must be a variation of the first. You must choose at least one different starting reagent.
You must justify your choice for your variation based on background reading, provide preliminary data and good
reasoning. As with the first synthesis, you must monitor the reaction as it progresses and you must characterize
your product using whatever methods are available in the lab. You will also submit your product for proton
spectra using high field NMR. NOTE: Do not scale up your reaction.
Equipment Available for Use
Anything normally available in the lab. If you need additional equipment, talk to your TA as soon as
possible to see if it can be provided.
Reagents Available for Use (Note that this list is NOT the same as in the journal article. USE THIS LIST)
• 100% Ethanol and Dichloromethane
•
4-hydroxycoumarin
•
Aldehydes
1. Benzaldehyde
2. p-tolualdehyde
3. p-bromobenzaldehyde
4. p-nitrobenzaldehyde
5. p-ethylbenzaldehyde
6. salicylaldehyde
7. p-hydroxybenzaldehyde
8. p-chlorobenzaldehyde
•
Amines
1. Morpholine
2. Pyrrolidine
3. Piperidine
4. Allylamine
Project Proposal Guidelines
Description
Basically your proposal is a very detailed pre-lab writing. You need to write the reaction schemes for your two
syntheses, a detailed procedure, a list of chemicals being used as well as relevant physical constants and safety hazards.
You should have enough detail so that you are ready to start when you enter the lab to work on your project.
Include all the sections listed below.
Write in your ELN so you can access the document easily during lab. Submit as a PDF using the assignment link provided
on Canvas
Proposal Sections:
1. Title and Group Members
2. Purpose of Experiment
a. Reaction Scheme for synthesis of (compound 4l)
b. Reaction Scheme for modified synthesis of new compound
3. Experimental Procedure:
a. Replication of synthesis
Enough procedural detail must be given so that anyone in your class would be able to repeat what you
plan to do. This should include details such as starting amounts of all reagents, solvent and catalyst, and
what glassware you plan to use. You must also give details how you plan to monitor, work up and
characterize your product.
b. Proposed modified synthesis of new compound
See Replication of synthesis, above.
4. Chemical Table
List chemicals being used as well as formula, relevant physical constants.
5. Safety Analysis:
Include all safety and hazard information specific to this project. Hazard information for each chemical
being used should be included (from Safety Data Sheets (SDS)).
6. References
List any references you use including the provided scientific paper. Use the same format used for references in
this document.
ELN Guidelines
Description
Your ELN for your project will be slightly different than for a typical experiment.
Please make sure you read and follow the guidelines given below.
All work should be done in your ELN. Submit using the link provided on Canvas
Sections
1. Title and Group Members.
2. Raw Data and Observations
a. This section should serve as your research notebook. Write down actual masses, volumes, etc. that you
use. Write down any observations that will help you draw conclusions later. Also, write any changes in
procedure from what was written in your proposal. This section must have a timestamp that matches
your lab class time. You may have two “Raw Data and Observations” sections in your ELN: one for each
class period.
3. Analysis Questions
a. Write a mechanism for both your synthesis of compound 4l and synthesis of new compound.
b. Give evidence that you monitored your reactions and determined when they were complete.
c. Give evidence whether or not purification was necessary and whether or not your final products were
pure (other than spectra).
d. Give evidence that your products were what you expected based on your reaction scheme. Your key
evidence should be your high field proton NMR spectra. You should have at least one other piece of
supporting evidence. Your proton NMR spectra must be included in your ELN submission and needs to
be interpreted. Draw a structure on the spectra and assign each peak to the corresponding hydrogen(s)
in the structure.
e. Calculate your percent yield. Show your work to get full credit.
4. Reflective Writing
a. Write the same sections you would write for a normal ELN.
b. If your one or both of your syntheses were successful, describe this completely in your Explain and
Evaluate section. Be sure to tie all evidence together in your explanation. Describe what you have
learned about the particular reaction you ran. Whether your reaction was successful or not, discuss the
mechanism of the expected reaction and what intermediates formed, what played to role of
nucleophile, electrophile and what is the rate determining step.
c. If either or both of your syntheses were not successful, carefully examine why in the Explain and
Evaluate section and discuss what you would do differently if you had the opportunity to repeat. If both
syntheses were successful, discuss what you would do differently to improve yield or cut down on
reaction time.
d. For the extend section, you may not restate anything from the introduction in this document. Use the
internet or look up some of the references given to provide different information.
Rubric: 332L Project Proposal
Category
Excellent
Group Members and
Title
Purpose of
Experiment
2 pts
Title and Partner(s) are given
10 pts
Schemes are given for both
syntheses and are correct. A
rational based on chemical
properties of starting material
chosen for second synthesis is given.
Procedure:
Replication
8pts
Complete: Reader could repeat
synthesis with provided
information.
Procedure:
Modified Synthesis
8 pts
Complete: Reader could repeat
synthesis with provided
information.
Chemical
Information and
Safety Table
10 pts
Each chemical used (including
solvents, etc.) is listed along with
properties relevant to being able to
complete the experiment as well as
safety information.
2 pts
Complete
References (3%)
Good/Acceptable
Not Used
8 pts
Minor changes are
necessary for schemes
to be complete and
correct and/or
rational is given, but
has minor flaws.
6 pts
Minor Omissions:
Reader could repeat
synthesis but would
have to make some
assumptions.
6 pts
Minor Omissions:
Reader could repeat
procedure but would
have to make some
assumptions.
8 pts
Minor Omissions
Not Used
Needs Improvement
Unacceptable
1 pt
One is missing
6 pts
Major changes for reaction
schemes are necessary to be
complete and correct. Rationale is
given, but has significant flaws.
0 pts
Both are missing
0 pts
Missing
5 pts
Major Omissions: Procedure is not
repeatable with the provided
information.
0 pts
Missing
5 pts
Major Omissions: Procedure is not
repeatable with the provided
information.
0 pts
Missing
6 pts
Major Omissions
0 pts
Missing
1 pt
Attempt made but has omissions
0 pts
Missing
Rubric: 332L Project ELN
Category
Excellent
Good/
Acceptable
Needs
Improvement
Missing
Group
Members and
Title
TA Points
2 pts
Title and Partner(s) are given
Not used
1 pt
One is missing
8 pts
Preparation for project:
Student came to lab ready to work and was not overly dependent on
TA. Other partner was not doing most of the work.
Lab courtesy and Safety:
Cleaning up messes, Clean and return shared equipment, Clean
balances
Close chemical containers, Following instruction especially with
regards to safety, Etc.
8 pts
Enough detail should be included here that the reader knows what the
student did when combined with procedure provided in proposal. Any
data should be recorded here such as Rf values, melting points, or
anything else relevant. There should be a data section for both project
lab periods with appropriate time stamps.
12 pts
All analysis questions are answered. Answers are thoughtful,
thorough, and sensible. Spectra have product structures drawn and
peaks labeled with corresponding hydrogens. Spectral labeling must
be easy to read (not too sloppy).
Explain and Evaluate
8 pts
Successful syntheses are described completely and evidence given
based on data. Student described what was learned about Mannich,
multicomponent reactions. The mechanisms for the expected
reactions are explained in terms of intermediates formed and what
role these intermediates play as well as what step is rate determining.
Unsuccessful syntheses are examined. If no product was obtained,
reasons for lack of success are given as well as a discussion of what
would be done differently if student had the opportunity to repeat the
reaction. If completely successful, students discuss what could be
changed to increase yield and/or reduce reaction time.
Extend to Content beyond the Lab:
2 pts
Students discuss how what they learned in lab is related to something
outside of lab (lecture, reading, news, etc. are possible sources).
Material given in the introduction may not be restated. References
used should be given.
6 pts
TA choice
4 pts
TA choice
0 pts
Both are
missing
0 pts
TA choice
6 pts
Minor mistakes
and/or omissions
4 pts
Major mistakes
and/or
omissions
0 pts
Missing
10 pts
Minor mistakes
and/or omissions
6 pts
Major mistakes
and/or
omissions
0 pts
Missing
6 pts
Minor mistakes
and/or omissions
4 pts
Weak or vague
explanations are
given for
success of
syntheses and
sources of error.
0 pts
Missing
Not used
1 pt
Some attempt
made but needs
a great deal of
work.
0 pts
Missing
Data and
Observations
Analysis
Questions
Reflective
Writing
Synthetic Communications1, 42: 3077–3088, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.575524
CATALYST-FREE, ONE-POT, EXPEDITIOUS SYNTHESIS
OF AMINOALKYLNAPHTHOLS AT ROOM
TEMPERATURE
Chhanda Mukhopadhyay,1 Sunil Rana,1 and Ray J. Butcher2
1
Department of Chemistry, University of Calcutta, Kolkata, India
Department of Chemistry, Howard University, Washington, DC, USA
2
GRAPHICAL ABSTRACT
Abstract Aminoalkylnaphthols possess several biological and catalytic activities. A methodology has been developed for the multicomponent one-pot synthesis of aminoalkylnaphthols
in dichloromethane under catalyst-free conditions at room temperature. The present
approach possesses several advantages such as excellent yields, quick reaction time, mild
reaction conditions, and very easy purification processes. Thirteen new compounds in
addition to six known compounds have been synthesized by this methodology.
Keywords Aminoalkylnaphthols; catalyst-free; dichloromethane; one-pot synthesis;
room temperature
INTRODUCTION
Recently, the synthesis of aminoalkylnaphthols has received special attention
from the scientific community because of their significant biological[1] and catalytic[2]
properties. These compounds, possessing multiple chelating centers, are potent inhibitors of metalloenzymes containing Fe, Cu, Zn, and Co ions as cofactors.[3–6] In
addition, these compounds have the ability to act as scavengers of heavy metals
(Hg, Cd, Pb, As, Sb).[7,8] They also show potent oxytocic activity.[9] A number of
Received February 12, 2011.
Address correspondence to Chhanda Mukhopadhyay, Department of Chemistry, University of
Calcutta, 92 APC Road, Kolkata 700009, India. E-mail: cmukhop@yahoo.co.in
3077
3078
C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER
Scheme 1. Synthesis of aminoalkylnaphthols.
aminomethylphenols have been reported in the literature[10] as chelating agents in
metal-catalyzed asymmetric induction in many reactions. Chiral Mannich bases
are frequently used as ligands in a variety of metal-mediated enantioselective carbon–carbon bond formation reactions.[11–17] Such importance of the aminoalkylnaphthols has caused us to pursue a simple and easy method for their synthesis.
Since 1900, aminoalkylnaphthols have been synthesized by the
three-component condensation of secondary amines, aromatic aldehydes, and
naphthols (Scheme 1). In 1900, Mario Betti synthesized aminoalkylnaphthols
(so-called Betti bases) for the first time.[18] After a long gap, Katritzky et al. in
1999 reported the synthesis of aminoalkylphenols by benzotriazole methodology
using phase-transfer catalysis.[19a] Saidi et al. synthesized the compounds with lithium perchlorate.[19b] Recently, Jha et al have developed the methodology of
p-toluene sulfonic acid–catalyzed microwave irradiation.[20] Kumar et al. explored
the synthesis by nonionic surfactant-catalysed methodology.[21] In addition to these,
a few other methodologies are also available in the literature.[22]
RESULTS AND DISCUSSION
Most of the earlier procedures for aminoalkylnaphthol synthesis[18–22] suffer
from harsh reaction conditions, catalyst nonrecyclability, or a need for column chromatography for further purification. Our main aim was to synthesize aminoalkylnaphthols while avoiding expensive catalysts, using mild reaction conditions, and
avoiding time-consuming column chromatography. After a thorough search for
proper catalysts and reaction medium for the standard reaction of pyrrolidine,
2-naphthol, and 4-bromobenzaldehyde, we found that dichloromethane at room
temperature (25–30 C) proved to be the best reaction medium (Table 1, entry 3),
and the product conversion was so high that no additional catalyst was required.
This is the most important aspect of our methodology. The workup procedure is also
very simple. After the completion of the reaction, checked by thin-layer chromatography (TLC), dichloromethane was pumped out by rotary evaporation. The product was purified by direct crystallization from ethylacetate and petroleum ether
(60–80 C), thus avoiding time-consuming column chromatography. This is the
second important aspect of our methodology.
Once the optimum condition was reached for the model reaction, various aromatic aldehydes and secondary amines were tried for this reaction. Aromatic aldehydes with slightly electron-withdrawing groups yielded the best results, while
electron-donating groups slightly decreased the yield. Aromatic aldehydes with
SYNTHESIS OF AMINOALKYLNAPHTHOLS
3079
Table 1. Choice of reaction medium for the synthesis of the aminoalkylnaphthols at room temperature
taking the standard reaction of 2-naphthol, 4-bromobenzaldehyde, and pyrrolidine
Entry
1
2
3
4
5
6
7
8
9
10
Solvents (5 ml)
Time (h)
Yield (%) (isolated)
Methanol
Ethanol
Dichloromethane
Dichloroethane
Acetonitrile
DMF
Water
DMSO
1,4-Dioxane
THF
2
2
2
2
2
2
2
2
2
2
55
60
92
67
45
55
58
40
35
53
Figure 1. X-ray structural analysis of a single crystal of 2-[(4-chlorophenyl)-piperidine-1-yl-methyl]naphthalen-1-ol (4q) (Table 2, entry 17) showing the crystallographic numbering (CCDC 800110). (Figure
is provided in color online.)
3080
C. MUKHOPADHYAY, S. RANA, AND R. J. BUTCHER
ortho-substitution also decrease the yield slightly. This may be due to the steric
effect. Of the secondary amines, piperidine, pyrrolidine, morpholine, N-methyl piperazine, and dimethylamine were used. In all cases, the yields of the desired products
were moderate to excellent. We further extended the scope of the reaction by using
4-hydroxycoumarin and 1-naphthol as nucleophiles in place of 2-naphthol, with
good yields. With 1-naphthol, the substitution occurs specifically at the 2-position
(and not at 4) because of the stability of the product by intramolecular six-membered
hydrogen-bond formation (further evidence in Fig. 1).
All the products are well characterized by melting points, infrared (IR), 1H
NMR, 13C NMR, and CHN analysis. In 1H NMR, the -NCH2 protons and in 13C
NMR, the -NCH2 carbons appear as broad peaks. This is due to electrical quadruple
moment of nitrogen. The crystal structure of 1-[(4-bromophenyl)-pyrrolidin1-yl-methyl]-naphthalen-2-ol (Table 2, entry 7) is given in Fig. 2. which shows a
strong hydrogen bonding between OH of 2 …
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