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Laboratory Experiment
Cite This: J. Chem. Educ. XXXX, XXX, XXX-XXX
qHNMR Analysis of Purity of Common Organic SolventsAn
Undergraduate Quantitative Analysis Laboratory Experiment
Peter T. Bell, W. Lance Whaley, Alyssa D. Tochterman, Karl S. Mueller, and Linda D. Schultz*
Department of Chemistry, Geosciences, and Physics, Box T-0540, Tarleton State University, Stephenville, Texas 76402, United States
S Supporting Information
ABSTRACT: NMR spectroscopy is currently a premier technique for structural
elucidation of organic molecules. Quantitative NMR (qNMR) methodology has
developed more slowly but is now widely accepted, especially in the areas of natural
product and medicinal chemistry. However, many undergraduate students are not
routinely exposed to this important concept. This article describes a simple and practical
lab experiment that has been successfully performed by students in a Quantitative
Analysis class for several years and is based on a comparison of relative integration areas
of species present in spectra of compound mixtures. In this experiment, 1H NMR
spectroscopy is used to determine the purity of common organic solvents using dimethyl
sulfoxide as an internal standard in D2O. Groups of students analyze unknown samples
containing one of the following solvents: methanol, ethanol, 2-propanol, tetrahydrofuran,
or acetone, to which water has been added as an impurity. Over a period of five years, 54
students analyzed samples ranging from 60% to 99% purity with an average error of
2.64%. This experiment fills a niche in the initial portion of a standard Quantitative Analysis lab sequence by differentiating
between qualitative and quantitative analysis, providing exposure to equipment not usually encountered in an introductory
analytical lab, and generating numerical data for students to analyze and evaluate.
KEYWORDS: First-Year Undergraduate/General, Second-Year Undergraduate, Analytical Chemistry, Organic Chemistry,
Laboratory Instruction, Hands-On Learning/Manipulatives, NMR Spectroscopy, Quantitative Analysis, Instrumental Methods
to qNMR8 detail the progress made in this area, and in 2014
absolute quantitative 1H NMR spectroscopy became listed in
the Guidelines for Authors as an accepted method for the
establishment of compound purity for papers published in the
Journal of Medicinal Chemistry.9 Although several abbreviations
describing qNMR techniques have been used in publications,
qHNMR is suitable for specification of methods using 1H NMR
H NMR spectroscopy can be used to determine the relative
amounts of components in mixtures by analyzing the relative
integration values of proton signals of each compound,
provided that the different compounds have sufficiently distinct
NMR resonances and the absolute amount of one major (>1%)
compound can be used as an internal standard.10,11 Some early
applications of qHNMR, including several in the field of
chemical education,12−19 utilized analysis of relative integration
areas, and a classic experiment for undergraduate Instrumental
Analysis involved the quantitative determination of a mixture of
benzene and ethyl alcohol in CDCl3 by 1H NMR spectroscopy
on the basis of relative integration areas.20 Some more recent
qHNMR experiments for the teaching laboratory have utilized
standard addition methods,21,22 and qHNMR has been
incorporated into kinetics and mechanistic studies.23−26
Nuclear magnetic resonance (NMR) theory was proposed as
long ago as 1925 by Wolfgang Pauli but was first demonstrated
independently in 1946 by Bloch and Purcell, for which they
shared the 1952 Nobel Prize. The first commercial NMR
spectrometer was marketed in 1953, and it became a common
analytical tool in the 1960s.1 Two indicators of the general
acceptance of the technique are that contemporary introductory organic chemistry texts contain entire chapters devoted
solely to NMR spectroscopy and that access to NMR
instrumentation is a requirement for American Chemical
Society undergraduate chemistry program certification. Small
benchtop instruments currently available have even been
transported to public schools to introduce high school students
to the concepts of NMR spectroscopy.2
NMR spectroscopy has many characteristics of a good
quantitative analytical method: it requires minimal sample, is
rapid and nondestructive, yields information on both the
identity and relative amount of each analyte present, and is now
readily accessible to most universities. Historically, NMR
spectroscopy has been considered almost exclusively a tool
for structural elucidation and to be of limited use in quantitative
applications. However, improvements in instrumentation have
changed this image, and quantitative NMR (qNMR) had
become a widely accepted technique by 2001, especially in the
areas of natural product and medicinal chemistry.3,4 An
excellent series of review articles5−7 and a Web site dedicated
© XXXX American Chemical Society and
Division of Chemical Education, Inc.
Received: May 22, 2017
Revised: September 19, 2017
DOI: 10.1021/acs.jchemed.7b00343
J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Laboratory Experiment
Figure 1. Partial 1H NMR spectrum of ethanol and DMSO in D2O.
commercial samples, but they can also be prepared by the
instructor. Student results should depend only on the care and
precision of the student’s lab technique.
The principles of qNMR make it an attractive candidate for
inclusion as a laboratory experiment in a Quantitative Analysis
course. Such an experiment fits well into the early portion of
the curriculum, where the foundations of analytical chemistry
are first introduced. A qHNMR experiment illustrates differences between qualitative and quantitative analysis and classical
and instrumental methods and provides practice in solution
preparation, pipetting, and dilution techniques. This experiment also generates numerical data that students can analyze
and evaluate for precision while the basic techniques for classic
gravimetric and volumetric analyses are still being covered in
lecture. The students have already been introduced to the use
of analytical balances and volumetric glassware during the lab
check-in process, and complexity of sample preparation is
minimal for this experiment. The use of D2O as an NMR
solvent allows investigation of many common water-soluble
components and eliminates hazards associated with qNMR
procedures that utilize CDCl3 or other toxic compounds, and
unknown sample preparation is fast and simple for the
instructor. The experiment described herein also utilizes some
volumetric equipment that is simple to use but may be new to
some students, such as the syringe-type pipets. Finally, the
experiment is fast, and individual students can obtain their raw
data in only one lab period.
Students are provided with a review of the fundamentals of
NMR theory and instrumentation at least 1 week prior to
performing the experiment. An essential consideration in this
experiment is that speed is crucial. Since most of the
compounds involved are volatile, all solutions should be
prepared and analyzed within a time frame of less than 1 h
to obtain optimal results. Therefore, unknown sample
preparation time by the instructor, student sample preparation
time, and instrument and operator availability must be carefully
scheduled. Ideally, the student should work with the instrument
operator, who explains the operational procedures and output
to the student so that the NMR spectrometer is not just a
“black box”.
However, the focus of the majority of these experiments has
been on the relative concentrations of the components of
mixtures, not the purity of an individual compound, which
should be a topic of interest to undergraduate students.
Although the above-referenced works bear testimony to the
increasing utility and acceptance of qHNMR as an analytical
technique, it is still not widely recognized in introductory
analytical chemistry courses. Therefore, a need exists for a
simple, practical laboratory experiment to introduce this
concept to undergraduate chemistry students utilizing safe,
less toxic (greener) chemicals with a focus on determination of
This experiment fits well into the early portion of a
traditional introductory course by familiarizing students with
the lab techniques of weighing on analytical balances and
precisely pipetting very small volumes of solvents. The students
also generate (and process) data from an instrument with
which they are familiar, but they use these data as the basis of
quantitative rather than qualitative analysis. This experiment can
be done during that awkward period early in the course when
basic material essential for performing later experiments is still
being covered in lecture.
The goal of this project was to develop a simple laboratory
experiment using 1H NMR spectroscopy to introduce
principles of quantitative analysis to a group of undergraduate
students with diverse levels of chemistry laboratory experience.
Although Quantitative Analysis is considered to be an
advanced-level course in a “typical” curriculum, individual
student scheduling issues typically lead to a class mixture
containing individuals with greatly varying degrees of previous
chemistry experience at the authors’ institution. However, the
majority of these students have already taken Organic
Chemistry and thus have been exposed to NMR theory and
spectral interpretation of structure. Additionally, this is the first
course that most students encounter in which the balance of
the grade is based on the accuracy of quantitative results.
Therefore, the “unknowns” must have a value that is known to
the instructor as a basis for the grade. Typically, these are
DOI: 10.1021/acs.jchemed.7b00343
J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
The basis of qHNMR is that the integration area of a peak is
directly proportional to the number of nuclei responsible for
that individual peak. Therefore, a pure sample of a specific
compound is not required for calibration; it is only necessary
that an identifiable resonance of the analyte does not overlap
resonances of other sample constituents. The concentration of
the analyte is then directly obtained by comparing the signal
areas of its protons with those of a known concentration of an
internal standard.1 The probability of overlapping resonances
becomes greater with increasing sample complexity, but this
should not be a factor in unknowns prepared by an instructor
by dilution of relatively pure compounds to obtain student
unknowns of known composition for analysis in a quantitative
analysis experiment.
Selection of an appropriate internal standard compound is
essential to a qNMR experiment. The standard should ideally
be inexpensive and readily available in a highly pure form,
contain a small number of magnetically equivalent protons that
do not resonate in an area of the spectrum that overlaps with
analyte peaks, be stable and soluble in the NMR solvent of
choice, have low volatility, and be nontoxic and inert.26 The
internal standard selected for this experiment, dimethyl
sulfoxide (DMSO) satisfies most of these requirements. It is
inexpensive and readily available in high purity, has six
magnetically equivalent protons that do not overlap with
those of the compounds being analyzed in this experiment, is
water-soluble, has low toxicity, and is nonreactive with the
analytes. It is hygroscopic and volatile, but no more so than the
compounds being analyzed.
The relevant portion of an NMR spectrum of ethanol and
DMSO is shown in Figure 1. It should be noted that although
both DMSO and ethanol have six protons, only five of the
ethanol protons are used for calculations because of the rapid
ethanol hydroxyl proton exchange with D2O.
The calculations are based on relative peak areas of the
analyte and internal standard as described by Wallace:10
Laboratory Experiment
A student handout briefly describing basic NMR theory and
instrumentation was prepared by the instructor using material
from a current Instrumental Analysis text1 and given to the
students 1 week prior to the experiment. The focus of the
handout was not on spectral interpretation, because that
information is presented in the Organic Chemistry courses.
The laboratory portion of the Quantitative Analysis course
on this campus consists of two three-hour lab periods per week.
However, for this experiment the students were assigned
specific lab times to arrive and begin their individual data
acquisitions, which were expected to require approximately one
hour per student. Students were scheduled at 30 minute
Upon arrival, each student first prepared a solution
containing approximately equal volumes of his or her “pure”
analyte and DMSO. To minimize the relative weight changes
caused by evaporation, sample volumes of about 10 mL of both
analyte and DMSO were used. All of the mixtures were
prepared by transferring these volumes into preweighed, ovendried, glass-stoppered 50 mL volumetric flasks, and the weights
of each were determined by difference. All of the weights were
determined to 0.1 mg on a Metler-Toledo AB 104-S analytical
balance, and when the requisite amounts of analyte and DMSO
had been combined, the flasks were immediately stoppered and
swirled to mix. Appropriate sample and D2O volumes were
transferred to glass NMR tubes using Eppendorf pipettes, and
NMR spectra were obtained as quickly as possible. After the
spectrum of the “pure” analyte with DMSO had been obtained,
the student returned to the lab where he/she received an
“unknown” analyte sample that had been freshly prepared by
the instructor. This sample contained analyte and an unknown
amount of deionized water. An NMR sample of the student
unknown mixture was prepared in the same manner as for the
pure analyte.
Spectra obtained prior to 2013 were obtained on a Varian
Gemini 200 MHz 1H FT-NMR spectrometer; later spectra
were obtained on a Bruker Fourier 300 spectrometer. As
previously noted, proper regulation of instrumental parameters
markedly improves the accuracy of relative proton integration
areas in a compound.
Specific details are included in the student lab handout in the
Supporting Information.5,30
All students doing this experiment in the same lab period
analyzed the same “pure” analyte and compared their results. It
should be noted that sample purity depends only upon the
actual amount of analyte present in a known sample mass. All
of the chemicals were purchased as 99.5% pure or better, and
most were in new, unopened bottles. However, the values of
some of these “pure” compounds were markedly less than
100%, as noted by Wells,27 because the analysis of purity had
been obtained by other methods and in some cases the bottles
had been previously opened and exposed to moisture.
The students calculated the purities of both their “pure”
analytes and their unknown solutions by means of the
relationship between the integration areas of the analyte and
the internal standard. Water was chosen to manipulate the
analyte concentration because it is a common impurity in
alcohols and is nontoxic. Then, since the unknowns had been
prepared by dilution of the “pure” analyte samples, a correction
factor was applied by dividing the experimental unknown value
by the experimental percentage of the pure analyte to obtain a
= a × s
where na and ns are the molar amounts, Aa and As are the
integral areas, and Na and Ns are the numbers of resonating
protons in the analyte and internal standard compounds,
Solutions for analysis are prepared by the students and
contain known masses of the analyte of unknown concentration
and the internal reference, so the molar amount of the internal
standard is related to the molar amount of the analyte in the
solution of unknown concentration. The molar amount of
analyte is converted to the mass of analyte, which is divided by
the mass of the analyte of unknown concentration analyzed to
give the purity of the analyte as percent by mass.
Although relative proton integration areas in a compound are
not always perfect, they can be optimized by regulating the
delay times between pulses as well as other instrumental
parameters, and when total integration areas of different
compounds are compared, good quantitative results at the
percent level are obtained for mixtures.28,29 This accuracy range
is typical of that obtained by students using commercial
unknown samples in a classical undergraduate Quantitative
Analysis course.
DOI: 10.1021/acs.jchemed.7b00343
J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Laboratory Experiment
normalized percentage for comparison purposes. Realistic
unknown values should be greater than 80%; therefore, only
a few unknowns with purities below this value were analyzed,
and none had a purity of less than 60%.
Student performance was evaluated using the same standards
as all other laboratory experiments in this course. Results were
reported as a component of a formal lab report that discussed
the basic theory of the chemistry and analytical principles of the
procedure. Separate evaluations were made of the accuracy of
the unknown results compared to the theoretical value, and the
quality of the content and written communication of the lab
reports was compared to standards expressed in rubrics that
were included in the course syllabus and are included in the
Supporting Information.
As per university policy for all experimental procedures
involving students, the primary author (course instructor)
underwent IRB training, and an IRB approval form was
submitted to the University Institutional Review Board for
review in 2015. The application was approved as Exempt
(under 45 CFR 46.101b1), and IRB protocols were followed
throughout the duration of the experiment. However, this
experiment had been in use since 2011, which preceded
implementation of these procedures on our campus, and some
of the data included in this article were obtained during prior
years. All of the information from this period was carefully
examined and subjected to the same standards regarding
participant confidentiality as the more current results.
Figure 2. Correlation of normalized qHNMR-based results with actual
mass percent of analyte for five common organic solvents in solvent−
water mixtures.
recommended as a student unknown. Because of the time
limitations in a structured laboratory class, the students in the
class analyzed only one pure sample and one mixture, but the
research students did analyze duplicate samples with good
correlation. The primary sources of error were found to be
weighing and/or pipetting errors by the students and errors
caused by sample evaporation if excessive time elapsed between
sample preparation and analysis.
Student outcomes for the qNMR experiment as measured by
grades on numerical results and lab reports were similar to
those of the traditional experiments in the Quantitative Analysis
class and are shown in Table 2 in the Supporting Information.
qNMR was not a topic covered in the textbook, so it was not
included among the exam topics for the course. Hence, student
feedback about the experiment was primarily anecdotal. Those
advanced students who had already been exposed to the NMR
instrument found the quantitative application of the instrument
enlightening, while those students who had been exposed only
to the theory of the instrument were pleased to actually prepare
samples and observe the operation of the instrument on an
individual basis. Some of the students who had completed only
General Chemistry were a bit overwhelmed by the instrument,
but they were also able to successfully complete the experiment
and write a satisfactory lab report. The main source of negative
feedback came from schedule breakdowns when delays
occurred and students had to wait for an extended period of
time before their turn to obtain spectra. However, when the
students received their unknown grades and were shown the
graph of their class results (similar to Figure 2 above),
complaints vanished and the students were impressed by the
outcome of the experiment and recognized the potential of the
method as a validation of purity.
Care must be taken in handling all chemicals. Methanol,
ethanol, 2-propanol, tetrahydrofuran, dimethyl sulfoxide, and
acetone are all flammable and toxic. Therefore, none of these
solvents should be exposed to an open flame or ingested. Small
amounts of excess ethanol and 2-propanol may be disposed of
by flushing down a sink with adequate volumes of water.
However, all of the samples containing other organic solvents
should be collected and disposed of with proper precautions.
Proper clothing, shoes, gloves, and goggles with splash
protection are required, and caution must be exercised in
handling glass NMR tubes to prevent injury.
The normalized results obtained by 54 undergraduate students
in Quantitative Analysis classes during the period 2011−2015
are shown in Table 1 in the Supporting Information. (The
instrument was not operational at the time the experiment was
scheduled in 2016). Errors were expressed as the absolute value
of the difference between the experimental and theoretical
values and were random in nature, as can be seen by the plot of
theoretical versus experimental values shown in Figure 2. The
average error was 2.64%, with a standard deviation of 1.87%.
Four results were eliminated by Q test at the 95% confidence
level31 and were excluded from the calculation of the average
value and Figure 2.
All of the results reported were obtained by students enrolled
in the Quantitative Analysis classes. However, in prior years
undergraduate research students performed this procedure
multiple times with all of the above analytes to validate the
method and generally obtained more consistent results. N,NDimethylformamide (DMF) was also examined but yielded
inconsistent results, possibly due to interactions between the
DMF and water. 32 Therefore, this compound is not
Analysis of the purity of water-soluble solvents on the basis of
relative 1H integration areas of a pure standard used to analyze
a second relatively water-soluble solvent by 1H NMR
spectroscopy with D2O solvent showed great promise as a
laboratory experiment in an undergraduate Quantitative
Analysis course. Optimization of instrumental parameters
increased the accuracy, and the use of large sample sizes and
rapid analysis after sample preparation minimized problems due
to evaporation. The technique was rapid, and sample
preparation time was minimal. Ethanol, methanol, 2-propanol,
tetrahydrofuran, and acetone mixtures of varying concenD
DOI: 10.1021/acs.jchemed.7b00343
J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Laboratory Experiment
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trations were analyzed using this technique by undergraduate
students with good results. Dimethyl sulfoxide proved to be
satisfactory as an internal standard. The goal of the experiment,
to demonstrate to undergraduate Quantitative Analysis
students the utility of qHNMR as a quantitative tool to assay
the purities of some common organic solvents, was achieved.
The experiment also worked well as an initial experiment in the
laboratory sequence.
S Supporting Information
The Supporting Information is available on the ACS
Publications website at DOI: 10.1021/acs.jchemed.7b00343.
Student laboratory handout, notes for instructors, sample
student results, and assessment rubrics for lab reports
Corresponding Author
Linda D. Schultz: 0000-0001-6086-1484
The authors declare no competing financial interest.
The authors thank the students in the Quantitative Analysis
class of 2015 for participating in the experiment and Dr. Bernat
Martinez for help with the abstract graphic. The financial
assistance of The Robert A. Welch Foundation, Chemistry
Departmental Grant AS-0012 is gratefully acknowledged.
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DOI: 10.1021/acs.jchemed.7b00343
J. Chem. Educ. XXXX, XXX, XXX−XXX
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