The Foundations of Physical Organic Chemistry - American Chemical

Chapter 5

Hydrogen Isotopes in Physical Organic Chemistry Downloaded by CORNELL UNIV on October 30, 2016 | http://pubs.acs.org Publication Date (Web): November 24, 2015 | doi: 10.1021/bk-2015-1209.ch005

Andrew Streitwieser* Dept. of Chemistry, University of California, Berkeley, California *E-mail: [email protected]

I was the fortunate recipient of the Norris Award in 1982 but I also played a role in the very first Norris symposium in honor of the first Norris awardee, Prof. Christopher K. Ingold. This first Norris award symposium was a full day affair on Sept 14, 1965, at the 150th American Chemical Society meetjng in Atlantic City, NJ. There were three talks in the morning session, by R. B. Woodward, me and Ingold in that order. Joe Bunnett was the chair (he also gave the final talk in the afternoon). While we were getting set up for the morning session, Joe approached me rather diffidently and hemmed and hawed a bit but I knew exactly what his concern was. Woodward was well known for giving beautiful and elegant talks. In a chalk talk he would start at the top left corner of the board, fill the board with clean graceful structures, and finish at the bottom right corner. But his talks were usually long – sometimes very long. I realized that no matter how long Woodward took for his talk I could not infringe on the awardee’s time. I assured Joe that I was aware of this problem and that I was prepared to give an accordian talk. No matter how little time Woodward left for me I would finish on time so that Ingold would have his full allotted time. As it turned out, our fears were groundless. Woodward finished in his allotted time, I gave my normal talk and Ingold gave his award talk as planned. Seventeen years later I was the Norris awardee “for his pioneering role in the development and application of new experimental and theoretical tools for the study of physical organic chemistry.” In this chapter I will emphasize the experimental tools, most of which involve isotopes of one © 2015 American Chemical Society Strom and Mainz; The Foundations of Physical Organic Chemistry: Fifty Years of the James Flack Norris Award ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

Downloaded by CORNELL UNIV on October 30, 2016 | http://pubs.acs.org Publication Date (Web): November 24, 2015 | doi: 10.1021/bk-2015-1209.ch005

form or another, and particularly deuterium. Deuterium has a number of uses as a tool in physical organic chemistry, many of which are not original with me. Its use as a tracer is one. With hydrogen – deuterium asymmetry there is the possibility of optical activity. In addition there are both equilibrium and kinetic isotope effects. These isotope effects are normally divided into primary and secondary isotope effects; primary when the bond to the hydrogen is broken, secondary when the bond is not broken but can be altered.

Discovery of Deuterium The existence of isotopes was realized in the early 1900’s during a period of confusing results from radiochemistry experiments (1) . By 1920, isotopes were reasonably well understood, although deuterium, the stable isotope of hydrogen, was not discovered until 1931 by Harold Urey. Ferdinand G. Brickwedde, a physicist friend of Urey’s at the National Bureau of Standards, allowed four liters of liquid hydrogen to evaporate slowly near the triple point. Spectroscopic study of the last milliliter in the Fall of 1931 allowed Urey and his assistant, Dr. G. M. Murphy, to identify the so-called Balmer lines of deuterium. These lines occurred in natural hydrogen but were so faint that they could have been “ghost” images on the photographic plate. In the enriched material, the signal was now much larger and was clearly real. With that Urey announced the discovery of deuterium (2, 3). Two years later, Urey received the Nobel prize in chemistry for the discovery of heavy water (4–6). This was achieved by electrolysis of water, a method conceived and developed by Edward W.Washburn of the Bureau of Standards and continued by Urey after Washburn’s death early in 1934 (7). It seems quite likely that Washburn would have shared this Nobel prize except for his untimely death. Pure heavy water was first accomplished by G. N. Lewis at Berkeley in 1933 (5, 6), but followed closely behind by Bonhoeffer in Frankfurt (8). Lewis also suggested the “deut” stem that Urey adopted in coining the name “deuterium” (9). What is amazing is how quickly deuterium went from being an oddity to a tool in chemistry. By 1935, there were already several exchange reactions that had been studied with heavy water with various organic and inorganic compounds and even with living materials like fungi. So much so that even as early as 1935, Wynne-Jones was able to write a Chemical Reviews article summarizing the results of the exchange reactions that had been run up to that time (10). Fifteen years later I was a graduate student at Columbia in the laboratory of William von Eggers Doering. In his group were several projects making use of deuterium, usually as a tracer, following the course of hydrogen in various reactions. An example was that of Alfred Wolf, whose lab bench was close to mine. Al used deuterium to trace hydrogen migrations during the acid-catalyzed rearrangements of fenchene to other terpenes (11). 78 Strom and Mainz; The Foundations of Physical Organic Chemistry: Fifty Years of the James Flack Norris Award ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Hydrogen-Deuterium Asymmetry As shown above, the idea of deuterium as a tracer was not strange to me. When it came time for me to think about post-doctoral work I applied to the Atomic Energy Commission for a post-doctoral fellowship. For the original project required for the application I proposed a base-catalyzed exchange study of esters using deuterium. This proposal was good enough to get my fellowship, but by the time I got ready to go to MIT to work with Jack Roberts, I thought of a better project. I proposed to synthesize an optically-active primary alcohol of the type RCHDOH in which the chirality comes from hydrogen – deuterium asymmetry. With it I could study the stereochemistry of various reactions at a primary alcohol center. The genesis of this idea is clear. In my PhD work with Doering my project was working with an optically-active tertiary alcohol. The first tertiary alcohol had been resolved by Harold Zeiss (12) before I got to Columbia, and my project was to follow-up that work and study that chemistry. Subsequent thinking about the stereochemistry of reactions of a primary alcohol is an obvious association. I had expected hydrogen-deuterium asymmetry to provide sufficient optical activity to be experimentally useful in studying its transformations based on recent results by others. The search for measureable optical activity in compounds of the type RCHDR’ had been tried for several years, but the first apparent success was that of Elliott R. Alexander, who took camphene and on reducing it with deuterium got the di-deuterio system having a small rotation (Figure 1) (13). That small rotation was a problem, because in those days, before chromatography, the purification of small amounts of liquids was difficult. Alexander did the control reaction with hydrogen to give product that was racemic but there was always the possibility that in the deuterium case a trace of some impurity which was highly optically active – we note that camphene itself has a very high optical activity – was present. It wouldn’t take much to give this tiny rotation. Ernest Eliel, shortly thereafter, looked at the same problem, but in a more straightforward way. He took optically active phenylethyl chloride and treated it with lithium aluminum deuteride to yield a deuterio-ethylbenzene that was optically active (Figure 1) (14). He had the same problem; the product is a liquid having a small rotation, but he was able to convert it to a solid derivative and then on numerous recrystallizations show that the optical activity did not change upon subsequent crystallizations. Thus, there is no question that his ethylbenzene really was optically active because of the hydrogen-deuterium asymmetry. I expected to prepare the optically active alcohol by use of a partially asymmetric reduction such as that being done in Doering’s laboratory at that time. A labmate, Dick Young, was studying the Meerwein-Ponndorf-Verley reduction using an optically active secondary alcohol as a hydride source to make other optically active alcohols (15). I first made 2-octanol-2-d by reduction of the ketone with LiAlD4 and resolved it in a standard manner. The alcohol was converted to its oxymagnesium salt by treatment with a Grignard reagent and was then allowed to react with butyraldehyde (Figure 2). This use of the magnesium derivative instead of the aluminum salt that is commonly used in the 79 Strom and Mainz; The Foundations of Physical Organic Chemistry: Fifty Years of the James Flack Norris Award ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Meerwein-Ponndoff-Verley reduction was suggested by Bill Saunders, who was also a post-doc with Jack Roberts at that time. His suggestion worked out quite well. Because my reaction involved the exchange of an aldehyde carbonyl group to a ketone carbonyl, the reaction has a much better driving force than the normal Meerwein-Ponndoff-Verley reactions using secondary alcohols to ketones. The presumed transition state is shown in Figure 3, a cyclic transition structure with the magnesium coordinating to the two oxygens. Of the two diasteriomeric transition structures the favored one is shown in which the smaller group is opposite the larger group on both sides of the coordination ring.

Figure 1. Early optically active deuterium compounds

80 Strom and Mainz; The Foundations of Physical Organic Chemistry: Fifty Years of the James Flack Norris Award ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 2. First preparation of optically active 1-butanol-1-d.

Figure 3. In the favored transition structure the smaller methyl is opposed by the larger propyl group and hexyl is opposed to hydrogen. In the alternative diasteriomer, the large propyl is opposed to the large hexyl.

I still had the same problem as my predecessors – proving that the small observed rotation was that of the butanol-d and not from some impurity. I made use of the famous experiment (Figure 4) of Hughes, Juliusburger, Masterman, Topley and Weiss in the mid 30’s in which they showed that in the radioactive iodine exchange of an SN2 reaction, the rate of racemization of the optically active iodide was exactly twice that of the rate of isotope exchange (16). This experiment was one of the important demonstrations that each SN2 reaction occurs with complete inversion of configuration. In my case, La Roux and Sugden had already published the rate of reaction of butyl bromide with bromide ion using radioactive bromine (17).



Figure 4. Each SN2 exchange of iodine isotopes occurs with inversion of configuration.

Treatment of the butanol-d with phosphorus tribromide gave optically active 1-bromobutane-1-d which was allowed to react with lithium bromide in 90% aqueous acetone under the same conditions as Le Roux and Sugden (17). After varying lengths of time the butyl bromide was isolated and its optical rotation was measured and compared with the radiochemical exchange rate as shown in Figure 5 (18). The good agreement shows that that the optical activity is truly that of the 1-deuterio species. My first graduate student who got his PhD with me, Bill Schaeffer, took over this problem. He made a large amount of the optically active alcohol and used it in several studies that resulted in a number of papers in the late 1950’s, under the general title of The Stereochemistry of the Primary Carbon. An example is his study of the reaction of the alcohol with thionyl chloride, an important procedure for the preparation of alkyl chlorides. The reaction first forms a chlorosulfite that decomposes to give the alkyl chloride and sulfur dioxide. When applied to our optically active butanol-1-d the product 1-chlorobutane-1-d was found to have about 90% inversion of configuration (19). This result suggested that almost all of the reaction involves an SN2 displacement of the type shown in Figure 6. At about the same time and independently of my work, Westheimer, Venneslan and Loewus showed that deutero acetaldehyde could be reduced in an enzymatic reduction to optically active ethyl alcohol. In their first experiment in 1953 the amount of ethyl alcohol that they made was too small to measure the optical activity directly (20). So they showed by a clever technique that their ethanol-d was enantiomerically pure and that the SN2 reaction used went with complete inversion of configuration. Later, enough of the alcohol was made so that the optical rotation could be measured (21). Enzyme routes have been used 82 Strom and Mainz; The Foundations of Physical Organic Chemistry: Fifty Years of the James Flack Norris Award ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


to prepare a number of optically active primary alcohols (22–26). This approach has the important advantage that it gives product with high enantiomeric purity but the method fails for some alcohols (27). We showed (28) that the use of isoborneol is advantageous compared to 2-octanol but other partially asymmetric chemical reducing agents have been developed that are improvements over my original synthesis (29, 30).

Figure 5. Racemization of 1-bromobutane-1-d with LiBr in 90% aqueous acetone. The line shown is that calculated friom the rate constants of Le Roux and Sugden (ref. (17) . The experimental points are shown with estimates of uncertainty. The dotted line is that calculated for isopropyl bromide showing that the observed racemization cannot be that of a secondary bromide derived from some rearrangement. This figure is taken from ref. (18) 83 Strom and Mainz; The Foundations of Physical Organic Chemistry: Fifty Years of the James Flack Norris Award ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 6. SN2 reaction on chlorosulfite gives inverted product

Within the next few years a number of optically active 1-deuterio primary alcohols had been prepared and their absolute configurations were determined. These compounds rapidly became quite valuable in the study of the mechanisms of various chemical and biochemical reactions (29). Many of the early studies have been reviewed (31, 32). Two examples will illustrate the range of applications. H. C. Brown’s partially asymmetric hydro-boration (33) method applied to cisbutene-1-d gave optically active butanol-1-d of relatively high optical purity but of opposite configuration from that expected on the basis of the accepted reaction mechanism. A small but significant change in this mechanism accounted for the observed configuration of the product; the new mechanism was also consistent with the other chemistry known for the reaction (34). Mosher (35) prepared optically active neopentyl alcohol, (CH3)3CCHDOH, and ran a number of reactions with the tosylate. The neopentyl system is known to rearrange readily under carbocation conditions and its t-butyl group is so close to the reaction center that SN2 reactions are relatively slow. Nevertheless, reaction with a number of nucleophiles was shown to proceed with complete inversion of configuration, just as normal SN2 reactions on less hindered systems.

Secondary α-Deuterium Isotope Effects Even early in the development of deuterium chemistry, in the middle 30’s, when many exchange reactions were being studied, it had been noted that reactions with deuterium were frequently slower than the corresponding reactions with hydrogen. Even then it was realized that this was probably an effect of zero-point energies. But it wasn’t until after the war that Jake Bigeleisen was able to publish his work with Maria Goeppert-Mayer on the theory of equilibrium isotope effects (36). Shortly thereafter, Bigeleisen also applied the theory to reaction rates as well. One expression of the theory for hydrogen-deuterium isotope effects is given as 1:



This equation embodies a number of approximations such as the Born-Oppenhimer approximation and Absolute Rate Theory (37–39). In essence, the isotope effect arises from differences in vibration frequencies between the reactant state and the transition state. Wolfsberg prefers to think in terms of the corresponding differences in force constants (40, 41), but these are essentially equivalent. One of the first projects I worked on when I got to Berkeley was an isotope effect of deuterium in the solvolysis reaction. The secondary deuterium effect in the β position had already been done and turned out to be useful as a measure of hyperconjugation (42, 43). Instead, I suggested to an undergraduate student, Bob Fahey (now a chemistry professor at UCSD), that we measure the effect of an α-deuterium. Bob compared the rate of solvolysis of cyclopentyl-1-d tosylate in acetic acid with that of the undeuterated compound (44, 45). Considering only the C-H stretching frequency, which is greater for the Csp2 –H bond of a carbocation than the Csp3 –H bond in the reacant I had anticipated an inverse isotope effect. I was quite surprised when Bob found that the reaction rate was actually slower for the deuterio system. I then quickly realized the importance of considering the bending vibrations. One in particular stood out, the out-of-plane bending of the α-CH bond in the carbocation. As shown in Figure 7 in which an aldehyde C-H is used as a model for a carbocation, the inplane bending vibration is similar to that in a tetrahedral C-H but the out-of-plane bending vibration has much lower frequency.

Figure 7. Some bending vibrations

With some additional approximations, including putting in the reduced masses of C-H and C-D and considering the isotope effect to come primarily from zero point energy differences (46), I simplified 1 to 2, in which the isotope effect is 85 Strom and Mainz; The Foundations of Physical Organic Chemistry: Fifty Years of the James Flack Norris Award ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


related directly to frequency differences between reactant state and transition state (45).

The largest frequency difference is that from a tetrahedral C-H bend to the out-of-plane Csp2 –H of the carbocation, about 550 cm-1 but this leads to an isotope effect of about kH/kD = 1.4, much higher than the observed kH/kD = 1.15. It was clear that the free carbocation is not a suitable model for the transition state – the leaving tosylate group is still close and would impede the vibration of the hydrogen. This interpretation was consistent with the result that Shiner had reported (47) of kH/kD = 1.0 for the SN2 reaction of isopropyl bromide with sodium ethoxide. In this case, the entering and leaving groups would doubly impede the H vibration leading to a higher frequency and a smaller isotope effect. This effect is summarized in Figure 8. In this figure A is a model for an isolated carbocation, B is a model for an SN1 transition state, C is that of an SN2 reaction and D shows the bending vibration of a tetrahedral hydrogen. The effect of the X and Y groups in increasing the zero point energy is apparent from the simplest particle-in-a-box model.

Figure 8. Out-of-plane bending motions in various structures

Alternatively, we can now make quite good calculations of vibration frequencies for different models although such computations usually apply to the gas phase. Moreover, in real molecules the various atomic motions frequently couple to give complex vibrations in which it can be difficult to perceive simple components such as the motions of only one hydrogen as in Figure 8. For 86 Strom and Mainz; The Foundations of Physical Organic Chemistry: Fifty Years of the James Flack Norris Award ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


demonstration purposes the computed frequencies in Figure 9 were made on chlorine compounds in which the heavy chlorines effectively do not couple with the motions of the light hydrogen and one can clearly see the effect of additional groups near the vibrating hydrogen. Structure A is that of an isolated carbocation with no group at either end of the bending motion of the hydrogen. B is a model of an ion pair with a group at one ond of the vibrating proton. C is a model of an SN2 reaction with groups at both ends hemming in the hydrogen. The lines attached to the hydrogen are the displacement vectors for the vibrations. The absence of such vectors on the other atoms indicates that they all are essentially motionless in these vibrations.

Figure 9. Effect on the vibration frequency of groups near the bending hydrogen

The net result of this analysis is that the α-deuterium provides a sensitive measure of the region near the α-hydrogen in the transition state. This interpretation was quickly accepted (48) by others and has become an important tool for the physical organic chemist. Our experimental results were soon confirmed by others (48, 49) and were extended to related solvolyses. Shiner (50) has given a thorough review on applications of the α-isotope on solvolytic displacement reactions. Lee and Wong (51) provided an important application in their studies of the neighboring group effect in solvolyses. As summarized in Figure 10, the solvolysis of endo-norbornyl brosylate gives an essentially normal α-d effect as expected for a solvolyis of the limiting type. The exo-isomer, however, shows a much lower isotope effect, indicative of neighboring group participation to give the bridged norbornyl cation intermediate. This and other examples have been reviewed by Sunko and Borcic (52) and by Scheppele (53). 87 Strom and Mainz; The Foundations of Physical Organic Chemistry: Fifty Years of the James Flack Norris Award ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 10. α-d Isotope effects in solvolysis of norbornyl brosylates. Another useful application has been to cycloaddition reactions. The question indicated in Figure 11 is whether one bond forms first to give an intermediate diradical or whether the two bonds form concurrently and, if so, whether they are of equal strength at the transition state or different.

Figure 11. Synchronicity question of cycloaddition reactions. α-Deuterium isotope effects have been used for this problem as shown in the recent example in Figure 12 (54). For a two-step reaction there would be no isotope effect at one end. The isotope effects found are on the low side and slightly different indicating that the reaction is concerted but not equal and with an early transition state. Note that the isotope effects are inverse because the CH bonds involved are changing from sp2 to sp3. 88 Strom and Mainz; The Foundations of Physical Organic Chemistry: Fifty Years of the James Flack Norris Award ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 12. Isotope effects in cycloaddition of nitrostyrene to cyclopentadiene (54).

Tritium Tritium is highly radioactive with a half-life of 12.3 years but as a weak beta-emitter it is safe in external use and needs only reasonable precautions in use. It is useful as a tracer just as deuterium but with some distinctive differences. In particular, it can be used to measure small amounts of reaction. For example, in early experiments in my laboratory we used tritium exchange to measure the kinetic acidities of hydrocarbons using a strongly basic system, cesium cyclohexylamide (CsCHA) in cyclohexylamine (CHA). Some measurements were relative to benzene; others referred to cyclohexane. To put all on the same scale we required the relative rates of benzene and cyclohexane. Under typical conditions benzene has a reaction half-life of about half a minute, whereas that of cyclohexane is several years. Nevertheless, we were able to run a mixture of both hydrocarbons in CHA containing tritium, taking several aliquots within a few minutes and spacing others over days. This type of procedure requires careful technique and pure materials. The results of three runs gave k(cyclohexane)/k(benzene) = 1.11 x 10-8, 1.05 x 10-8, 0.97 x 10-8 (55). The good reproducibility suggests that the results are reliable. We were also able to measure the primary isotope effect for the exchange with cyclohexane. Deuterium exchange with cyclohexane is too slow to be practical but could be done using tritium exchange. We used a mxture of cyclopentane and cycloheptane in CHA containing tritium with cyclohexane-d12 in one run and cyclohexane in another. The relative rate cyclopentane/cycloheptane should be the same in both runs and serves as a check. One can show that for small extents of reaction, the rate of incorporation of tritium into cyclohexane-d12 is actually kD. The experimental results gave k(cyclopentane)/k(cycloheptane) = 7.5 and 7.8 for the two runs (56). These results were part of a larger study on the kinetic acidities of cycloalkanes (57, 58). The isotope effect found in this study was kH/kD = 6.5 after correction for the small amount of H in the C6D12 (55). These results with tritium point out that as a highly radioactive element, it can be uniquely useful for measuring slow hydrogen exchange rates. One limitation, however, needs to be added. The experimental kinetic acidity measured by the 89 Strom and Mainz; The Foundations of Physical Organic Chemistry: Fifty Years of the James Flack Norris Award ACS Symposium Series; American Chemical Society: Washington, DC, 2015.

rate of incorporation of tritium into a molecule does not tell us which hydrogen positions are involved. This is not a problem for symmetrical molecules like benzene in which all of the hydrogens are equivalent. It is a limitation for cyclohexane; the reactivity discussed above does not distinguish between the exo and endo-hydrogens. The measured kinetic acidity is the average of the two positions.


Acknowledgments At the time of my Norris award in 1982 I was just finishing my third decade at Berkeley. During that time some 168 undergraduate, graduate and postdoctoral coworkers had worked in my laboratory and I thank them for enjoying chemistry with me. I also thank the several funding agencies (PRF, AFOSR, NIH, NSF) for making it all possible.

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