356 Chem.

Educator 2002, 7, 356–358

Syn and Anti Isomer Preference in Oximes: An Undergraduate Organic

Chemistry Experiment

Michael D. Mosher* and Scott Meisenbach

Department of Chemistry, University of Nebraska at Kearney, Kearney, NE, 68849-1150, mosherm@unk.edu

Received September 9, 2002. Accepted October 18, 2002.

Abstract: An experiment is described that links a nucleophilic carbonyl addition reaction to a study of structure–
activity relationships. Students prepare a series of oximes (from readily available ketones and aldehydes) and,
with the use of NMR, define the ratio of syn and anti isomers formed in the reaction. From these data, a
quantitative assessment of the steric hindrance of hydrogen, methyl, ethyl, isopropyl, and t-butyl can be obtained.

Background and Introduction van der Waals radius of the substituent compared to the radius
of hydrogen (eq 2) [6]. While this parameter does a good job
A quantitative study of the effects of substitution on the in defining the steric bulk of methyl, t-butyl, and other
behavior of a molecule (be it chemical or physical properties) symmetrical substituents, this approach to defining steric bulk
is known as a quantitative structure–activity relationship becomes difficult for unsymmetrical substituents. The
(QSAR). QSARs have been utilized in basic research to assist parameter is defined as
in the determination of reaction mechanisms. They have also
been implemented in the modification of existing drugs to υ x = rv X − 1.20 (2)
provide more effective alternatives. In fact, the discipline of
medicinal chemistry relies on QSAR to a great degree.
Properties of substituent groups, such as their steric size, where rvX is the minimum van der Waals radius of substituent
surface area, and polarizability, are assigned quantitative X. Many other examples of steric parameters exist [7, 8]
values in QSAR treatments, and those values are correlated to The idea of steric hindrance is usually implemented in the
some observable property in a series of molecules (i.e., organic chemistry lecture in a qualitative sense. It is used to
reactivity, efficacy versus disease, toxicity, and illustrate the potential-energy relationships among the various
carcinogenicity). conformations of butane, the greater stability of equatorial
Steric hindrance is one of the major molecular effects versus axial substitution on cyclohexane ring systems, and the
discussed in organic chemistry courses. It is used to help difference in rates between SN2 reactions (see eq 3) [9];
define how the size of a substituent relates to the reactivity of a however, little quantitation of the differences in the
particular molecule. The effect of steric hindrance in the substituents is provided.
outcome of a reaction was first noted in 1879 [1]. Meyer [2], in
1895, proposed a method to quantitatively assign steric CH3 < CH3CH2 < (CH3)2CH < (CH3)3C (3)
hindrance in the esterification of substituted benzoic acids
(using the atomic weights of ortho substituents). The volume To address this deficiency, we envisioned the generation of
of the substituents has been argued as a better descriptor of a laboratory experiment that would use QSAR to quantitatively
steric hindrance [3]. Since that time, various attempts to deal develop the relationship observed in eq 3. A search of the
with steric hindrance in a quantitative sense have been made literature yielded a few published experiments for the organic
[4]. laboratory that show qualitative effects of steric hindrance on
By dealing with electronic and steric properties separately, reactivity. For example, the determination of the relative rate
Taft was able to more clearly define structure activity of substitution of alkyl halides [10] was identified as a good
relationships [5]. Examination of the hydrolysis of esters under example of a qualitative laboratory; however, this and other
acidic conditions led to his development of the σ* parameter laboratory experiments do not provide quantitative correlation
(the inductive-field effect). The σ* parameter contains the between the reaction rate and the substituent with terms such
steric parameter shown in eq. 1. This parameter (Es) relates the as Es. An obvious need exists to implement a laboratory
rate of hydrolysis of a substituted ester versus that of an experiment that covers structure-reactivity relationships in
unsubstituted ester. This relationship is an indicator of the greater detail.
steric bulk about the carbonyl reaction center. The reaction to form an oxime from commercially available
aldehydes and ketones is a good reaction system for
introducing quantitative steric effects. Oximes may be
k 
Es = log  x  (1) discussed in the organic chemistry lecture as a product of the
 kH A reaction of hydroxylamine with a ketone or aldehyde. The
mechanism of the reaction involves two major steps (see
Charton envisioned another approach to defining steric Figure 1): the addition of hydroxylamine to the carbonyl
hindrance. His steric parameter, υx, was based on the minimum group, and the elimination of water from the intermediate.

© 2002 Springer-Verlag New York, Inc., S1430-4171(02)06623-4, Published on Web 11/1/2002, 10.1007/s00897020623a, 760355mm.pdf
Syn and Anti Isomer Preference in Oximes Chem. Educator, Vol. 7, No. X, 2002 357

H OH Because the reaction is typically carried out under conditions

O O that favor thermodynamic control, the effect of steric bulk on
O
R R'
R R'
the product distribution most likely arises due to the difference
R R' N
H OH N
in the thermodynamic stabilities of the syn and anti products.
H H OH Given that the syn product would exhibit more steric
NH2 OH OH hindrance, it is thus less stable than the anti product, and it is
predicted to exist as the minor component of the product
mixture.
The experiment outlined below describes a laboratory
OH experiment based on an existing study [12] of the
R R' stereochemical outcome of the reaction of hydroxylamine with
R R'
N substituted aldehydes and ketones. The experiment illustrates
OH N
H OH the use of standard organic chemistry equipment, a
straightforward workup procedure, and the use of a common
OH derivative to the determination of stereochemical concerns in a
Figure 1. Mechanism of oxime formation. (The mechanism described reaction. The experiment also includes the use of 1H NMR and
13
here is the base-catalyzed mechanism. Rate studies indicate that C NMR in the undergraduate laboratory.
oxime formation is most rapid at pH = 4.)
Experimental Procedure
O O O

H Students work individually to prepare a single oxime from a list

(see Figure 2 and Table 1.) of available aldehydes and ketones using
acetaldehyde acetone 2-butanone the conditions of thermodynamic control to determine the outcome of
the reaction. In a class of 18 students, each of the oximes of the
compounds listed in the table is analyzed three times in order to
O O O provide the entire set of data for quantitative correlation. The oximes
are easily prepared according to published procedures (see
supplementary material for the experimental method). Simple
extractive isolation and evaporation provides the desired oximes as a
3-methyl-2-butanone pinacolone acetophenone mixture of syn and anti stereoisomers (> 95% yield). Further
purification of the product mixtures is not performed [11]. The ratio of
Figure 2. Structures of the compounds used in this experiment. oxime isomers in the product mixture is measured by 1H NMR and/or
13
C NMR and compared to the ratios determined by the other students
Table 1. List of Compounds and Steric Parameters Used in the in the laboratory. Because each oxime is prepared and analyzed
Experiment multiple times, a reduction in the error associated with the incorrect
Compound Esa υ xb Substituent
measurement of NMR integration ratios is obtained.
Once the average ratios of syn and anti oximes are found, the
Acetaldehyde 0.00 0 H information is correlated to the steric parameters indicated in Table 1.
Acetone –1.24 0.52 methyl Sample information determined from 1H- NMR analysis of the
2-Butanone –1.31 0.56 ethyl compounds is shown in Table 2. The percent syn isomer was obtained
3-Methyl-2-butanone –1.71 0.76 i-propyl by comparison of the integration of the methyl signal that
Pinacolone –2.78 1.24 t-butyl corresponded to the two stereoisomers. Alternative comparison of the
Acetophenone –3.43 0.57 phenyl integration of the methyl signal in the 13C NMR provided similar
a results.
The steric parameters are based on the nonmethyl substituent. b The
steric parameters are based on the volume of the nonmethyl substituent
In almost every case, the methyl signal for the syn isomer did not
according to Charton. overlap with that of the anti isomer. In those cases where signal
overlap was apparent, an alternate signal was compared (see the
supplementary material for an example of this.) The student-
Table 2. Average Syn and Anti Oxime Ratios Determined by 1H calculated values for the percent syn isomer compare well to values
NMR (Syn is defined here as the nonmethyl substituent residing cis to found in the literature (Table 2) [13].
the OH group of the oxime) Correlation of the results by the students can be accomplished
Compound CH3 Signal Location % syna % synb using Microsoft Excel, Kaleidograph, Cricket Graph, Delta Graph or
(ppm) (calc) (lit) other similar graphing programs. An example of the correlation,
Acetaldehyde 1.62; 1.47 63 61 completed using MS Excel, is shown in Figures 3 and 4. From the
correlation coefficient (R2), obtained by noting the graphical trend of
Acetonec 1.73, 1.72 50 50
the results, it is made apparent that the volume (size) of the substituent
2-Butanone 1.75, 1.73 29 26
is a better indicator of the stereochemical outcome of the
3-Methyl-2-butanone 1.76, 1.73 19 9 thermodynamically controlled formation of an oxime (compare Figure
Pinacolone 1.86, 1.68 1 0 3 to Figure 4). Students then can be asked to estimate the approximate
Acetophenone 2.61, 2.34 15 6 syn/anti ratio of oximes that would form under these conditions for a
a
These values were determined from the experimental data collected in series of methyl ketones. Given the Es and υx values and the
this work. b These values were obtained from reference 12. c Acetone is completed QSAR for these new substituents, this process is relatively
symmetrically substituted; thus, it should not be considered as a mixture of straightforward.
syn and anti isomers. It is included here to aid in the preparation of the
structure–reactivity relationship.

© 2002 Springer-Verlag New York, Inc., S1430-4171(02)06623-4, Published on Web 11/1/2002, 10.1007/s00897020623a, 760355mm.pdf
358 Chem. Educator, Vol. 7, No. X, 2002 Mosher and Meisenbach

described above clearly allows one to illustrate a structure-

versus-reactivity relationship and provides the student with a
70 better understanding of the mechanism of nucleophilic addition
60 to a carbonyl.
50 y = 15.166x + 59.074

Acknowledgment. The authors wish to acknowledge the

2
R = 0.8625
40
financial assistance of the Department of Chemistry at the
30
University of Nebraska at Kearney in the completion of this
20 work.
10

0
Supporting Materials. A detailed experimental procedure,
0.00 -0.50 -1.00 -1.50 -2.00 -2.50 -3.00 -3.50 -4.00 a student handout, and a sample proton NMR spectrum (with
Es values integration) are included in a zip file (http://dx.doi.org/
10.1007/s00897000623b).
Figure 3. Correlation of Es with percent syn. Note the relatively poor
correlation coefficient.
References and Notes
1. Menschutkin, N. Ann. Chem. 1879, 195, 334.
2. Meyer, V. Chem. Ber. 1895, 28, 1254.
70
3. Wegscheider, R. Monatsh. Chem. 1895, 16, 75.
60
4. Skrabal, A., Zahorka, A. Monatsh. Chem. 1925, 46, 559; Prevost, C.
50
y = -15.549x + 63.24 Compt. Rend. Acad. Sci. 1942, 214, 357; Palomaa, M.H. Chem. Ber.
40
2
R = 0.9913 1942, 75, 336.

30
5. Taft, R. W. J. Am. Chem. Soc, 1952, 74, 3120; Taft, R. W. In Steric
Effects in Organic Chemistry; Newmann, M. S., Ed.; Wiley: New
20 York, 1956, Chapter 13.
10 6. Charton, M. J. Am. Chem. Soc., 1969, 91, 615; Charton, M. Prog.
0
Phys. Org. Chem. 1971, 8, 235.
0.00 1.00 2.00 3.00 4.00 5.00 7. Hancock, C. K.; Meyers; E. A., Yager; B. J. J. Am. Chem. Soc. 1961,
υ x 83, 4211; Idoux, J. P.; Hwang, P. T. R.; Hancock, C. K. J. Org.
Chem. 1973, 38, 4239.
Figure 4. Correlation of Charton's parameter (υx) with percent syn. 8. For a description of these parameters, see Hansch, C.; Leo, A.
Note the relatively high correlation coefficient. Exploring QSAR: Fundamentals and Applications in Chemistry and
Biology; American Chemical Society: Washington, DC, 1995.
Conclusion 9. See for example: Carey, F. A. Organic Chemistry, 4th ed.; McGraw-
Hill: Boston, MA, 2000.
Reiteration of the general experimental procedure (reflux 10. See, for example: Fieser, L. F.; Williamson, K. L. Organic
setup, extraction, evaporation), detailed explanation of the Experiments, 8th ed.; Houghton Mifflin: Boston, MA, 1998, pp 220–
mechanism of an important reaction in organic chemistry, and 222.
the use of NMR to measure ratios of products in a mixture 11. Proof of an oxime was accomplished by TLC of the reaction mixture
helps to strengthen a student's skills in the organic laboratory. and an authentic sample of the corresponding oxime. Alternatively,
Moreover, the chance to incorporate a quantitative structure– the oxime can be comfirmed by IR spectroscopy.
reactivity relationship into the undergraduate organic 12. Karabatsos, G. J., Taller, R. A. Tetrahedron 1968, 24, 3347.
chemistry laboratory can be a useful way to emphasize how the 13. Longer reaction times (8 h, 12 h, 1 day) did not significantly alter the
structure of a molecule relates to its reactivity. The experiment ratio of syn and anti isomers.

© 2002 Springer-Verlag New York, Inc., S1430-4171(02)06623-4, Published on Web 11/1/2002, 10.1007/s00897020623a, 760355mm.pdf