Organic Chemistry Research Proposal
Organic Chemistry Research Proposal
Some of you may be thinking about going on to graduate school in Chemistry,
Biology, or a similar discipline. Many students are unprepared to judge whether they
would enjoy graduate school based on their undergraduate experience. In graduate school
it is common to spend most of one’s time, not on classwork, but on undertaking original
research. Original research has its own joys and its own frustrations. It is the aim of this
laboratory to give you a little experience with research so that you can make an informed
decision as to whether it is for you. Read pp. 449-457 in Lehman to see what sort of
advice and preparation are suggested there and follow the instructions herein.
Team Project—Individual Work
The only way we can expect to get meaningful results within the quarter is to
work together as a team. Your team will be made up of those at the same lab bench. The
whole class will all be working on the same general topic (cyclization of hydrazones, see
below) but each team will work independently on any aspect of these reactions that they
wish. You must work together to decide on a research proposal that appeals to all of you.
The team should define a problem, develop a hypothesis, plan a course of action in which
each member works independently to obtain results applicable to this hypothesis,
evaluate the results of the entire team to reach a conclusion, report your team’s results in
an independent research report.
Cyclization of Hydrazones
Acyl hydrazones such as 1 are synthesized from the reaction of acylhydrazides with
ketones or aldehydes. Based on the substitution of the carbonyl group (X and Y) and the
hydrazide (Z), there are several possible hydrazones that can be made. Some of these are
known but there may be some that have never been reported in the literature.
O H N Z
X Y H2N O
Hydrazones themselves can be oxidatively cyclized with lead tetraacetate. The
cyclization can yield three different heterocycles: an oxadiazole (2), a ∆3 oxadiazoline
(3), or an imino ∆3 oxadiazoline (4), depending on the nature of the substituents and
N Z N Nu
N X=R ∆3 oxadiazoline, 3
O Nu solvent
X Y Y
Pb(OAc)4 N NR
1 N imino ∆3 oxadiazoline, 4
Z = NHR X O
Oxadiazoles, 2, are well-studied aromatic heterocycles that have been used as herbicides,
insecticides, fungicides, and organic light-emitting diodes (OLEDs). Oxadiazolines, 3
and 4, have been used as carbene precursors for cyclopropanations and other reactions.
1. Optimize the yield and purity of a novel compound (2, 3, or 4) or of a novel route to a
known compound. Most oxadiazoles, 2, are made by means other than those shown here.
First, search the literature to make sure that the compound is new or that your suggested
method is substantially different from that used by others to synthesize the target. You
may want to make your own ketone starting material in order to get a unique product.
Each member of the team should have a series of solvents, temperatures, or
concentrations and determine the optimum reaction time and yield. Synthesize the
product using the best reaction conditions then purify and characterize the product with
IR, NMR, mp, etc.
2. Each team-member makes a different derivative (known or unknown) in a logical
series. Vary X, Y, Z, or nucleophilic solvent in a consistent way by varying the sterics,
electronics (donating/withdrawing), conjugation, etc. and see what kind of difference this
alteration has on:
a. The rate or yield of product (or product ratio)
b. The UV photoluminescence of 2 (reported to emit blue light).
c. The insecticidal activity of 2.
d. The herbicidal activity of 2.
e. The ability of 3 or 4 to undergo thermal cyclopropanations (see below).
f. The ability of 3 or 4 to undergo photochemical cyclopropanations (see below).
3. Various ∆3 oxadiazolines have been shown to yield carbenes (XYC:) on heating or
with light via a 1,3-dipolar cycloreversion. The preferred pathway may be that shown in
black below but other pathways are theoretically possible (shown in gray) and the
intermediate diazo compounds or carbonyl ylides could react with alkenes in 1,3-dipolar
addition reactions to give other products. Each team member could try different
conditions with the aim of optimizing the cyclopropane or any of the five-membered
1,3-dipolar Nu R
cycloreversion X X
Y Y R'
X Z carbene
N Z - N2
N Nu Y O Nu
Y carbonyl ylide R
Nu Nu R'
X Z N X N Z
Possible 1,3-dipolar Y Nu Y Nu
R R R R R R
4. Instead of making oxadiazolines, 3, in a nucleophilic solvent, utilize an intramolecular
nucleophile to generate a new oxadiazoline. Each team member could work on different
variants of Y: with accessible nucleophile attached, without nucleophile, with
Nu N Z
X X O
5. Do any other project that has not been done before. The best projects are those in
which each team member works in parallel (that is, no one waits on anyone else) and one
that will still be interesting even if one team member gets no results. Before you get too
far along in the process, give me your rough ideas to get feedback early. Make sure you
clearly define what each team member will do.
Doing a literature search is essential to find out what is already known about your
research proposal and, later, to find out what is known about possible rationales for your
experimental results. A thorough literature search would entail using the Chemical
Abstracts to search the entire body of published literature. During this short time-frame it
makes more sense to search the literature to which we have ready access. We have access
to journals from four publishers: The American Chemical Society (ACS), Elsevier,
Wiley, and Kluwer. Each student should clearly indicate which databases were searched
personally. Indicate the keywords and the parameters (searching on the full text / abstract
/ title / keywords, applicable dates, etc.). Be careful to select all dates and all journals but
do not worry if there are older articles to which we do not have access. Give a proper
reference for each article that you have personally read.
Search Sites (in order of their relative usefulness)
Elsevier: click on search from http://www.sciencedirect.com/
Kluwer: click on advanced search from http://journals.kluweronline.com/
Internet Resources: Use www.google.com or a similar search engine but keep
in mind the inherent unreliability of information that is not peer-reviewed.
Developing a Proposal
The group should work together to define a problem in which everyone is interested.
Search the literature to ensure that the problem isn’t already answered and to get
background information. Based on your knowledge of the chemistry and literature
develop a hypothesis to be tested (the hypothesis could be as open ended as, “by varying
reaction conditions an optimal procedure for synthesis of the novel compound X will be
found”). Define a plan with specific reaction conditions, amounts, etc that will allow each
student to work in parallel on the project. The available chemicals will be listed on the
course website to help you develop a feasible plan. The proposal should have the
A brief statement defining the problem, a hypothesis, and how that hypothesis will be
A brief summary of what is already known about the problem (with proper references).
Attach a page from each student showing the literature search keywords, parameters, and
databases used, and the results obtained. Make a list of the full articles that were read.
Detailed procedures should be provided for each team member, listed by name.
You’ll want to check out several literature procedures for compounds as similar to the
one you intend to synthesize to compare ease and yield. The following, however, are
typical of the procedures you might find.
Typical procedures for preparation of hydrazones:
(Method A) Reflux hydrazides with aldehydes or ketones in methanol in the presence of
two drops of acetic acid. The product crystallizes out of solution and is relatively pure
after washing and drying.
(Method B) Utilize a Hickman-head still as a Dean-Stark trap to remove water. Reflux
hydrazides with aldehydes or ketones in toluene. The product crystallizes out of solution
and is relatively pure.
Typical procedures for cyclization reactions:
(Method C, without nucleophile) The hydrazone is added in small portions and with
stirring to lead tetraacetate (slight excess) in dichloromethane cooled with ice. After
addition is complete, the reaction mixture is left in the ice bath for 3 h. Lead diacetate is
removed by filtration through a bed of Celite. Most of the solvent is evaporated and the
residue is shaken with an aqueous solution of 5% sodium bicarbonate and extracted
several times with dichloromethane. The organic layer was dried and evaporated to give
crude product which can be further purified by column chromatography.
(Method D, in the presence of an alcohol as nucleophile) Oxidative cyclization of an
hydrazone with lead tetraacetate in the presence of an alcohol, either neat or in
dichloromethane, yields a mixture of the desired 2-alkoxyoxadiazoline and the
corresponding 2-acetoxy-oxadiazoline. The acetoxy moiety is saponified by adding
strong base to the crude reaction mixture, and the remaining alkoxyoxadiazoline is
extracted and purified by vacuum distillation.
(Specific example with methanol as solvent) A solution of hydrazide in methanol is
added dropwise to a solution of lead tetraacetate in methanol at 0 ˚C. After warming to
room temperature and approximately four hours of reaction time the yellow color of the
mixture should disappear. Potassium hydroxide in methanol is added and the resultant
mixture is stirred overnight tightly capped. The mixture is extracted with
dichloromethane, dried with magnesium sulfate, and the solvent is evaporated. The
residue can be purified by vacuum distillation and/or column chromatography (silica, 5%
EtOAc in hexane).
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