In the Laboratory
W
Kinetic Isotope Effect in the Chromic Acid Oxidation of Secondary Alcohols Charles E. Harding,* Christopher W. Mitchell, and Jozsef Devenyi Department of Chemistry, The University of Tennessee at Martin, Martin, Tennessee 38238; *
[email protected] A distinguishing feature of deuterium is that its covalent bonds to other atoms (e.g., C–D bonds) occupy a lower ground-state vibrational energy than the corresponding bonds with protium (C–H bonds). As explained by Isaacs (1), the result is that the breaking of a C–D bond requires a greater energy of activation than the breaking of a corresponding C–H bond. According to the Arrhenius theory, a greater activation energy translates into a rate constant (k D) in a reaction where a C–D bond is broken that is smaller than the rate constant (kH) in a reaction where a C–H bond is broken. Experimentally determined values for kH/kD of 5 to 8 (or more) are common (2). As has been stated by El Seoud (3), several mechanistic uses of the kinetic isotope effect are given in any introductory organic chemistry course. We reviewed a variety of organic laboratory textbooks and searched the JCE Index to try to locate isotope effect experiments suitable for use in the introductory organic laboratory. Although we located a pair of lecture demonstrations (4, 5) and a few experiments (6–8), it is clear that a good selection involving reactions commonly conducted in the introductory organic laboratory and utilizing today’s equipment is not available. We have developed and tested two exercises that can provide instructors with additional examples of this powerful technique. In broad outline, the chromic acid oxidation of secondary alcohols is usually described to introductory students as involving the steps summarized in Figure 1. A previous work 1.
2.
Cr2O72− + H2O + 2 H+
R
O
H
+
C R
2 H2CrO4
HO
Cr
OH
H C
R
O
R
H C
R
O
OH
50 mg
O Cr
OH
OH
+ H2O
O R C R
4.
HCrO3-
O
+ H3O+ + HCrO3−
series of steps to Cr 3+
Figure 1. Mechanism of chromic acid oxidation of secondary alcohols.
1042
D +
C OH
Excess Na2Cr2O7 H2SO4 acetone-water, 20oC
50 mg
+ H2O
O Cr
Benzhydrol-d1 was prepared from benzophenone by a method similar to that reported by Stewart (10) and was used in connection with the commercially available nondeuterated compound. The mass spectrum of the nondeuterated compound exhibits a strong molecular ion at m/z = 184, whereas that of the deuterated material appears at m/z = 185. With a computercontrolled GC–MS system, it is possible to study a mixture of these closely related compounds using the “specific ion monitoring”, or “SIM” mode. The features of this method have been described (11). A simple competition experiment is conducted in which students treat roughly equal amounts of deuterated and nondeuterated benzhydrol with an excess of chromic acid in acetone–water solvent as indicated in the equation. Initially and every 20 min thereafter, 50-µL aliquots are removed and quenched with bisulfite.
C
O
3.
Experimental Procedure and Results
H
OH
O R
demonstrated that there is an isotope effect in this reaction and identified the rate-determining step (9). It is easy to prepare secondary alcohols with C–D bonds (at the functional carbon) corresponding to the C–H bonds that are shown in the mechanism. If step 2 is the rate-determining step, there would be no primary isotope effect. On the other hand, if the breaking of the C–H bond in step 3 is rate determining, then an isotope effect should be observed. We have devised a short qualitative experiment to allow students to discover for themselves that there is an isotope effect in this oxidation reaction. A second experiment allows for the determination of the value for kH/kD if the instructor so desires.
The quenched samples are then processed and analyzed by GC–MS with the detector set to monitor only ions at m/z = 184.15 and 185.15. The merged single-ion chromatograms at different sampling times from one such experiment are displayed in Figure 2. The 184 and 185 peaks at time zero are essentially the same size. With increasing time, the area of the 184 peak relative to that of the 185 decreases, thus demonstrating the existence of an isotope effect. It should be stressed that this demonstration is purely qualitative. The presence of significant M – 1 and M + 1 peaks in the spectra of these compounds, coupled with any fractionation caused by loss of H subsequent to ionization, makes the quantitation necessary to evaluate kH/kD from a competition experiment of this type difficult and clearly beyond the scope of an
Journal of Chemical Education • Vol. 77 No. 8 August 2000 • JChemEd.chem.wisc.edu
In the Laboratory
Figure 2. Ion chromatograms at different sampling times in the oxidation of a mixture of benzhydrol–benzhydrol-d1.
Standard curve (H)
Area ratio
1.5
1.0
0.5
0.0 0.0
y = 1.1796 x − 0.034
0.3
0.6
0.9
1.2
Concentration / ( mg/mL)
OH PhCHPh
Standard curve (D)
Area ratio
1.5
1.0
0.5
0.0 0.0
0.3
0.6
0.9
1.2
Concentration / ( mg/mL) y = 1.5244 x − 0.1135
Figure 3. Standard curves for the determination of concentrations of (above) nondeuterated and (below) deuterated benzhydrol in reaction mixtures.
Table 1. Student Results for the Oxidation of Nondeuterated Benzhydrol Time/min
introductory exercise. A simple alternative, making use of diphenyl ether as an internal standard, has been developed where the pseudo-first-order rate constants kH and kD are determined separately for each compound. This ether has a molar mass similar to that of benzhydrol, is inert under the oxidation reaction conditions, and elutes from the GC column about 1.5 min before the alcohol. Although the analytical work involved is routinely carried out using chromatographic software packages, we agree with Magee and Hand (12) that students should perform the “manual version” at least once during their training. Standards are prepared that contain diphenyl ether at a constant concentration of 0.40 mg/mL while the benzhydrol concentration is varied from 0.25 to 1.0 mg/mL. GC traces monitoring ions at 170.2 and 184.15 (185.15 for benzhydrol-d1) are obtained and integrated. A plot of area ratios (benzhydrol/standard) vs concentration of benzhydrol is prepared. Typical examples for the nondeuterated and deuterated compounds are provided in Figure 3. For obtaining pseudo-first-order kinetic data, an appropriate amount of benzhydrol, a carefully measured amount of diphenyl ether, and a 30-fold excess of sodium dichromate are dissolved in acetone–water in a flask equipped with a magnetic stirrer. The flask and its stirred contents are held in a water bath at 20 °C and the reaction initiated by adding 600 µL (a 30-fold excess) of concentrated H2SO4. The diphenyl ether concentration in the reaction mixture is 0.40 g/mL. A sketch of the reaction equation is:
Variable At /(mg/mL)
ln A0 /At
15
1.004
0.159
30
0.819
0.363
45
0.696
0.525
60
0.585
0.699
75
0.483
0.890
Excess chromic acid o
acetone-water, 20 C
O PhCPh
The integrated form of the rate equation as it applies to this system is ln A0/At = kHt, where A0 is the initial concentration of benzhydrol and At is the amount present at a given time. The pseudo-first-order rate constant is directly proportional to the concentration of the chromic acid and it is imperative that reagent concentrations be the same in both experiments, H and D. A 50-µL sample of the reaction mixture is removed and quenched immediately after the addition of the H2SO4 (the A0 sample). Subsequent samples are removed and quenched every 15 min thereafter. These samples are then processed and analyzed by GC–MS with the detector set to monitor only the standard at m/z = 170.2 and the nondeuterated benzhydrol at m/z = 184.15. The concentrations of benzhydrol are then determined by use of the standard curve. Student results in a run where A0 was 1.177 mg/mL are summarized in Table 1. A plot of ln A0/At vs time produces a straight line, as illustrated in Figure 4. The slope of the line gives a value of about 0.012 min᎑1 for kH. An analogous experiment is conducted with benzhydrol-d1. Because of the relatively slower rate of this reaction, however, the time between samples must be increased from 15 to 100 min. A plot of the data obtained is presented in Figure 5. A value of 0.0016 min᎑1 for kD was obtained from the plot. Thus the value for kH/kD for this system was determined to be 0.012 min᎑1/0.0016 min᎑1 or 7.5. This value compares favorably with that of 7.0 reported by Westheimer for the chromic acid oxidation of 2-propanol/2-propanol-d1 (9).
JChemEd.chem.wisc.edu • Vol. 77 No. 8 August 2000 • Journal of Chemical Education
1043
In the Laboratory
Rate constant (D)
Rate constant (H) 0.9
1.0 0.8
0.9
0.7
0.8
0.6
ln (Ao /At)
ln (Ao /At)
0.7 0.6 0.5 0.4
0.5 0.4 0.3
0.3 0.2
0.2
0.1
0.1 0.0
0.0 0
10
20
30
40
50
60
70
80
0
100
Time / min
200
300
400
500
Time / min y = 0.0016x + 0.0194
y = 0.0119x - 0.0058
Figure 4. Plot of ln A0/At vs time for the oxidation of nondeuterated benzhydrol.
Figure 5. Plot of ln A0/ A t vs time for the oxidation of deuterated benzhydrol.
Conclusions
Acknowledgments
We have outlined a method to demonstrate qualitatively that there is a kinetic isotope effect in the chromic acid oxidation of benzhydrol. The method developed is a general one and can be used with any secondary alcohol that exhibits a strong molecular ion peak in its mass spectrum. A mass spectrometer must be available, and the instructor or an advanced student would need to prepare deuterated alcohols by the LiAlD4 reduction of the appropriate ketone. A group of three or four students can easily conduct this exercise in a single laboratory period and at the same time complete the normal week’s work. In fact, the experiment can be accomplished by analyzing only two samples—the initial one and one after about an hour. We have also described a procedure for the determination of kH/kD in the benzhydrol/benzhydrol-d1 system. Again, the method is a general one and can be utilized in any system for which a suitable internal standard can be found. The time required for kH determination is about 2.75 h. Actual laboratory time for kD is about the same with the provision that samples must be collected over an eight-hour period. The experiment involves a reaction familiar to students and provides a clear illustration of an important technique in mechanistic organic chemistry. We have conducted both of these exercises a great number of times in our laboratories, with consistently good results.
We would like to acknowledge the NSF-ILI program for funds used in the purchase of the GC–MS system and the UT Martin Office of Faculty Research for its support of this work. Special thanks are expressed to Trudy Henderson and Jefferson S. Rogers for help in preparing the manuscript.
Hazards Chromic acid is highly toxic and has been reported to be a carcinogen. Consult an MSDS for complete information regarding toxicity.
1044
W
Supplemental Material
Supplemental material for this article is available in this issue of JCE Online. Literature Cited 1. Isaacs, N. S. Experiments in Physical Organic Chemistry; MacMillan: New York, 1969. 2. Sykes, P. A Guidebook to Mechanisms in Organic Chemistry; Longman: New York, 1965. 3. El Seoud, O. A.; Bazito, R. C.; Sumodjo, P. T. J. Chem. Educ. 1997, 74, 562. 4. Binder, D. A.; Eliason, R.; Axtell, D. D. J. Chem. Educ. 1986, 63, 536. 5. Zollinger, H. J. Chem. Educ. 1957, 34, 249. 6. McGuiggan, P.; Eliason, R.; Anderson, B.; Botch, B. J. Chem. Educ. 1987, 64, 718. 7. Jones, J. L. J. Chem. Educ. 1967, 44, 31. 8. Henderson, J. J. Chem. Educ. 1988, 65, 349. 9. Westheimer, F. H.; Nicolaides, N. J. Am. Chem. Soc. 1949, 71, 25. 10. Stewart, R. J. Org. Bio. Chem. 1957, 79, 3057. 11. Hill, D. W.; McSharry, B. T.; Trzupek, L. S. J. Chem. Educ. 1988, 65, 907. 12. Magee, J. H.; Herd, H. C. J. Chem. Educ. 1999, 76, 252.
Journal of Chemical Education • Vol. 77 No. 8 August 2000 • JChemEd.chem.wisc.edu
