Racemization and Isomerization

The use of n.m.r. line-broadening for dynamic studies of racemization processes has been of prime importance in recent years. A useful book has appeared concerned with the chemical applications of n.m.r. in paramagnetic molecules which deals in part with this subject.  

Cobalt(iii) Complexes.— At 303.1 K the rate constant for the trans cis isomerization of the [Co(en)2(OCOCH2C02HXOH2)] ion is 10 A = 28.0 s , the activation energy being 27.6 kcal mol and 9.5 cal mol. The isomerization is postulated to occur by elimination of the co-ordinated water molecule to give a trigonal-bipyramidal transition state. Replacing the hydrogen malonate ion by the less basic benzoate ion increases the reaction rate from 10 = 220 s to 10 A = 384 s- at 318.1 K and pH 1.5. 

The kinetics of isomerization of [Co(NH3)4(OH2)2] and [Co(en)2(OH2XOH)] + ions have been measured as a part of the studies of other reactions of these two ions. The kinetics of tetramerization and isomerization of the [Co(NH8)4(OH2)(OH)] + and [Co(NH3)4(OH)2]+ ions have been investigated by stopped-flow and pH-stat experiments. The cis-trans isomerization of [Co(en)2(OH2XOH)] + ions was measured as part of a study of the reaction of the cw-isomer with acetylacetone. At 298.1 K and p = 0.25 mol 1 the rate constants for the trans cis and cis- trans rearrangements are 4 x 10 and 1 x 10 s respectively. The kinetics of isomerization of cis- and trani -[Co(en)2(N02)2] have also been reported.  

Basic oxyanions (e.g. phosphate, selenite, sulphate) have a profound effect upon 

Several dissociative mechanisms involving trigonal-bipyramidal intermediates are postulated, the trend in reaction rates being related to the ability of X to stabilize the intermediate formed by a process of ji-donation. Twist mechanisms can be ruled out because of the large entropies of activation. The S-bonded thiot anato-complex rra j-[Co(acac)2(SCN)py] was also synthesized by the following reaction  

General.—Two reviews dealing with the rearrangement reactions of metal chelates have appeared. - N.m.r. lineshape analysis plays a dominant role in mechanistic studies of this type, and a permutational analysis has been described for the coalescence behaviour of n.m.r. spectra in experiments involving complexes of the type cw-[M(LL)2X2], cw-[M(LL)aXY], and cw-ENKLLOXJ.  

Novel linkage isomers of thiocyanate ion are also reported from studies of the reaction of Hgi with the [Co(NH8)6SCN] + ion. The immediate product is the [Co(NH3)s(SCNHg)] + ion, which undergoes aquation and isomerization to yield the [Co(NH3)5HaO] + and [Co(NH8)6(NCSHg)] + ions respectively.  

Concerted base hydrolysis and Bailar inversion of the /l-cis -[Co(en)2Cl2]+ ion has been established by a circular dichroism study [equation (18)]. Base hydrolysis of the /l-c/j-[Co(en)aCl(OH)]+ ion is reported to proceed with complete retention of configuration in contrast to an earlier investigation of this reaction. The results of these studies were considered previously.  

Two reports of the rates and activation parameters for the racemization of [Co(en)2(amine)(H20)] + ions (amine = py or benzylamine or MeNHa, BuNHa, y-picoline, isoquinoline, imidazole, or benzimidazole ) have appeared. A mechanism involving dissociation of the co-ordinated water molecule to give a trigonal-bipyramidal intermediate is believed to be involved. The steric course of the base hydrolysis of [Co(en)2(amine)Cl] + ions was considered previously.  

High-speed liquid chromatography has been used to separate cis- and trans-[Co(en)2Cl2]+ ions, and by this method the rate of the first-order isomerization process has been measured in methanol solution.  

Cobalt(m) Complexes.—Specific rate constants kt + k i of equation (12)] and derived composite activation parameters have been determined for the isomerization 

The activation enthalpy of 28.5 kcal mol is in the expected region for a cobalt(m) substitution process. It is interesting that the equilibrium constant for equation (12) appears to be invariant with temperature in other words the enthalpy change for reaction (12) is very close to zero. Rates of isomerization of [Co(en)2(OAc)a]+ in dimethyl sulphoxide, both in the absence and in the presence of added acetate, have been measured. An increase in rate on adding acetate is ascribed to the formation of more reactive ion-pairs. In chloroform solution, the rate constant for rra j- cis-[Co(acac)2(N3)2] is approximately 4 X 10 s at 35 °C for [Co(acac)2(N02)2] the rate of isomerization is less, ca. 8 x 10 s at 35 °C.  

Isomerization of [Co(en)(NH3)3(OH)] + and of [Co(en)(NH3)2(OH)2]+ has been extensively studied by spectrophotometry in dilute aqueous solution. Recent kinetic results for the former isomerization obtained by the use of Co n.m.r. spectroscopy, in concentrated solutions, are consistent with the early spectrophotometric results. The [Co(en)(NH3)2(OH)2]+ cation exists in three isomeric forms. The observed isomerization paths and their respective rate constants, also obtained by Co n.m.r. spectroscopy, are shown in Table 27. The proposed mechanism for these isomerizations involves reversible dissociation of one end of the ethylenediamine ligand from the cobalt. Isomerization of mer- or yhc-[Co(en)(NH3)3(OH)] + was not detected, even after 

Serpone and D. G. Bickley, Progr. Inorg. Chem., 1972, 17 (part 2), 391. 

There are two cw-isomers of [Co(trien)(OH2)2] +, the a- (41) and the /3- (42) forms. Both the a- and the S-forms isomerize to a mixture of a- and /S-isomers there is no isomerization to the trans-Iorm. The rate of isomerization is equal to the rate of racemization for the a-isomer over the pH range (1 pH 3) investigated a term in [H+] in the rate law is ascribed to parallel reaction of the hydroxoaquo-complex [Co(trien)(OH2)(OH)] +. It proved impossible to study the isomerization of the j8-isomer spectrophotometrically as the spectroscopic change involved was too small. Racemization of this /5-isomer follows the rate law 

Two studies of the rraw-[Co(en)2(OHa)2] + ion at high pressures indicate that the water exchange rate proceeds by a dissociative /d mechanism involving a square-pyramidal intermediate [A K =+5.9 0.2 cm mol(pressure-independent) at 

Bickley and N. Serpone, Inorg. Chim. Acta, 1977, 25, L139. 

Racemization of cw-equatorial [CoCLXOHa)] (L=ethylenediaminetriacetate ion, H2O is in a /raws -position to the tertiary N-atom of L) occurs below pH 6.5 with a rate law of the form Rate= rac[OH-][Co(L)(OH2 ]. Although the pX of the coordinated H2O molecule is ca. 8 and the pKa. of the secondary amine group of L is 15 0.5 (Xn), it is believed that racemization occurs by the Nlcb mechanism involving deprotonation of the NH group  

With this scheme k = kracKw/KN, and, assuming that ATw/Xm does not vary with temperature, logk is in the range 4.2—5.1 between 40 and 60 °C. Activation parameters associated with Ar oc are H =22 kcal mol and AS =26 cal K- mol- . A comparison of [Co(L)(OHa)] with [Co(L)(OH)]- ion shows that the latter ion does not racemize at a measurable rate, presumably because loss of the co-ordinated OH- group is more difficult than loss of co-ordinated HaO. When L=iV-methyl-ethylenediaminetriacetate ion, the absence of the secondary amine group reduces the rate of racemization by a factor of more than 10.  

Isomerization of 5-c/j-[Co(edda)(OH2)2] ion to the a-c -species involves the formation of hydroxy-aqua-complexes  

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Some chemical reactions also obey first-order kinetics. Isomerization and racemization reactions are normally first-order. Note that whereas nuclear... 

T. Geiger and S. Clarke, Deamidation, isomerization and racemization at asparaginyl and aspartyl residues in peptides, J. Biol. Chem, 262, 785 (1987). 

Table 8. Propagation constants of isomeric and racemic y-benzyl glutamate NCA.

Deamidation, isomerization and racemization. These three reactions are common degradation pathways of proteins and peptides. These reactions are especially prevalent for peptides containing asparagine (Asn) and glutamine (Gin) residues. In the deamidation reaction, the Asn or Gin amide... 

Geiger T, Clark S. Deamidation, isomerization, and racemization at asparagi-nyland aspartyl residues in peptides. J Biol Chem 1987 262(2) 785-794. 

The results are relevant to the mechanism of the isomerization and racemization of triorganotin halides, which may include the selective cleavage of the bridging halogen bonds in unsymmetrical intermediates X—SnR3—Y—SnR3—D (D = donor) like 53. 

A considerable amount of effort has been devoted to M(dike)3 complexes because by using unsymmetrical diketonate ligands, the processes of isomerization and racemization can be studied simultaneously. Since isomerization can occur only by a dissociative pathway, it is often possible to exploit well-designed experiments to yield information on the pathways for both isomerization and racemization. 

Oxalate (ox, 204 ) complexes of Cr° have been known since the very beginning of coordination chemistry. Thus, the resolution of chiral [Cr(ox)3] with strychninium counterion by Werner in 1912 prodnced the first optically active anionic coordination compound. There also exists a series of bis(oxalato) complexes of the type [Cr(ox)2X2] + , where X can be any of a variety of nentral donors (e g. H2O, NH3, etc.) or anionic ligands (e g. SCN, N3, etc.). These compounds have been used to study the mechanism of cis/trans isomerization and racemization of optically active octahedral coordination compounds. 

Reaction sequence 45 shows this process at C-13 of linolenic acid for simplicity, but comparable cyclization also occurs at C-10 in linolenic acid and at C-8, C-9, C-11, and C-12 in arachidonic acid (252). The cyclic product mixes of oxidized Ln and An typically show multiple positional and geometric isomers (227, 266). In the interest of space, the isomerization and racemization that accompanies cyclization will not be discussed here. The reader is referred to papers by Gardner (6, 267) and Porter (7, 11, 252, 268) for more details. 

Stereomutation is a term that encompasses cis-trans isomerization and racemization of substituted cyclic molecules. Its detection in cyclopropanes requires at least two substituents (either or both of which could be isotopic labels) on two different carbons. 

The symbols k and k in equation 1 represent respectively the phenomenological rate constants for cis-trans isomerization and racemization. From this equation one can see that a pure Smith mechanism k = k 2 = ) would give kjk = 2. A pure Benson mechanism [ki = ki2 =0) would give kjk = 1. Finally, a pure Hoffmann mechanism (kj = = 0) would give kjk = 0. 

Typical structures of the complexes ((127)-(132)) are illustrated (see also Scheme 19). All the compounds have been characterized by X-ray crystallography, except for (127) and (130) for the latter, the crystal structure of a V111 analog is available.630-636 In addition, a series of articles by Kanno et al. on isomerization and racemization of the Cr111 complexes of substituted 2,2 -bipyridine-l,l -dioxide ligands637-639 continued the earlier works of these authors on the stereochemistry of metal complexes with bidentate aromatic A-oxide ligands.1... 

From studies of isomerizations and racemizations of optically active octahedral coordination compounds, Fujiwara and Bailar [78] concluded that none of the several mechanisms proposed was capable of accounting for the observations for all of the reactions investigated. 

Elimination degradation pathways are also possible. Decarboxylation, in which a carboxylic acid releases a molecule of CO2, occurs for p-aminosalicylic acid.24 Oxidation is very common as well, largely due to the presence of oxygen during manufacture and/or storage. Several examples can be found in Yoshioka and Stella.14 Isomerization and racemization reactions are other degradation pathways. Two compounds which undergo isomerization reactions are amphotericin B25 and tirilizad.26... 

Cleavage of a C-H bond followed by reformation of the same bond on hydrolysis often takes place without formation of other products than the stereoisomer(s) of the starting material. Such reactions have therefore been used to perform isomerization and racemization of cyclopropanes on a preparative scale (Section 5.2.4.). The reaction sequence is also a very important tool in the studies of mechanisms of reactions involving cyclopropanes. By quenching the reactions with deuterium oxide rather than water, formation of one or several C-D bonds at active sites has been observed in numerous cases. However, these reactions... 

These are very similar to those of the bromo analogs described in Section 28-E, except that the isomerization and racemization rates are slower.4 The visible absorption spectrum of the trans isomer in dilute acid (extrapolated to t 0) showed =31.1, eJiS1 = 9.6, = 30.9. The tail of the very strong charge-... 

Eq. (37) is the basic kinetic model for isomerizations and racemizations. For example, the kinetic constants of an alanine racemase of Bacillus stearothermophilus are found to be... 

Other chirally modified platinum, cobalt and rhodium complexes give lower inductions, although sometimes with higher aldehyde and branched product yields (Table 1). A strong dependance of chemo-, regio- and stereoselectivity on reaction conditions and conversion rates is observed, sometimes with contradictory results. Attempts to optimize the chemo- and re-gioselectivity usually lead to lower asymmetric inductions. Moreover, since double-bond isomerization and racemization take place under hydroformylation conditions, the results reported do not necessarily reflect the primary asymmetric induction of the starting alkene. 

A concerted, suprafacial hydrogen migration in this reaction has been proved by the isomerization and racemization of optically active indene derivatives25. When heated to 140°C, neat l-methyl-3-f T/-butylindene (12) isomerizes to 3-methyl-l-ffr/-butylindene (13) with an estimated equilibrium constant of 5.5 for 12 13. Using optically pure (—)-l-deutero-l-methyl-3-t r/-... 

Drug substances used as pharmaceuticals have diverse molecular structures and are, therefore, susceptible to many and variable degradation pathways. Possible degradation pathways include hydrolysis, dehydration, isomerization and racemization, elimination, oxidation, photodegradation, and complex interactions with excipients and other drugs. It would be very useful if we could predict the chemical instability of a drug based on its molecular structure. This would help both in the design of stability studies and, at the earliest... 

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