Synthesis and NMR Analysis of N-Methyl-2 - (4 - Bromo-Phenyl) Morpholine: An Advanced Undergraduate Laboratory Experiment

1 / VOL. 2, NO.
1 ISSN 1430-4171
THE CHEMICAL EDUCATOR http://journals.springer-ny.com/chedr
© 1997 SPRINGER-VERLAG NEW YORK, INC. 10.1007/s00897970105a
Laboratory and Demonstration
Synthesis and NMR Analysis

of N-Methyl-2-(4′-bromo-
phenyl)morpholine: An
Advanced Undergraduate
Laboratory Experiment
DAVID B. RUSTERHOLZ*, MAGDALENA PALA AND
KENDIE RUNGE
The University of Wisconsin–River Falls
410 S. Third St.
River Falls, WI 54022
[email protected]
N
uclear magnetic resonance spectroscopy holds a
Through the premier position as a tool for structure elucidation
in organic chemistry. With the increased
advent of high- availability of high-field Fourier-transform
field FT-NMR…, spectrometers in undergraduate laboratories, there is an
increased need for good instructional experiments. We
undergraduates describe a reliable one-step synthesis of a moderately complex
structure, and a straightforward 1H NMR spectral assignment
are increasingly
problem that illustrates the use of coupling constants for the
able to gain determination of positional relationships, geminal coupling,
and correlation spectroscopy (COSY) for the identification of
experience with coupled signals [1].
NMR
spectroscopic
Introduction
techniques. Nuclear magnetic resonance spectroscopy is the organic
chemist’s most important tool for structure elucidation.
2 / VOL. 2, NO. 1 ISSN 1430-4171
© 1997 SPRINGER-VERLAG NEW YORK, INC. S 1430-4171 (97)01105-9
Through the advent of high-field FT-NMR instruments and the support of programs
such as the NSF ILI, undergraduates are increasingly able to gain experience with
NMR spectroscopic techniques. These opportunities require well-planned educational
experiences at both the introductory and advanced laboratory levels. Thus, a variety of
NMR spectroscopy exercises for undergraduates have been reported [2, 3]. These
include experiments with special features such as microscale preparation [4],
photochemical equilibrium [5], proton exchange in a biochemically relevant compound
[6], polymers [7], conformational analysis of an organometallic compound [8], 13C
NMR [9], and correlation spectroscopy [10].
We recently obtained an FT-NMR instrument and thus required a suitable exercise for
advanced laboratory students that would reinforce basic concepts in 1H NMR
spectroscopy and extend these with some more advanced challenges in spectral
interpretation. This synthesis and spectral interpretation problem thoroughly satisfies
our needs.
The experiment consists of two parts: (1) the synthesis and purification of racemic N-
methyl-2-(4′-bromophenyl)morpholine (MBPM), and (2) assignment of the signals in
the 1H NMR spectrum of this compound. In the first part of the experiment, students
conduct an overnight reflux followed by an extractive workup and a vacuum
distillation. The overall experiment can be shortened by having a laboratory assistant
prepare a quantity of MPBM to be provided to the students. MBPM was found to be
ideally suited for this experiment because it can be easily prepared and purified, and
because the seven hydrogens on the morpholine ring generate nonoverlapping signals
in the 200-MHz 1H NMR spectrum. Although the appearance of the 1H spectrum is
initially complex, a systematic analysis of coupling constants and eventual
consideration of the COSY spectrum lead to an unambiguous assignment of all of the
signals.
Chemistry
The synthesis is based upon a procedure first described by Yordanova et al. [11] in
which the morpholine ring is formed by treating an α-haloketone with an N-substituted
ethanolamine in refluxing 90% formic acid.
3 / VOL. 2, NO. 1 ISSN 1430-4171
2 + 2+ 2
1
%U 1
&+ &+
%U 90% HCOOH %U
The reaction is thought to proceed via an initial SN2 displacement of bromide from the
α-haloketone, followed by hemiacetal formation.
2+
2 2 2
+2
%U 1 1
&+ &+
2+
%U %U %U
+
1
&+
The hemiacetal is then reduced in a Leuckart–Wallach-like reduction by formic acid,

which is accompanied by the evolution of carbon dioxide.
2 2 2
+2
1 1 1
&+ H
+
&+ &+
–H2O +
%U %U %U + CO2
2 2
NMR Analysis
Students begin the second part of the experiment by collecting a normal 1H NMR
spectrum of the product in CDCl3 (Figure 1). Initially, the large singlet for the N-
methyl group and the splitting pattern for the para-substituted aromatic ring are noted.
Expansion of the 1.5–5.0-ppm region reveals the detail of the signals arising from the
seven hydrogen atoms on the morpholine ring (Figure 2). The sample for which the
spectra are shown is a typical student product (note the impurities at 2.3–2.5 and 2.8–
3.6 ppm). Cleaner material can be obtained by collecting a narrower boiling fraction
during the vacuum distillation.
4 / VOL. 2, NO. 1 ISSN 1430-4171
FIGURE 1. 200 MHz PROTON NMR SPECTRUM, 1.5–8.0 ppm.
FIGURE 2. EXPANDED 200 MHz PROTON NMR SPECTURM, 1.5–3.0 ppm.

5 / VOL. 2, NO. 1 ISSN 1430-4171
Students begin their analysis by identifying the lone proton on C2 (See the numbering
scheme for the morpholine ring in the Instructions for Students, or Supplemental
Figures sections.) as the source of the most deshielded signal (4.4 ppm) of the
morpholine ring protons. Examination of molecular models and consultation of the
Karplus relationship [12] aid in deducing the expected splitting pattern for the C2
hydrogen. The signals from the C6 axial and equatorial hydrogens are found next in
the 3.6–4.0 ppm region (Figure 3). Analysis of these signals requires consideration of
the presence of geminal coupling. Students may recognize two general features of
these signals which are exhibited also in the remaining signals: equatorial hydrogens
are more deshielded than axial hydrogens on the same carbon, and an axial hydrogen
signal generally appears as a triplet or a triplet of doublets.
At this point, assignment of the remaining signals is greatly facilitated by the

availability of a COSY spectrum (Figure 4). Coupling of H2ax with H3ax and H3eq, and
coupling of the C6 hydrogens to H5ax and H5eq are easily identified. Identification of
the axial and equatorial hydrogen signals for C3 and C5 then follows readily
(Figure 5). With a higher field instrument (>200 MHz), long-range coupling between
H3eq and H5eq may be observed.
Synthetic Procedure
In a 100-mL round-bottom flask containing a magnetic stirbar was placed 4.5g (0.060
mole) of N-methylethanolamine. With water cooling, 3.1 g (0.060 mole) of 90%
formic acid solution was cautiously added. After mixing for several minutes, 8.34 g
(0.030 mole) of 2,4′-dibromoacetophenone (Caution: Lachrymator) was added, a
water-cooled condenser was attached, and the mixture was heated at reflux for 20
hours. The mixture was cooled, treated with 30 mL of 2M HCl, and extracted with 3 ×
50 mL of ether. The ether extracts were discarded and the aqueous phase was cooled
and made basic with 4M NaOH. The mixture was extracted with 3 × 50 mL ether. The
ether extracts were combined and dried over MgSO4. After filtering, the ether was
removed with a rotary evaporator and the crude product was transferred to a small
flask and distilled under vacuum. Yield: 3.5 g (45%). (Lit. bp 136–7 °C at 5 torr; lit.
mp 35–38 °C [11].)
6 / VOL. 2, NO. 1 ISSN 1430-4171
FIGURE 4. COSY SPECTURM, 1.0–5.0 ppm.

7 / VOL. 2, NO. 1 ISSN 1430-4171
Instructions for Students

A handout which may be copied and distributed for student use is available in the
document 21dr1897.pdf (43.0 Kbytes). The author would appreciate hearing from
anybody who has enjoyed using this experiment or who would like to offer
suggestions for its improvement.
Supplemental Figures
Figures showing the numbering system for the morpholine ring and showing typical
coupling values found for H2ax, H6eq, and H6ax are available in the document
21dr2897.pdf (20.9 Kbytes).
ACKNOWLEDGEMENT
The authors gratefully acknowledge the support of a National Science Foundation

Grant DUE-9351245 and the State of Wisconsin Laboratory Modernization Program
8 / VOL. 2, NO. 1 ISSN 1430-4171
for the purchase of the Bruker DPX-200 FT-NMR instrument that was used to record
the spectra described in this report.
REFERENCES
1. A preliminary report of this work was presented at the National Meeting of the American
Chemical Society, Orlando, FL, August, 1996.
2. Fairless, B. J.; Ragsdale, G.; Kerby, C. J. Chem. Educ. 1974, 51, 61.
3. Brown, T. M.; Dronsfield, A. T.; Ellis, R. J. Chem. Educ. 1990, 67, 518.
4. Clark, T. J. J. Chem. Educ. 1995, 72, 375.
5. Glaros, G.; Cromwell, N. H. J. Chem. Educ. 1971, 48, 204.
6. Murray, C. J.; Duffin, K. L. J. Chem. Educ. 1991, 68, 683.
7. Viswanathan, T.; Watson, F.; Yang, D. T. C. J. Chem. Educ. 1991, 68, 685.
8. Diaz, A.; Radzewich,C.; Wicholas, M. J. Chem. Educ. 1995, 72, 937.
9. Rablen, P. R.; Deuber, M. A.; Lim, A. C.; Dickson, R. M.; Wintner, C. E. J. Chem. Educ. 1991,
68, 796.
10. Branz, S. E.; Miele, R. G.; Okuda, R. K.; Straus, D. A. J. Chem. Educ. 1995, 72, 659.
11. Yordanova, K.; Shvedov, V.; Dantchev, D. Chem. Ber. 1982, 115, 2635.
12. Silverstein, R. M.; Bassler, G. C.;Morrill, T. C. Spectrometric Identification of Organic

Compounds, 5th ed.; Wiley: New York, 1991; p 197.

Synthesis and NMR Analysis of N-Methyl-2 - (4 - Bromo-Phenyl) Morpholine: An Advanced Undergraduate Laboratory Experiment

Uploaded by

Copyright:

Available Formats

Synthesis and NMR Analysis of N-Methyl-2 - (4 - Bromo-Phenyl) Morpholine: An Advanced Undergraduate Laboratory Experiment

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Synthesis and NMR Analysis of N-Methyl-2 - (4 - Bromo-Phenyl) Morpholine: An Advanced Undergraduate Laboratory Experiment

Uploaded by

Copyright:

Available Formats

1 / VOL. 2, NO.

Laboratory and Demonstration

Synthesis and NMR Analysis

The hemiacetal is then reduced in a Leuckart–Wallach-like reduction by formic acid,

FIGURE 1. 200 MHz PROTON NMR SPECTRUM, 1.5–8.0 ppm.

FIGURE 2. EXPANDED 200 MHz PROTON NMR SPECTURM, 1.5–3.0 ppm.

At this point, assignment of the remaining signals is greatly facilitated by the

FIGURE 3. EXPANDED 200 MHz PROTON NMR SPECTURM, 3.5–4.5 ppm.

FIGURE 4. COSY SPECTURM, 1.0–5.0 ppm.

FIGURE 5. EXPANDED 200 MHz PROTON NMR SPECTURM, 1.7–2.8 ppm.

Instructions for Students

The authors gratefully acknowledge the support of a National Science Foundation

4. Clark, T. J. J. Chem. Educ. 1995, 72, 375.

5. Glaros, G.; Cromwell, N. H. J. Chem. Educ. 1971, 48, 204.

6. Murray, C. J.; Duffin, K. L. J. Chem. Educ. 1991, 68, 683.

8. Diaz, A.; Radzewich,C.; Wicholas, M. J. Chem. Educ. 1995, 72, 937.

12. Silverstein, R. M.; Bassler, G. C.;Morrill, T. C. Spectrometric Identification of Organic

You might also like