Applications of benchtop NMR in the organic chemistry instructional laboratory

Article abstract of DOI:10.1002/mrc.5031

The instructional organic chemistry laboratory has been substantially improved through the implementation of benchtop NMR analysis. When used in conjunction with unknown reaction components in multi-outcome experiments, NMR analysis transforms the laborat

Full text of DOI:10.1002/mrc.5031

Morrison Richard W. (Orcid ID: 0000-0002-2807-6379)
Applications of Benchtop NMR in the Organic Chemistry Instructional
Laboratory
Richard W. Morrison* and Mengqi Zhang
Department of Chemistry, The University of Georgia, Athens, Georgia 30602 United States
ABSTRACT
The instructional organic chemistry laboratory has been substantially improved through the
implementation of benchtop NMR analysis. When used in conjunction with unknown reaction
components in multi-outcome experiments, NMR analysis transforms the laboratory exercise
into an investigative inquiry wherein students elucidate structures for their products and
thereby deduce their unknown reaction components. This analytical approach closely models
the research laboratory and is a valuable preparatory tool for undergraduate researchers. Three
newly developed multi-outcome experiments based upon the Diels-Alder cycloaddition, the
synthesis of carboxylic amides, and the Friedel-Crafts alkylation are herein described to
illustrate the utility of benchtop NMR analysis in the instructional laboratory.
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BACKGROUND
Historically, the introduction of NMR spectroscopy into the organic chemistry instructional
laboratory faced several significant challenges.[1-3] Perhaps the most significant of these was
the cost of the instrument. Even early 60MHz and 90MHz fixed magnet instruments were cost
prohibitive for many institutions. With the advent of high field instruments, purchase and
maintenance costs increased significantly.[4,5] Consequently, NMR analysis in the instructional
laboratory remained out of reach for several decades.
Chemistry departments that were fortunate to find sufficient resources to purchase NMR
spectrometers, either internally or externally through large equipment grants, grappled with the
second major challenge: user time and access to the instrument. Research use of high field
spectrometers was prioritized, rendering instructional access infrequent. The development and
implementation of robotic arms to introduce NMR sample tubes to the spectrometer somewhat
increased access to the NMR for instructional purposes. However, the logistics of processing
several hundred student sample tubes were daunting, making sample turnaround time a serious
obstacle. Therefore, NMR analysis as an analytical tool in instructional laboratories for
students at large enrollment institutions remained unfeasible.
Benchtop NMR spectrometers provide a remedy for these formidable challenges. Modern
benchtop NMR spectrometers can be obtained for less than ten percent of the cost of a new
high field instrument. Their compact size allows them to be placed in the instructional
laboratory, circumventing the need for a separate space or facility. They do not require
additional personnel specially trained for maintenance and upkeep. Such duties can be
successfully performed by graduate student assistants. And, undergraduate students can obtain
a spectrum of their sample within two minutes, thereby substantially reducing individual user
time on the instrument.
With all of these advantages, there has remained some reluctance to incorporate benchtop
NMRs into the instructional laboratory. Indeed, spectra can be produced by computer
applications, and idealized spectra that depict excellent signal dispersion and resolution can
simplify NMR interpretation for inexperienced students. However, spectra obtained
individually by students from samples they prepare in a laboratory experiment constitute a
powerful instructional tool. Students acquire a sense of individual ownership of their results.
And, exposure to actual results in contrast to idealized results better prepares students for
further studies as undergraduate researchers beyond the introductory instructional laboratory.
Thus, a well-considered set of experiments yielding product spectra that can be successfully
interpreted by newcomers to NMR analysis is transformative, changing the undergraduate
instructional laboratory from a brief introduction of experimental techniques and organic
transformations to a robust preparatory experience that produces researchers that are prepared
to engage in actual research projects in faculty research laboratories.
EXPERIMENT DESIGN AND DEVELOPMENT
Experiment design for the organic chemistry instructional laboratory is constrained by several
requirements within which the instructional curriculum must operate. First of all, laboratory
experiments must be safe for inexperienced students. This requires that experimental
procedures minimize the use of chemicals and reagents that are potentially dangerous.
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Secondly, experiments must be designed to consistently give results in good yield. In a
research laboratory, the apparent failure of an experiment can be helpful in planning and
modifying future experiments. However, failure to achieve a positive result in the instructional
laboratory is problematic because of the time required to trouble shoot the problem, identify
the cause for the unsuccessful outcome, and modify the experiment procedure for a second
trial. This analysis may lead a student investigator far astray from the desired objective of the
experiment and consequently from the intended exposure to procedures and techniques
associated with the experiment.
Thirdly, there is a significant time constraint in the
instructional laboratory. A synthetic transformation that requires a 6-hour traditional reflux
followed by a 1-hour workup is suitable for the research laboratory but not for a 3-hour
instructional laboratory period.
Perhaps the most challenging aspect of experiment design and development pertains to its
pedagogical value. A typical laboratory exercise requires all students to perform the same
procedure thereby obtaining the same product or result. For example, if all students perform
the Fischer esterification reaction to form aspirin, the grade or assessment for each student is
determined by the calculated percent yield of the product and its purity, most commonly
analyzed by melting point determination, along with the standard lab report submission. This
experiment design is woefully lacking in exposure to modern analytical instrumentation and it
does not fully engage students in experimentation and analysis. Furthermore, a newly designed
experiment of this type that is introduced into the instructional laboratory curriculum has
diminishing pedagogical value in subsequent semesters as the same unoriginal results and
analyses are shared with the next generation of students.
NMR ANALYSIS OF UNKNOWNS
The introduction of benchtop NMR analysis into the organic chemistry instructional laboratory
represents a significant advancement that addresses several of the aforementioned challenges.[6-
8]
NMR analysis is best applied with the use of unknowns. An unknown is a component of the
reaction, such as a starting substrate or reagent set, that leads to an individualized result. The
identity of the substrate or reagent is unknown to the student researcher. Thus, unknowns allow
all students to explore the same transformation while obtaining different products. The product
structures are determined by NMR analysis. As a result of pairing NMR analysis with unknown
reaction components, structure elucidation becomes a standard and integral component of an
instructional laboratory experiment and the instructional laboratory more closely models the
actual research experience.
At the University of Georgia, we have developed and implemented a library of experiments
with unknown substrates or reagent sets, called multi-outcome Experiments (MOEs). For
example, we modified the Fischer esterification reaction to include several unknown
alcohols.[9,10] Students perform a standard acid-catalyzed esterification using the same
carboxylic acid but with individually assigned unknown alcohols. The structures for the
product esters are elucidated by 1H NMR analysis using the benchtop NMR spectrometer. The
identity of the unknown alcohol is thus deduced. In this manner, the incorporation of unknowns
individualizes the experimental results for all students without significantly changing the
experimental procedure. And, analysis of these individualized experimental results entails the
use NMR spectrometry, the most common and powerful analytical tool presently available for
structure elucidation.
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THREE EXAMPLES OF NMR ANALYSIS IN MULTI-OUTCOME EXPERIMENTS
Example 1: The Diels-Alder Cycloaddition
The Diels-Alder cycloaddition reaction is an important reaction in organic synthetic
methodology.[11-13] A common example is the reaction of anthracene and maleic anhydride
which is driven to completion by the formation of an insoluble and easily isolated solid.
However, the Diels-Alder cycloaddition reaction is not widely explored in the instructional
laboratory due in large part to the equilibrium under reaction conditions between the starting
diene, dienophile and cycloaddition product and also the time required for the reaction to go to
completion.
These challenges can be successfully addressed in an MOE by reacting freshly prepared
cyclopentadiene and one of four unknown dialkylacetylene dicarboxylates in a microwave
promoted reaction using a catalyst. The reaction is completed in 30-minutes, leaving the
balance of the time for structure analysis by benchtop NMR. Figure 1 shows a student-
1
generated H NMR spectrum of the cycloaddition product obtained from the reaction of
cyclopentadiene and dimethylacetylene dicarboxylate. The product spectrum allows students
to assign the methyl protons of the methyl esters (b), the bridgehead protons of the
norbornadienyl ring (c), and the vinylic protons (d). Moreover, the spectrum clearly shows the
diastereotopic bridge protons (a,a'), which is an important instructional aspect of this NMR
analysis.
For comparison, Figure 2 shows a student-generated 1H NMR spectrum of the cycloaddition
product obtained from the reaction of cyclopentadiene and diisopropylacetylene dicarboxylate.
Again, the proton signals can be readily identified and assigned.
Example 2: Amide Synthesis
Given the biological importance of the peptide bond, inclusion into the instructional laboratory
of an amide synthesis is a worthwhile and informative exercise.[14] An MOE that utilizes acetic
anhydride and an array of unknown amines to synthesize amides can be accomplished in a
facile 10-minute reaction that is catalyzed by Al2O3. Structures of the product amides can be
elucidated by benchtop 1H NMR and the unknown amine reactants are thus deduced. Figure
3 shows the 1H NMR spectrum for N-benzylacetamide. The spectrum resolution is excellent
and the doublet at 4.25 ppm stimulates an in-depth discussion of spin coupling. For
comparison, Figure 4 shows the 1H NMR spectrum for N-(tert-butyl)acetamide.
Example 3: Friedel-Crafts Alkylation
Electrophilic substitution on an aromatic ring is a widely used synthetic transformation.[15,16]
One important example, the Friedel-Crafts alkylation reaction, is explored through an MOE
that utilizes benchtop 1H NMR. The acid-catalyzed reaction of 1,4-dimethoxybenzene with an
array of unknown alcohols produces white solids in good yields within 30 minutes. The
products are recrystallized in hot methanol. The identity of the unknown alcohol is deduced
by 1H NMR analysis of the corresponding alkylation products. Figure 5 shows the 1H NMR
spectrum of 1,4-di-tert-butyl-2,5-dimethoxybenzene, formed by the Friedel-Crafts alkylation
reaction of 1,4-dimethoxybenzene with tert-butyl alcohol. The 1H NMR spectrum of 1,4-di-
tert-pentyl-2,5-dimethoxybenzene is shown in Figure 6.
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Conclusions
The instructional organic chemistry laboratory is greatly enhanced by the inclusion of 1H NMR
analysis using benchtop spectrometers. These instruments are easily maintained and operated.
In conjunction with multi-outcome experiments, students are now able to study a given
transformation and obtain individualized results. Students are more engaged and invested in
their own experimental results thus enriching their instructional laboratory experience.
1
Product structures are elucidated through analysis of student generated H NMR spectra and
unknown components are thereby deduced. The laboratory experience models reactions and
analyses performed in faculty research labs and in this way it more thoroughly prepares
undergraduate researchers. It is clear that benchtop NMR analysis has transformed the
instructional laboratory experience into an exciting investigative experience for students and is
a welcome addition for chemistry faculty that work with undergraduate researchers in their
faculty research laboratories.
References
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Hall, London, 1967.
[2] T. C. Farrar, An Introduction To Pulse NMR Spectroscopy, Farragut Press, Chicago,
1987.
[3] R. Freeman, A Handbook of Nuclear Magnetic Resonance, Longman Scientific &
Technical, Essex, England, 1988.
[4] H. Gunther, Angew. Chem. Int. Ed. Engl. 1983, 22, 350.
[5] F. Dalitz, M. Cudaj, M. Maiwald, G. Guthausen, Prog. Nuc. Mag. Res. Spec. 2012, 60,
52.
[6] M. Isaac-Lam, J. Chem. Ed., 2014, 91, 1264-1266
[7] S. D. Riegel, G. M. Leskowitz Trend. Anal. Chem. 2016, 83, 27-38.
[8] M. Grootveld, B. Percival, M. Gibson, Y. Osman Anal. Chim. Acta, 2019, 1067, 11-30.
[9] K. L. Yearty, C. E. Glessner, R. W. Morrison, J. Chem. Educ. 2019, 96(10) 2194.
[10] K. L. Yearty, J. T. Sharp, E. K. Meehan, D. R. Wallace, D. M. Jackson, R. W. Morrison,
J. Chem. Educ. 2017, 94(7) 932.
[11] O. Diels, K. Alder, Justus Liebigs Annalen der Chemie. 1928, 460, 98.
[12] M. J. Dewar, S. Olivella, J. J. Stewart, Journal of the American Chemical Society
1986, 108(19), 5771.
[13] S. Danishefsky, T. Kitahara, Journal of the American Chemical Society. 1974, 96(25),
7807.
[14] C. A. G. N. Montalbetti, V. Falque, Tetrahedron. 2005, 61(46), 10827.
[15] C. Friedel, J. M. Crafts, Compt. Rend. 1877, 84, 1392.
[16] C. Friedel, J. M. Crafts, Compt. Rend. 1877, 84, 1450.
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Figure 1. 1H NMR spectrum of dimethyl (1R,4S)-bicyclo[2.2.1]hepta-2,5-diene-2,3-
dicarboxylate obtained from an 82MHz PicoSpin benchtop NMR. The signal at 5.41 is
residual solvent.
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Figure 2. 1H NMR spectrum of diisopropyl (1R,4S)-bicyclo[2.2.1]hepta-2,5-diene-2,3-
dicarboxylate obtained from an 82MHz PicoSpin benchtop NMR. The signal at 5.38 is
residual solvent.
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1
Figure 3. H NMR spectrum of N-benzylacetamide obtained from an 82MHz PicoSpin
benchtop NMR.
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1
Figure 4. H NMR spectrum of N-(tert-butyl)acetamide obtained from an 82MHz PicoSpin
benchtop NMR.
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1
Figure 5. H NMR spectrum of 1,4-di-tert-butyl-2,5-dimethoxybenzene obtained from an
82MHz PicoSpin benchtop NMR.
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Figure 6. 1H NMR spectrum of 1,4-di-tert-pentyl-2,5-dimethoxybenzene obtained from an
82MHz PicoSpin benchtop NMR.
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Applications of Benchtop NMR in the Organic Chemistry
Instructional Laboratory
Richard W. Morrison* and Mengqi Zhang
The instructional organic chemistry laboratory is substantially improved
through the implementation of benchtop NMR analysis. When used in
conjunction with unknown reaction components in multi-outcome
experiments, NMR analysis transforms the laboratory exercise into an
investigative inquiry wherein students elucidate structures for their products
and thereby deduce unknown reaction components. This analytical approach
closely models the research laboratory and is a valuable preparatory tool for
undergraduate researchers. Three newly developed experiments for the
instructional laboratory illustrate the utility of benchtop NMR.
This article is protected by copyright. All rights reserved.