1. CHE-215-002
Research Methods in Organic Synthesis
January 2016
Gustavus Adolphus College
Prof. Scott Bur
Office: 303B, Nobel Hall Website:moodle.gac.edu
Telephone: 933-7038
Email: sbur@gustavus.edu
Textbook: None
Supplies: None
Classroom: NHS 305, Nobel Hall; 301, Nobel Hall (lab)
Goals for the Class
In pharmaceutical research and development, a privileged structure is the structure
of a compound that is known to be active in whichever screen was used to evaluate the
compound. For our project, there are several privileged structures.
We will be exploring the literature for synthetic routes to each of these structures
as a class, devising synthetic routes that allow is to generate numerous analogs, and
executing those syntheses. Testing of the compounds will take place at the University of
Minnesota in Will Pomerantz's lab.
Structure of Class
Unless otherwise instructed, we will meet in the mornings for approximately 30
minutes (room 305) to go over questions and detail new techniques. The remainder of
the day will be spent doing research (laboratory or library). We will break for Chapel (10
- 10:30 am) and lunch (can be variable) and try to finish by 4 pm each day.
S S
N
O
OH
3F5
OH
O
Cl
Cl
11E7
N
N
N
H
F
F
F
8E2
S
OH
O
Cl
2G11
2. Homework:
This course is primarily a laboratory research course, but there will be a
substantial amount of literature searching, data analysis, and presentation of data.
Assignments will include:
• A literature review of known synthetic methods for the structural classes to
which one of the lead compounds belongs. This will be assessed through
classroom presentations.
• A synthetic plan, including retrosynthetic analysis and proposal of reagents
and conditions to accomplish the synthesis of an analog of a lead compound.
This will be assessed through a written proposal
• A literature review of protein:protein binding domains.
• Final laboratory report describing the synthetic methods, experimental
conditions, and characterization of compounds. (See below)
Exams:
There will be no exams.
Grading:
The class is pass/fail. Passing is defined as being engaged in all activities, and making
demonstrable process toward completing the synthesis of a target molecule. Minimally,
this would include completion of a literature search and presentation of "current state" to
the class, completion of synthetic plan, and some forward progress on execution of the
planned synthesis.
Student Learning Objectives:
Upon completion of the course, students will be able to:
• Use SciFinder to search for chemical information
• Develop a synthetic plan for making some small molecules
• Design an experiment
o Identify experimental variables
o Select appropriate reaction conditions
o Assemble appropriate equipment for conducting the experiment
o Employ an appropriate reaction work up
o Develop a safety plan for executing the experiment
• Isolate pure compounds from complex mixtures
• Elucidate the structures of new compounds
• Communicate experimental conditions and compound characterization in writing
Disability Services
Gustavus Adolphus College is committed to ensuring the full participation of all
students in its programs. If you have a documented disability (or you think you may have
a disability of any nature) and, as a result, need reasonable academic accommodation to
participate in class, take tests or benefit from the College’s services, then you should
speak with the Disability Services staff, for a confidential discussion of your needs and
appropriate plans. Course requirements cannot be waived, but reasonable
3. accommodations may be provided based on disability documentation and course
outcomes. Accommodations cannot be made retroactively; therefore, to maximize your
academic success at Gustavus, please contact Disability Services as early as possible.
Disability Services (www.gustavus.edu/advising/disability/) is located in the Academic
Support Center. Disability Services Coordinator, Kelly Karstad, (kkarstad@gustavus.edu
or x7138), can provide further information.
Academic Honesty
Academic honesty in, perhaps, more of an issue in this class than in other
chemistry classes. Not only do I expect you to do your own work, you will be asked to
do outside research on some of the compounds we will discuss and make. Be certain to
clearly cite your references. Citation styles in chemistry are substantially different than
other fields, so we will learn how to properly cite material as we go.
By enrolling in this course, you are bound by the Gustavus Honor Code
"On my honor, I pledge that I have not given, received, nor tolerated
others' use of unauthorized aid in completing this work."
Reference Desk Assistance
The library’s Reference Desk provides one-on-one guidance to help you with your
research. The reference librarians will help you find information on a topic, develop
search strategies for papers and projects, search library catalogs and databases, and
provide assistance at every step. No appointment necessary. Visit
www.gustavus.edu/library/reference_question.html for hours, location, and more
information.
Safety
Safety in a laboratory is everyone's responsibility. As such, there are a few things
everyone must consider:
1) Wear the appropriate protective equipment when in the lab
a) Safety Glasses / Goggles
b) Closed-toe shoes
c) Gloves
2) Work with hazardous materials in a fume hood
3) No eating or drinking in lab
4) Don't do any unauthorized experiments
5) Don't put unused chemicals back into the stock container
6) Don't sniff (or eat) the chemicals
7) Label everything.
8) Know where safety equipment is located! (fire extinguisher, shower, etc.)
9) Know the compounds with which you are working! (MSDS)
If an unsafe situation develops, tell your instructor immediately.
4. Campus Safety and Security can be reached at 8888.
Many of these things seem obvious. Some deserve special comment. One should
never taste a chemical in the lab. The Food and Drug Administration has very strict
standards that all food grade and pharmaceutical compounds must follow.
5. Lab Notebooks
Introduction
The proper documentation of experimental procedures, data, and observations is as
important in the practice of experimental science as the experiment itself. Without such
documentation, it is impossible to reproduce an experiment, report it to others, or, the
case where a new, important discovery has been made, to prove who the discoverer is.
These are important issues when considering patent applications for potential drug
candidates. The laboratory notebook is the primary means of documenting procedures,
observations, discoveries, and data, and so must be maintained with care.
General Considerations
The laboratory notebook has the following characteristics:
a.) It must be written legibly and in ink. Ink entries are relatively permanent,
while pencil entries are abraded away with time and eventually cannot be
read. Writing so that others can read the laboratory notebook is essential, so
that any other person knowledgeable in organic chemistry would know
exactly what you did and observed, and would be able to reproduce the
experiment based on your notes.
b.) All observations and data are written directly into the notebook. Writing them
elsewhere and copying them into the notebook allows for copying errors. In
addition, if you receive help from others or from reference books to complete
your laboratory, acknowledge the person or literature reference. There is
nothing wrong with obtaining help, as long as you acknowledge the source!
You will notice that all of the experiments in this course pack reference other
people for experimental details.
c.) Nothing should be erased. Mistakes should be crossed out with a single line,
so that the original information is still readable beneath the cross-out.
d.) Only laboratory work is recorded in the notebook. Class notes, library
reference work are not useful to others reading your record of experimental
procedures and observations.
e.) Your descriptions of procedures, observations, and data should be sufficiently
detailed to allow another to repeat the experiment and confirm your results
only using your notebook as a guide. This includes "landmark" observations
to confirm that the reaction is proceeding as expected. This includes color
changes or precipitate formation at particular point in the reaction. Note also
whether or not starting materials and/or products are soluble in the reaction
solvent.
Following these guidelines, the experiment should be recorded as it is conducted in the
notebook
6. Format Guide
a.) Use a bound notebook
b.) Number every page in your notebook before starting the first laboratory.
c.) Reserve pages 1-3 for a Table of Contents, and update that table after each lab
period.
d.) Use ink.
e.) Date all notebook pages as you add data to your notebook.
f.) Do not skip pages.
g.) Do the pre-lab portion of your notebook writing before you come to lab by
entering the following:
a. Reaction scheme at the top of the page.
b. The date on which the experiment was started in the top right corner.
c. References (i.e. pages from your text, other sources used from the
library for physical characteristics of your reagents).
d. A table of reagents, listing the relevant physical properties of the
compounds involved, including the predicted products. This includes,
molecular masses, quantities (grams and moles), boiling points,
densities, etc. You will likely need an additional reference to obtain
this data (e.g. Aldrich, CRC, Merck Index).
h.) Enter what you do and observe directly into the notebook as you perform the
experiment during the lab. If you anticipate the collection of data, set up a
table in advance in your notebook, which will make it easy to record and
evaluate the data later. Again, the running account of the experiment
should be written while the work is being done. Things to note:
a. All measurements that you make (i.e. masses and volumes).
b. Observations you make of colors, physical states (solid, oil, liquid),
and behavior of a reaction, especially changes in any of these
properties.
c. Any difficulties that you have with the procedure.
i.) After you have completed the experiment, complete any calculations needed
and enter them directly into the notebook. These calculations may include
percent yields, estimated uncertainty, interpretations drawn from data, and a
presentation of your results. In addition, an explanation of observations you
made in your running account and discussion of possible sources of error.
Example
On the next page, you will find an example from my research notebook. While not
perfect, anyone who is trained in organic chemistry should be able to reproduce this
experiment.
7.
8. 6
Lab Reports
While this is not a writing class, the effective communication of experimental
results is an important aspect of experimental sciences. "Effective communication" is
more than just writing about what you did and what you got. In order for you to learn
how chemists communicate (in a formal way) with each other, we will try to follow a
standard publication style of write up.
A publication consists of at least 4 discernable parts: an abstract (brief summary),
an introduction (why are you doing the experiments), results and discussion (what
happened, why, and what does it mean), and an experimental section. You will find each
of these parts described in more detail below:
Abstract
This provides a very brief description of what you are trying to do, and then what
the specific results of your experiments are. These are somewhat tricky because you
want to be very precise but very brief.
Introduction
One must place their experiments into context by explaining why the results are
important. For this class, that means you must provide a reason why the molecules we
are making could be interesting. Accordingly, the introduction of your report should
provide enough background that a reader will find your experiments interesting enough to
continue reading. Think of writing a paper like telling a story: You need a "hook" up
front so people don't tune out. This section should also provide a quick overview of what
your experiments plan to show.
Results and Discussion
The next section describes how you conducted the experiments (especially if you
employed a "non-standard" technique), and what happened during the experiments. This
is not where you provide a running commentary of the experimental procedure. Rather,
this gives you a chance to provide a brief description of the reactions, including any
interesting mechanisms, and outline the important discoveries made because of the
reactions. Use the questions at the end of each experiment (in the "Reports" section) to
guide your discussion points.
Experimental
This is where you provide a running commentary about how each reaction was
run. Many call this section the "Materials and Methods" section since it spells out what
materials were used and which methods were applied to get the results discussed in the
9. 7
body of the paper. This section should contain sufficient detail that anyone who has been
trained in organic chemistry can follow the procedure(s). It should also list relevant
physical data for the isolated compound(s). This includes, but is not limited to, NMR
(both 1H and 13C data), IR, melting point or boiling point, and mass spectrum.
Example
Look in the primary literature of organic chemistry for examples of how a paper
should be written. A good place for short, simply written papers is Organic Letter. You
can access Org. Lett. at http://pubs.acs.org/journals/orlef7/index.html. The Journal of
Organic Chemistry is another good place to look. All the journals to which you have
access are listed on the library's web site.
Many styles can be used when writing a paper. When looking through papers,
note that the "introduction" and "results/discussion" sections are not clearly shown with
separate headers. This is common for shorter papers.
Below is an example of an experimental procedure that is in an accepted style. I
will expect your reports to follow a similar format. For example, the amounts of reagents
are not reported in just grams, but mL and or mmols. Note also that colors of reaction
mixtures should be noted here. You should note when a color changes and when/if any
precipitate is formed. Reports that I find lacking in style will be returned for a rewrite, so
spend some time to get it right the first time through. Many manuscripts for short papers
are 8 - 10 pages when typed. Obviously, 10 typed pages is overkill for the projects on
which you will be working. I will leave the length of each report up to you: be as
complete as possible, but be brief. No one wants to read more than is necessary to
understand what you are reporting.
2-Triisopropylsiloxyfuran (1.95a). To a solution of Et3N (9.76 mL, 7.08 g, 70.0
mmol) and 2-(5H)-furanone (3.55 mL, 4.20 g, 50.0 mmol) in anhydrous CH2Cl2 (50 mL)
at 0 ˚C was added TIPS-OTf (16.13 mL, 18.39 g, 60.0 mmol) over 15 min. Stirring was
continued at 0 ˚C for 15 min and then at rt for 16 h. The amber solution was diluted with
Et2O / petroleum ether (1:1, 250 mL) and successively washed with cold saturated
aqueous NaHCO3 (2 x 150 mL) and cold saturated aqueous CuSO4 (150 mL). The
organic phase was dried (MgSO4) and concentrated to afford a yellow liquid that was
distilled (65 ˚C, 0.35 mmHg) to yield 11.48 g (95%) of 1.95a as a clear, colorless oil. 1H
NMR (250 MHz) δ 6.77 (dd, J = 2.2, 1.1 Hz, 1 H), 6.17 (dd, J = 3.1, 2.2 Hz, 1 H), 5.09
(dd, J = 3.1, 1.1 Hz, 1 H), 1.33-1.15 (m, 3 H), 1.07 (d, J = 6.7 Hz, 18 H); 13C NMR (62.9
MHz) δ 157.0, 131.8, 111.1, 83.4, 17.5, 12.2; IR (neat) 1617, 1611 cm-1.
OO
Si
2
3
4
5
1.95a
6
7
