2214:'s enantioselective synthesis of kapakahines B and F, macrocycle formation was proposed to occur via two isomers of the substrate. The more easily accessible, lower energy isomer led to the undesired product, whereas the less stable isomer formed the desired product. However, because the amide-bond-forming step was irreversible and the barrier to isomerization was low, the major product was derived from the faster-reacting intermediate. This is an example of a Curtin–Hammett scenario in which the less-stable intermediate is significantly more reactive than the more stable intermediate that predominates in solution. Because substrate isomerization is fast, throughout the course of the reaction excess substrate of the more stable form can be converted into the less stable form, which then undergoes rapid and irreversible amide bond formation to produce the desired macrocycle. This strategy provided the desired product in >10:1 selectivity.
2266:
bond isomers. The reaction provided good selectivity for the desired isomer, with results consistent with a Curtin-Hammett scenario. Initial oxidative cycloruthenation and beta-hydride elimination produce a vinyl-ruthenium hydride. Hydride insertion allows for facile alkene isomerization. It is unlikely that the reaction outcome mirrors the stability of the intermediates, as the large CpRu group experiences unfavorable steric interactions with the nearby isopropyl group. Instead, a Curtin–Hammett situation applies, in which the isomer favored in equilibrium does not lead to the major product. Reductive elimination is favored from the more reactive, less stable intermediate, as strain relief is maximized in the transition state. This produces the desired double bond isomer.
2097:
2247:
formed from the other ortho-alkoxy group is primed to undergo a sigmatropic rearrangement to yield the desired compound. Pirrung and coworkers reported complete selectivity for the desired product over the product resulting from a 1,4-methyl shift. This result suggests that oxonium ylide formation is reversible, but that the subsequent step is irreversible. The symmetry-allowed sigmatropic rearrangement must follow a pathway that is lower in activation energy than the 1,4-methyl shift, explaining the exclusive formation of the desired product.
359:
2153:
tetrahedral intermediate. Initially, the less stable isomer predominates, as it is formed more quickly from the stannyl acetal. However, allowing the two isomers to equilibrate results in an excess of the more stable primary alkoxy stannane in solution. The reaction is then quenched irreversibly, with the less hindered primary alkoxy stannane reacting more rapidly. This results in selective production of the more-substituted monoester. This is a Curtin–Hammett scenario in which the more stable isomer also reacts more rapidly.
2122:
2251:
2006:
2157:
1939:
2041:
2198:
1972:
2177:
2146:
2240:
2173:
kcal/mol. Experimentally, the observed product ratio was 91:9 in favor of the product derived from the lower-energy transition state. This product ratio is consistent with the computed difference in transition state energies. This is an example in which the conformer favored in the ground state, which experiences reduced A(1,3) strain, reacts through a lower-energy transition state to form the major product.
2270:
2026:
2221:
1662:
2236:, a potent antifungal agent, a Curtin–Hammett situation was observed. A key step in the synthesis is the rhodium-catalyzed formation of an oxonium ylide, which then undergoes a sigmatropic rearrangement en route to the desired product. However, the substrate contains two ortho-alkoxy groups, either of which could presumably participate in oxonium ylide generation.
1369:
2092:
for hydrogenation of the two enantiomers. The transformation occurs via the lower-energy transition state to form the product as a single enantiomer. Consistent with the Curtin–Hammett principle, the ratio of products depends on the absolute energetic barrier of the irreversible step of the reaction,
2036:
is minimized is at an energy minimum, giving 99:1 selectivity in the ground state. However, transition state energies depend both on the presence of A(1,3) strain and on steric hindrance associated with the incoming methyl radical. In this case, these two factors are in opposition, and the difference
1950:
A second category of reactions under Curtin–Hammett control includes those in which the less stable conformer reacts more quickly. In this case, despite an energetic preference for the less reactive species, the major product is derived from the higher-energy species. An important implication is that
2265:
A potential Curtin-Hammett scenario was also encountered during the enantioselective total synthesis of (+)-allocyathin B2 by the Trost group. The pivotal step in the synthesis was a Ru-catalyzed diastereoselective cycloisomerization. The reaction could result in the formation of two possible double
2193:
The Curtin–Hammett principle has been invoked to explain selectivity in a variety of synthetic pathways. One example is observed en route to the antitumor antibiotic AT2433-A1, in which a
Mannich-type cyclization proceeds with excellent regioselectivity. Studies demonstrate that the cyclization step
2141:
of 1,2-diols. Ordinarily, the less-hindered site of an asymmetric 1,2-diol would experience more rapid esterification due to reduced steric hindrance between the diol and the acylating reagent. Developing a selective esterification of the most substituted hydroxyl group is a useful transformation in
1917:
One category of reactions under Curtin–Hammett control includes transformations in which the more stable conformer reacts more quickly. This occurs when the transition state from the major intermediate to its respective product is lower in energy than the transition state from the minor intermediate
2209:
A Curtin–Hammett scenario was invoked to explain selectivity in the syntheses of kapakahines B and F, two cyclic peptides isolated from marine sponges. The structure of each of the two compounds contains a twisted 16-membered macrocycle. A key step in the syntheses is selective amide bond formation
2246:
Obtaining high selectivity for the desired product was possible, however, due to differences in the activation barriers for the step following ylide formation. If the ortho-methoxy group undergoes oxonium ylide formation, a 1,4-methyl shift can then generate an undesired product. The oxonium ylide
2117:
product being formed in its absence. Equilibration between the two alkyllithium complexes was demonstrated by the observation that enantioselectivity remained constant over the course of the reaction. Were the two reactant complexes not rapidly interconverting, enantioselectivity would erode over
2001:
has proposed that the hypothetical reaction of cyclohexyl iodide with radiolabeled iodide would result in a completely symmetric transition state. Because both the equatorial and axial-substituted conformers would react through the same transition state, ΔΔG would equal zero. By the Curtin–Hammett
1985:
It is hypothetically possible that two different conformers in equilibrium could react through transition states that are equal in energy. In this case, product selectivity would depend only on the distribution of ground-state conformers. In this case, both conformers would react at the same rate.
1967:
with methyl iodide is a classic example of a Curtin–Hammett scenario in which a major product can arise from a less stable conformation. Here, the less stable conformer reacts via a more stable transition state to form the major product. Therefore, the ground state conformational distribution does
393:
the relative activation energies. This misunderstanding may stem from failing to appreciate the distinction between "the difference of energies of activation" and "the difference in transition state energies". Although these quantities may at first appear synonymous, the latter takes into account
324:
were at identical energies, the product ratio would depend only on the activation barriers of the reactions leading to each respective product. However, in a real-world scenario, the two reactants are likely at somewhat different energy levels, although the barrier to their interconversion must be
52:
the energy barriers from each of the rapidly equilibrating isomers to their respective products. Stated another way, the product distribution reflects the difference in energy between the two rate-limiting transition states. As a result, the product distribution will not necessarily reflect the
2172:
of asymmetric alkenes has also been studied as an example of Curtin–Hammett kinetics. In a computational study of the diastereoselective epoxidation of chiral allylic alcohols by titanium peroxy complexes, the computed difference in transition state energies between the two conformers was 1.43
2152:
The asymmetric diol is first treated with a tin reagent to produce the dibutylstannylene acetal. This compound is then treated with one equivalent of acyl chloride to produce the stannyl monoester. Two isomers of the stannyl ester are accessible, and can undergo rapid interconversion through a
1100:
1934:
conformers is much faster than the rate of amine oxidation. The conformation which places the methyl group in the equatorial position is 3.16 kcal/mol more stable than the axial conformation. The product ratio of 95:5 indicates that the more stable conformer leads to the major product.
2017:
When ground state energies are different but transition state energies are similar, selectivity will be degraded in the transition state, and poor overall selectivity may be observed. For instance, high selectivity for one ground state conformer is observed in the following radical
53:
equilibrium distribution of the two intermediates. The Curtin–Hammett principle has been invoked to explain selectivity in a variety of stereo- and regioselective reactions. The relationship between the (apparent) rate constants and equilibrium constant is known as the
614:
240:
1766:
1657:{\displaystyle {\frac {}{}}\approx {\frac {k_{2}K}{k_{1}}}={\frac {e^{-\Delta G_{2}^{\ddagger }/RT}e^{-\Delta G^{\circ }/RT}}{e^{-\Delta G_{1}^{\ddagger }/RT}}}=\exp {\big (}-(\Delta G_{2}^{\ddagger }-\Delta G_{1}^{\ddagger }+\Delta G^{\circ })/RT{\big )}}
2774:
Cui, M.; Adam, W.; Shen, J. H.; Luo, X. M.; Tan, X, J.; Chen, K. X.; Ji, R. Y.; Jiang, H. L. (2002). "A Density-Functional Study of the
Mechanism for the Diastereoselective Epoxidation of Chiral Allylic Alcohols by the Titanium Peroxy Complexes".
2627:
M. Kitamura; M. Tokunaga; R. Noyori (1993). "Quantitative expression of dynamic kinetic resolution of chirally labile enantiomers: stereoselective hydrogenation of 2-substituted 3-oxo carboxylic esters catalyzed by BINAP-ruthenium(II) complexes".
2112:
lithiation reactions. In the reaction below, it was observed that product enantioselectivities were independent of the chirality of the starting material. The use of (−)-sparteine is essential to enantioselectivity, with
2863:
Nakao, Yoichi; Yeung, Bryan K. S.; Yoshida, Wesley Y.; Scheuer, Paul J.; Kelly-Borges, Michelle (1995). "Kapakahine B, a cyclic hexapeptide with an .alpha.-carboline ring system from the marine sponge
Cribrochalina olemda".
2660:
Peter Beak; Amit Basu; Donald J. Gallagher; Yong Sun Park; S. Thayumanavan (1996). "Regioselective, Diastereoselective, and
Enantioselective Lithiation−Substitution Sequences: Reaction Pathways and Synthetic Applications".
69:
The Curtin–Hammett principle applies to systems in which different products are formed from two substrates in equilibrium with one another. The rapidly interconverting reactants can have any relationship between themselves
851:
1860:
2693:; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashis, H. (1989). "Stereoselective hydrogenation via dynamic kinetic resolution".
1358:
1234:
839:
2142:
synthetic organic chemistry, particularly in the synthesis of carbohydrates and other polyhydroxylated compounds. Stannylene acetals have been used to efficiently achieve this transformation.
2002:
principle, the distribution of products should then be 50% axial substituted and 50% equatorial substituted. However, equilibration of the products precludes observation of this phenomenon.
1909:
Three main classes of reactions can be explained by the Curtin–Hammett principle: either the more or less stable conformer may react more quickly, or they may both react at the same rate.
485:
111:
1674:
2370:
Jeffrey I. Seeman (1983). "Effect of
Conformational Change on Reactivity in Organic Chemistry. Evaluations, Application, and Extensions of Cutin–Hammett/Winstein–Holness Kinetics".
728:
2093:
and does not reflect the equilibrium distribution of substrate conformers. The relative free energy profile of one example of the Noyori asymmetric hydrogenation is shown below:
1918:
to the other possible product. The major product is then derived from the major conformer, and the product distribution does not mirror the equilibrium conformer distribution.
316:
reactant ratio, but is instead determined by the relative energies of the transition states (i.e., difference in the absolute energies of the transition states). If reactants
1154:
1278:
2037:
in transition state energies is small compared to the difference in ground state energies. As a result, poor overall selectivity is observed in the reaction.
25:
2501:
Luis
Carballeira; Ignacio Pérez-Juste (1998). "Influence of calculation level and effect of methylation on axial/equatorial equilibria in piperidines".
1095:{\displaystyle {\frac {}{}}\approx {\frac {d}{dt}}{\Big /}{\frac {d}{dt}}={\frac {k_{2}}{k_{1}}}\approx {\frac {k_{2}K}{k_{1}}}={\frac {k_{2}K}{k_{1}}}}
3042:
2331:
845:
with the second approximate equality following from the assumption of rapid equilibration. Under this assumption, the ratio of the products is then
2984:
2812:
58:
1771:
with the energy difference of the transition states, giving us a simplified equation that captures the essence of the Curtin-Hammett principle:
1951:
the product of a reaction can be derived from a conformer that is at sufficiently low concentration as to be unobservable in the ground state.
1926:
An example of a Curtin–Hammett scenario in which the more stable conformational isomer reacts more quickly is observed during the oxidation of
2437:
1778:
3047:
2514:
2194:
is irreversible in the solvent used to run the reaction, suggesting that Curtin–Hammett kinetics can explain the product selectivity.
381:. A common but false assertion is that the product distribution does not in any way reflect the relative free energies of substrates
78:, conformational isomers, etc.). Product formation must be irreversible, and the different products must be unable to interconvert.
3004:
2957:
2901:
2695:
2630:
2557:
Rodney D. Otzenberger; Kenneth B. Lipkowitz; Bradford P. Mundy (1974). "Quaternizations in the 8-azabicyclonon-3-ene series".
325:
low for the Curtin–Hammett scenario to apply. In this case, the product distribution depends both on the equilibrium ratio of
1283:
1159:
3067:
748:
2472:
P. J. Crowley; M. J. T. Robinson; M. G. Ward (1977). "Conformational effects in compounds with 6-membered rings-XII".
2320:
609:{\displaystyle {\ce {\bf {{C}\ {\it {<-{\bf {{A}{\it {\ <=>\ {\bf {{B}\ {\it {->\ {\bf {D}}}}}}}}}}}}}}}}
235:{\displaystyle {\ce {\bf {{C}\ {\it {<-{\bf {{A}{\it {\ <=>\ {\bf {{B}\ {\it {->\ {\bf {D}}}}}}}}}}}}}}}}
3043:
https://web.archive.org/web/20111005191716/http://www.joe-harrity.staff.shef.ac.uk/meetings/CurtinHammettreview.pdf
2069:
1761:{\displaystyle \Delta \Delta G^{\ddagger }=(\Delta G_{2}^{\ddagger }-\Delta G_{1}^{\ddagger })+\Delta G^{\circ }}
2826:
Chisholm, J. D.; Van
Vranken, D. L. (2000). "Regiocontrolled synthesis of the antitumor antibiotic AT2433-A1".
1236:
also remains roughly constant throughout the reaction. In turn, integration with respect to time implies that
355:
free energy profile of a typical reaction under Curtin-Hammett control is represented by the following figure:
2663:
2401:
2899:
Newhouse, T.; Lewis, C. A.; Baran, P. S. (2009). "Enantiospecific Total
Syntheses of Kapakahines B and F".
2828:
2777:
2747:
2559:
1363:
In terms of the ground state and transition state energies, the product ratio can therefore be written as:
2955:
Pirrung, M. C.; Brown, William, L.; Rege, S.; Laughton, P. (1991). "Total synthesis of (+)-griseofulvin".
664:
2096:
619:
In order for rapid equilibration to be a good assumption, the rate of conversion from the less stable of
2084:
conformers and irreversible hydrogenation place the reaction under Curtin–Hammett control. The use of a
3062:
2065:
344:. Both factors are taken into account by the difference in the energies of the transition states (ΔΔ
2528:
Y. Shvo; E.D. Kaufman (1972). "Configurational and conformational analysis of cyclic amine oxides".
3048:
https://web.archive.org/web/20120402124752/http://evans.harvard.edu/pdf/smnr_2009_WZOREK_JOSEPH.pdf
2448:
2282:
2745:
Roelens, S. (1996). "Organotin-Mediated
Monoacylation of Diols with Reversed Chemoselectivity".
2598:
1897:
taken into account by the energy difference of the transition states leading to the products, ΔΔ
1317:
1193:
1109:
918:
2978:
2806:
2530:
2474:
1280:
likewise takes on an approximately constant value through the course of the reaction, namely
75:
41:
33:
2399:
Jeffrey I. Seeman (1986). "The Curtin–Hammett
Principle and the Winstein–Holness Equation".
2064:
The Curtin–Hammett principle can explain the observed dynamics in transformations employing
2612:
Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K.; Trach, F. (2004).
2410:
2556:
8:
352:
45:
29:
2414:
2591:
2998:
Trost, B. M.; Dong, L.; Schroeder, G. M. (2005). "Total synthesis of (+)-Allocyathin B
1239:
479:
A generic reaction under Curtin–Hammett can be described by the following parameters:
3021:
2918:
2881:
2845:
2794:
2543:
2487:
2316:
2292:
2287:
441:. By combining terms, the product ratio can be rewritten in terms of the quantity ΔΔ
21:
2954:
2341:
2108:
Dynamic kinetic resolution under Curtin–Hammett conditions has also been applied to
3013:
2966:
2910:
2873:
2837:
2786:
2756:
2723:
2704:
2672:
2659:
2639:
2568:
2539:
2510:
2483:
2418:
2381:
2372:
2345:
2336:
2134:
2109:
2089:
358:
2941:
2586:
2085:
2053:
1998:
2690:
2052:
The Curtin–Hammett principle is used to explain the selectivity ratios for some
2731:
2033:
2121:
2047:
48:
ratio will depend both on the difference in energy between the two conformers
3056:
2885:
1866:
Thus, although the product ratio depends on the equilibrium constant between
1106:
In other words, because equilibration is fast compared to product formation,
54:
2349:
467:°. Inspection of the energy diagram (shown above) makes it apparent that ΔΔ
3025:
2922:
2849:
2798:
2250:
2233:
1931:
1668:
Importantly, inspection of the energy diagram above allows us to identify
71:
2005:
2515:
10.1002/(SICI)1096-987X(199806)19:8<961::AID-JCC14>3.0.CO;2-A
2169:
2019:
1927:
2970:
2877:
2708:
2643:
2572:
2471:
2385:
2156:
635:
must be at least 10 times slower than the rate of equilibration between
336:
on the relative activation barriers going to the corresponding products
2211:
2081:
1960:
1938:
1855:{\displaystyle {\frac {}{}}\approx e^{-\Delta \Delta G^{\ddagger }/RT}}
3017:
2914:
2841:
2790:
2760:
2676:
2340:, 2nd ed. (the "Gold Book") (1997). Online corrected version: (1994) "
2197:
2040:
2611:
2422:
2313:
Advanced Organic Chemistry Part A Structure and Mechanisms (2nd ed.).
2138:
1971:
1945:
2997:
2898:
2773:
2689:
1930:. In the case of N-methyl piperidine, inversion at nitrogen between
1912:
1904:
568:
539:
506:
405:
Mathematically, the product ratio can be expressed as a function of
389:; in fact, it reflects the relative free energies of the substrates
194:
165:
132:
2500:
1980:
1964:
647:
37:
2825:
2114:
2438:"The Curtin-Hammett Principle and the Winstein-Holness Equation"
2176:
2145:
2626:
2239:
2269:
2025:
2220:
1989:
2059:
584:
548:
210:
174:
2048:
Application to stereoselective and regioselective reactions
2128:
471:
is precisely the difference in transition state energies.
365:
The ratio of products only depends on the value labeled ΔΔ
2216:(I think there's an error in the Scheme. See Talk pages.)
2133:
The Curtin–Hammett principle has been invoked to explain
278:, respectively. When the rate of interconversion between
2862:
2163:
44:), each going irreversibly to a different product, the
1353:{\displaystyle {\frac {d}{dt}}{\Big /}{\frac {d}{dt}}}
1229:{\displaystyle {\frac {d}{dt}}{\Big /}{\frac {d}{dt}}}
300:, then the Curtin–Hammett principle tells us that the
40:
that interconvert rapidly (as is usually the case for
1781:
1677:
1372:
1286:
1242:
1162:
1112:
854:
751:
667:
488:
114:
32:. It states that, for a reaction that has a pair of
2118:
time as the faster-reacting conformer was depleted.
2527:
2204:
1877:the difference in energy between the barriers from
834:{\displaystyle {\frac {d}{dt}}=k_{2}\approx k_{2}K}
2590:
2257:
2075:
1946:Case II: Less stable conformer reacts more quickly
1854:
1760:
1656:
1352:
1272:
1228:
1148:
1094:
833:
722:
608:
234:
2398:
2369:
2311:Carey, Francis A.; Sundberg, Richard J.; (1984).
1913:Case I: More stable conformer reacts more quickly
1905:Classes of reactions under Curtin–Hammett control
373:will be the major product, because the energy of
3054:
2991:
2227:
1981:Case III: both conformers react at the same rate
1921:
394:the equilibrium constant for interconversion of
2721:
2012:
2856:
2494:
2365:
2363:
2361:
2359:
2357:
2103:
2088:results in a higher-energy and a lower-energy
1954:
308:product ratio is not equal to the equilibrium
1649:
1567:
2983:: CS1 maint: multiple names: authors list (
2811:: CS1 maint: multiple names: authors list (
270:are the rate constants for the formation of
2767:
2744:
2738:
2605:
2354:
2232:In the first enantioselective synthesis of
423:or in terms of the corresponding energies Δ
2683:
2620:
2465:
2188:
2183:
2060:Application to dynamic kinetic resolution
3005:Journal of the American Chemical Society
2958:Journal of the American Chemical Society
2902:Journal of the American Chemical Society
2866:Journal of the American Chemical Society
2696:Journal of the American Chemical Society
2631:Journal of the American Chemical Society
2948:
2819:
2655:
2653:
2521:
2129:Application to regioselective acylation
3055:
2935:
2929:
2550:
2435:
2392:
2210:to produce the correct macrocycle. In
1968:not reflect the product distribution.
1156:throughout the reaction. As a result,
2892:
2715:
2585:
2164:Application to asymmetric epoxidation
723:{\displaystyle {\frac {d}{dt}}=k_{1}}
531:
157:
2650:
248:is the equilibrium constant between
2593:Stereochemistry of Carbon Compounds
589:
558:
554:
525:
496:
492:
215:
184:
180:
151:
122:
118:
13:
2597:. New York: McGraw–Hill. pp.
2503:Journal of Computational Chemistry
2337:Compendium of Chemical Terminology
2268:
2249:
2238:
2219:
2196:
2175:
2155:
2144:
2120:
2095:
2039:
2024:
2004:
1970:
1937:
1826:
1823:
1745:
1721:
1700:
1681:
1678:
1620:
1599:
1578:
1523:
1488:
1449:
570:
541:
508:
357:
196:
167:
134:
14:
3079:
3036:
2728:Methods in Carbohydrate Chemistry
2072:and enantioselective lithiation.
2205:Synthesis of kapakahines B and F
1802:
1789:
1393:
1380:
1332:
1297:
1263:
1247:
1208:
1173:
1133:
1117:
1050:
1027:
994:
971:
933:
898:
875:
862:
824:
797:
762:
713:
678:
2579:
2076:Noyori asymmetric hydrogenation
2070:Noyori asymmetric hydrogenation
1994:2 reaction of cyclohexyl iodide
402:, while the former does not.
89:that equilibrate rapidly while
2429:
2325:
2305:
2258:Synthesis of (+)-allocyathin B
1806:
1798:
1793:
1785:
1739:
1697:
1633:
1575:
1397:
1389:
1384:
1376:
1336:
1328:
1301:
1293:
1267:
1259:
1251:
1243:
1212:
1204:
1177:
1169:
1137:
1129:
1121:
1113:
1054:
1046:
1031:
1023:
998:
990:
975:
967:
937:
929:
902:
894:
879:
871:
866:
858:
828:
820:
801:
793:
766:
758:
717:
709:
682:
674:
1:
2664:Accounts of Chemical Research
2436:Wzorek, Joseph (2009-12-18).
2402:Journal of Chemical Education
2315:New York N.Y.: Plenum Press.
2298:
2228:Synthesis of (+)-griseofulvin
1922:Example: piperidine oxidation
474:
64:
2829:Journal of Organic Chemistry
2778:Journal of Organic Chemistry
2748:Journal of Organic Chemistry
2560:Journal of Organic Chemistry
2544:10.1016/0040-4020(72)84021-3
2488:10.1016/0040-4020(77)80202-0
2080:Rapid equilibration between
2013:Example: radical methylation
1893:, both of these factors are
377:is lower than the energy of
7:
2276:
2104:Enantioselective lithiation
1955:Example: tropane alkylation
286:is much faster than either
81:For example, given species
10:
3084:
3068:Physical organic chemistry
2066:dynamic kinetic resolution
1149:{\displaystyle /\approx K}
2342:Curtin–Hammett principle
101:turns irreversibly into
93:turns irreversibly into
18:Curtin–Hammett principle
2938:Antifungal Chemotherapy
2350:10.1351/goldbook.C01480
2283:Transition state theory
2032:The conformer in which
2936:Davies, R. R. (1980).
2273:
2254:
2243:
2224:
2201:
2189:Synthesis of AT2433-A1
2184:Synthetic applications
2180:
2160:
2149:
2125:
2100:
2044:
2029:
2009:
1975:
1942:
1863:
1856:
1762:
1658:
1354:
1274:
1230:
1150:
1096:
835:
724:
610:
362:
348:in the figure below).
236:
76:constitutional isomers
42:conformational isomers
34:reactive intermediates
2272:
2253:
2242:
2223:
2200:
2179:
2159:
2148:
2124:
2099:
2043:
2028:
2008:
1974:
1941:
1857:
1774:
1763:
1659:
1355:
1275:
1231:
1151:
1097:
836:
725:
611:
361:
237:
2445:Evans Group Seminars
1779:
1675:
1370:
1284:
1240:
1160:
1110:
852:
749:
665:
486:
112:
2971:10.1021/ja00022a075
2878:10.1021/ja00136a026
2709:10.1021/ja00207a038
2644:10.1021/ja00054a020
2573:10.1021/jo00917a008
2415:1986JChEd..63...42S
2386:10.1021/cr00054a001
1738:
1717:
1616:
1595:
1540:
1466:
581:
545:
519:
353:reaction coordinate
207:
171:
145:
30:Louis Plack Hammett
26:David Yarrow Curtin
2274:
2255:
2244:
2225:
2202:
2181:
2161:
2150:
2126:
2101:
2045:
2030:
2010:
1976:
1943:
1852:
1758:
1724:
1703:
1654:
1602:
1581:
1526:
1452:
1350:
1270:
1226:
1146:
1092:
831:
720:
606:
363:
232:
20:is a principle in
3063:Chemical kinetics
3018:10.1021/ja0435586
2965:(22): 8561–8562.
2915:10.1021/ja901573x
2909:(18): 6360–6361.
2872:(31): 8271–8272.
2842:10.1021/jo000911r
2836:(22): 7541–7553.
2791:10.1021/jo016015c
2761:10.1021/jo960453f
2755:(16): 5257–5263.
2722:Whistler, R. L.;
2703:(25): 9134–9135.
2677:10.1021/ar950142b
2614:Organic Reactions
2293:Gibbs free energy
2288:Chemical kinetics
1810:
1554:
1433:
1401:
1348:
1313:
1273:{\displaystyle /}
1224:
1189:
1090:
1058:
1002:
949:
914:
883:
778:
694:
648:rate of formation
591:
586:
582:
560:
556:
550:
546:
533:
527:
520:
498:
494:
217:
212:
208:
186:
182:
176:
172:
159:
153:
146:
124:
120:
22:chemical kinetics
3075:
3030:
3029:
3012:(9): 2844–2845.
2995:
2989:
2988:
2982:
2974:
2952:
2946:
2945:
2942:Wiley & Sons
2933:
2927:
2926:
2896:
2890:
2889:
2860:
2854:
2853:
2823:
2817:
2816:
2810:
2802:
2785:(5): 1427–1435.
2771:
2765:
2764:
2742:
2736:
2735:
2719:
2713:
2712:
2687:
2681:
2680:
2657:
2648:
2647:
2624:
2618:
2617:
2609:
2603:
2602:
2596:
2587:Eliel, Ernest L.
2583:
2577:
2576:
2554:
2548:
2547:
2525:
2519:
2518:
2498:
2492:
2491:
2469:
2463:
2462:
2460:
2459:
2453:
2447:. Archived from
2442:
2433:
2427:
2426:
2423:10.1021/ed063p42
2396:
2390:
2389:
2373:Chemical Reviews
2367:
2352:
2329:
2323:
2309:
2234:(+)-Griseofulvin
2135:regioselectivity
2110:enantioselective
2090:transition state
1861:
1859:
1858:
1853:
1851:
1850:
1843:
1838:
1837:
1811:
1809:
1805:
1796:
1792:
1783:
1767:
1765:
1764:
1759:
1757:
1756:
1737:
1732:
1716:
1711:
1693:
1692:
1663:
1661:
1660:
1655:
1653:
1652:
1640:
1632:
1631:
1615:
1610:
1594:
1589:
1571:
1570:
1555:
1553:
1552:
1545:
1539:
1534:
1514:
1513:
1512:
1505:
1500:
1499:
1479:
1478:
1471:
1465:
1460:
1439:
1434:
1432:
1431:
1422:
1418:
1417:
1407:
1402:
1400:
1396:
1387:
1383:
1374:
1359:
1357:
1356:
1351:
1349:
1347:
1339:
1335:
1323:
1321:
1320:
1314:
1312:
1304:
1300:
1288:
1279:
1277:
1276:
1271:
1266:
1258:
1250:
1235:
1233:
1232:
1227:
1225:
1223:
1215:
1211:
1199:
1197:
1196:
1190:
1188:
1180:
1176:
1164:
1155:
1153:
1152:
1147:
1136:
1128:
1120:
1101:
1099:
1098:
1093:
1091:
1089:
1088:
1079:
1075:
1074:
1064:
1059:
1057:
1053:
1045:
1044:
1034:
1030:
1019:
1018:
1008:
1003:
1001:
997:
989:
988:
978:
974:
966:
965:
955:
950:
948:
940:
936:
924:
922:
921:
915:
913:
905:
901:
889:
884:
882:
878:
869:
865:
856:
840:
838:
837:
832:
827:
816:
815:
800:
792:
791:
779:
777:
769:
765:
753:
729:
727:
726:
721:
716:
708:
707:
695:
693:
685:
681:
669:
615:
613:
612:
607:
605:
604:
603:
602:
601:
600:
599:
598:
597:
596:
595:
594:
593:
592:
583:
580:
579:
578:
564:
557:
547:
544:
535:
528:
521:
518:
517:
516:
502:
495:
241:
239:
238:
233:
231:
230:
229:
228:
227:
226:
225:
224:
223:
222:
221:
220:
219:
218:
209:
206:
205:
204:
190:
183:
173:
170:
161:
154:
147:
144:
143:
142:
128:
121:
3083:
3082:
3078:
3077:
3076:
3074:
3073:
3072:
3053:
3052:
3039:
3034:
3033:
3001:
2996:
2992:
2976:
2975:
2953:
2949:
2934:
2930:
2897:
2893:
2861:
2857:
2824:
2820:
2804:
2803:
2772:
2768:
2743:
2739:
2720:
2716:
2688:
2684:
2671:(11): 552–560.
2658:
2651:
2625:
2621:
2610:
2606:
2584:
2580:
2555:
2551:
2526:
2522:
2499:
2495:
2470:
2466:
2457:
2455:
2451:
2440:
2434:
2430:
2397:
2393:
2368:
2355:
2330:
2326:
2310:
2306:
2301:
2279:
2263:
2261:
2230:
2207:
2191:
2186:
2166:
2131:
2106:
2086:chiral catalyst
2078:
2062:
2054:stereoselective
2050:
2015:
1999:Ernest L. Eliel
1996:
1993:
1983:
1957:
1948:
1924:
1915:
1907:
1864:
1839:
1833:
1829:
1819:
1815:
1801:
1797:
1788:
1784:
1782:
1780:
1777:
1776:
1752:
1748:
1733:
1728:
1712:
1707:
1688:
1684:
1676:
1673:
1672:
1648:
1647:
1636:
1627:
1623:
1611:
1606:
1590:
1585:
1566:
1565:
1541:
1535:
1530:
1519:
1515:
1501:
1495:
1491:
1484:
1480:
1467:
1461:
1456:
1445:
1441:
1440:
1438:
1427:
1423:
1413:
1409:
1408:
1406:
1392:
1388:
1379:
1375:
1373:
1371:
1368:
1367:
1340:
1331:
1324:
1322:
1316:
1315:
1305:
1296:
1289:
1287:
1285:
1282:
1281:
1262:
1254:
1246:
1241:
1238:
1237:
1216:
1207:
1200:
1198:
1192:
1191:
1181:
1172:
1165:
1163:
1161:
1158:
1157:
1132:
1124:
1116:
1111:
1108:
1107:
1084:
1080:
1070:
1066:
1065:
1063:
1049:
1040:
1036:
1035:
1026:
1014:
1010:
1009:
1007:
993:
984:
980:
979:
970:
961:
957:
956:
954:
941:
932:
925:
923:
917:
916:
906:
897:
890:
888:
874:
870:
861:
857:
855:
853:
850:
849:
823:
811:
807:
796:
787:
783:
770:
761:
754:
752:
750:
747:
746:
712:
703:
699:
686:
677:
670:
668:
666:
663:
662:
627:to the product
588:
587:
574:
573:
569:
563:
562:
561:
553:
552:
551:
540:
534:
530:
529:
524:
523:
522:
512:
511:
507:
501:
500:
499:
491:
490:
489:
487:
484:
483:
477:
462:
455:
445:alone, where ΔΔ
440:
433:
422:
415:
369:in the figure:
299:
292:
269:
262:
214:
213:
200:
199:
195:
189:
188:
187:
179:
178:
177:
166:
160:
156:
155:
150:
149:
148:
138:
137:
133:
127:
126:
125:
117:
116:
115:
113:
110:
109:
67:
12:
11:
5:
3081:
3071:
3070:
3065:
3051:
3050:
3045:
3038:
3037:External links
3035:
3032:
3031:
2999:
2990:
2947:
2928:
2891:
2855:
2818:
2766:
2737:
2732:Academic Press
2714:
2682:
2649:
2638:(1): 144–152.
2619:
2604:
2601:–156, 234–239.
2578:
2567:(3): 319–321.
2549:
2538:(3): 573–580.
2520:
2509:(8): 961–976.
2493:
2482:(9): 915–925.
2464:
2428:
2391:
2353:
2324:
2303:
2302:
2300:
2297:
2296:
2295:
2290:
2285:
2278:
2275:
2262:
2259:
2256:
2229:
2226:
2206:
2203:
2190:
2187:
2185:
2182:
2165:
2162:
2130:
2127:
2105:
2102:
2077:
2074:
2068:, such as the
2061:
2058:
2049:
2046:
2014:
2011:
1995:
1991:
1988:
1982:
1979:
1956:
1953:
1947:
1944:
1932:diastereomeric
1923:
1920:
1914:
1911:
1906:
1903:
1849:
1846:
1842:
1836:
1832:
1828:
1825:
1822:
1818:
1814:
1808:
1804:
1800:
1795:
1791:
1787:
1773:
1769:
1768:
1755:
1751:
1747:
1744:
1741:
1736:
1731:
1727:
1723:
1720:
1715:
1710:
1706:
1702:
1699:
1696:
1691:
1687:
1683:
1680:
1666:
1665:
1651:
1646:
1643:
1639:
1635:
1630:
1626:
1622:
1619:
1614:
1609:
1605:
1601:
1598:
1593:
1588:
1584:
1580:
1577:
1574:
1569:
1564:
1561:
1558:
1551:
1548:
1544:
1538:
1533:
1529:
1525:
1522:
1518:
1511:
1508:
1504:
1498:
1494:
1490:
1487:
1483:
1477:
1474:
1470:
1464:
1459:
1455:
1451:
1448:
1444:
1437:
1430:
1426:
1421:
1416:
1412:
1405:
1399:
1395:
1391:
1386:
1382:
1378:
1346:
1343:
1338:
1334:
1330:
1327:
1319:
1311:
1308:
1303:
1299:
1295:
1292:
1269:
1265:
1261:
1257:
1253:
1249:
1245:
1222:
1219:
1214:
1210:
1206:
1203:
1195:
1187:
1184:
1179:
1175:
1171:
1168:
1145:
1142:
1139:
1135:
1131:
1127:
1123:
1119:
1115:
1104:
1103:
1087:
1083:
1078:
1073:
1069:
1062:
1056:
1052:
1048:
1043:
1039:
1033:
1029:
1025:
1022:
1017:
1013:
1006:
1000:
996:
992:
987:
983:
977:
973:
969:
964:
960:
953:
947:
944:
939:
935:
931:
928:
920:
912:
909:
904:
900:
896:
893:
887:
881:
877:
873:
868:
864:
860:
843:
842:
830:
826:
822:
819:
814:
810:
806:
803:
799:
795:
790:
786:
782:
776:
773:
768:
764:
760:
757:
732:
731:
719:
715:
711:
706:
702:
698:
692:
689:
684:
680:
676:
673:
617:
616:
577:
572:
567:
543:
538:
515:
510:
505:
476:
473:
460:
453:
438:
431:
420:
413:
297:
290:
267:
260:
243:
242:
203:
198:
193:
169:
164:
141:
136:
131:
66:
63:
9:
6:
4:
3:
2:
3080:
3069:
3066:
3064:
3061:
3060:
3058:
3049:
3046:
3044:
3041:
3040:
3027:
3023:
3019:
3015:
3011:
3007:
3006:
2994:
2986:
2980:
2972:
2968:
2964:
2960:
2959:
2951:
2943:
2939:
2932:
2924:
2920:
2916:
2912:
2908:
2904:
2903:
2895:
2887:
2883:
2879:
2875:
2871:
2867:
2859:
2851:
2847:
2843:
2839:
2835:
2831:
2830:
2822:
2814:
2808:
2800:
2796:
2792:
2788:
2784:
2780:
2779:
2770:
2762:
2758:
2754:
2750:
2749:
2741:
2733:
2729:
2725:
2724:Wolfrom, M. L
2718:
2710:
2706:
2702:
2698:
2697:
2692:
2691:Noyori, Ryōji
2686:
2678:
2674:
2670:
2666:
2665:
2656:
2654:
2645:
2641:
2637:
2633:
2632:
2623:
2615:
2608:
2600:
2595:
2594:
2588:
2582:
2574:
2570:
2566:
2562:
2561:
2553:
2545:
2541:
2537:
2533:
2532:
2524:
2516:
2512:
2508:
2504:
2497:
2489:
2485:
2481:
2477:
2476:
2468:
2454:on 2017-09-18
2450:
2446:
2439:
2432:
2424:
2420:
2416:
2412:
2408:
2404:
2403:
2395:
2387:
2383:
2380:(2): 83–134.
2379:
2375:
2374:
2366:
2364:
2362:
2360:
2358:
2351:
2347:
2343:
2339:
2338:
2333:
2328:
2322:
2321:0-306-41198-9
2318:
2314:
2308:
2304:
2294:
2291:
2289:
2286:
2284:
2281:
2280:
2271:
2267:
2252:
2248:
2241:
2237:
2235:
2222:
2218:
2217:
2213:
2199:
2195:
2178:
2174:
2171:
2158:
2154:
2147:
2143:
2140:
2136:
2123:
2119:
2116:
2111:
2098:
2094:
2091:
2087:
2083:
2073:
2071:
2067:
2057:
2055:
2042:
2038:
2035:
2034:A(1,3) strain
2027:
2023:
2021:
2007:
2003:
2000:
1987:
1978:
1973:
1969:
1966:
1962:
1952:
1940:
1936:
1933:
1929:
1919:
1910:
1902:
1900:
1896:
1895:automatically
1892:
1888:
1884:
1880:
1876:
1873:
1869:
1862:
1847:
1844:
1840:
1834:
1830:
1820:
1816:
1812:
1772:
1753:
1749:
1742:
1734:
1729:
1725:
1718:
1713:
1708:
1704:
1694:
1689:
1685:
1671:
1670:
1669:
1644:
1641:
1637:
1628:
1624:
1617:
1612:
1607:
1603:
1596:
1591:
1586:
1582:
1572:
1562:
1559:
1556:
1549:
1546:
1542:
1536:
1531:
1527:
1520:
1516:
1509:
1506:
1502:
1496:
1492:
1485:
1481:
1475:
1472:
1468:
1462:
1457:
1453:
1446:
1442:
1435:
1428:
1424:
1419:
1414:
1410:
1403:
1366:
1365:
1364:
1361:
1344:
1341:
1325:
1309:
1306:
1290:
1255:
1220:
1217:
1201:
1185:
1182:
1166:
1143:
1140:
1125:
1085:
1081:
1076:
1071:
1067:
1060:
1041:
1037:
1020:
1015:
1011:
1004:
985:
981:
962:
958:
951:
945:
942:
926:
910:
907:
891:
885:
848:
847:
846:
817:
812:
808:
804:
788:
784:
780:
774:
771:
755:
745:
744:
743:
741:
737:
704:
700:
696:
690:
687:
671:
661:
660:
659:
657:
653:
650:for compound
649:
644:
642:
638:
634:
630:
626:
622:
575:
565:
536:
513:
503:
482:
481:
480:
472:
470:
466:
459:
452:
448:
444:
437:
430:
426:
419:
412:
408:
403:
401:
397:
392:
388:
384:
380:
376:
372:
368:
360:
356:
354:
349:
347:
343:
339:
335:
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