Precursors and Intermediates

Let us interrupt our discussion of phenol biosynthesis at this point to consider some of the difficulties which arise in in vivo isotope experi- 

A precursor is any substance in the organism under investigation that can be converted into the natural product being studied. It may itself lie directly on the synthetic pathway or be capable of being converted into a compound which does. 

A natural intermediate is a precursor which has been shown to be present in the organism being investigated. 

An obligatory intermediate, finally, is the only intermediate possible in a biosynthetic pathway. 

It is relatively easy to determine whether a substance serves as a precursor or not. By means of tracer experiments and experiments in cell-free systems, it is also usually possible to determine whether this substance is a natural intermediate. To identify a substance as an obligatory intermediate is the most difficult step. This is because it must always be borne in mind that the organism may be provided with an unknown, but more important, means of synthesizing the natural product under investigation. The biosynthesis of secondary plant materials is a field where such surprises can never be excluded. 

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The derivatives of the aminophenols have important uses both in the photographic and the pharmaceutical industries. They are also extensively employed as precursors and intermediates in the synthesis of more compHcated molecules, especially those used in the staining and dye industry. All of the major classes of dyes have representatives that incorporate substituted aminophenols these compounds produced commercially as dye intermediates have been reviewed (157). Details of the more commonly encountered derivatives of the aminophenols can be found in standard organic chemistry texts (25,158). A few examples, which have specific uses or are manufactured in large quantities, are discussed in detail in the following (see Table 6). 

The Ostwald Step Rule, or the rule of stages postulates that the precipitate with the highest solubility, i.e., the least stable solid phase will form first in a consecutive precipitation reaction. This rule is very well documented mineral formation via precursors and intermediates can be explained by the kinetics of the nucleation process. The precipitation sequence results because the nucleation of a more soluble... 

The development of an impurity profile for a dosage form follows many of the same principles as in the drug substances however, instead of identifying all precursors and intermediates, the analyst will identify and place all of the components of the dosage form (excipients, preservatives, and others) and their affiliated impurity profiles within a master profile. Here again additional method development may be needed to... 

The mass spectra obtained at different femtosecond time delays show the changes of the precursor and intermediate species. At negative times there is no signal present. At time zero, the parent mass (84 amu) of the precursor cyclopentanone is observed whereas the intermediate mass of 56 amu is not apparent. As the time delay increases, a decrease of the 84 mass signal was observed for the 56 mass, first an increase and then a decrease of the signal was observed. The 56 mass corresponds to the parent minus the mass of CO, and its dynamics directly reflect the nature of the transition-state region. 

The first project, gathering eight teams from six EC countries where more than 140 new extractants were prepared and studied, not counting all the precursors and intermediates. Tests carried out with these compounds on simulated and real waste showed the excellent chemical and radiolytic performance of calixarene derivatives. 

Z11,E14-16 CoA, which is then chain shortened to Z9,E12-14 CoA, or alternatively Z1 l-16 CoA is chain shortened to Z9-14 CoA and then a A12 desaturase produces Z9,E12-14 CoA. Both pathways are possibilities based on the previous identification of a A14 desaturase in the Asian com borer (Zhao et al., 1990) and a A12 desaturase in some other insects (de Renobales et al., 1987). To differentiate between the two possible pathways, D9-Zll-16 acid (Z 11-[13,13,14,14,15, 15,16,16,16-2H9]hexadecenoic acid and D2-Z9-14 acid (Z9-[13,14-2H2] tetradecenoic acid) were applied to the glands. The results indicate that D9-Z11-16 acid was chain shortened to Z9-14 acid but was not converted to Z9,E12-14 CoA. This indicates that chain shortening occurs and incorporation of D2-Z9-14 acid into Z9,E12-14 CoA indicates that a A12 desaturase is present. The D9-Zll-16 acid was not incorporated into Z9,E12-14 CoAbecause of an isotope effect. This labeled compound had nine deuteriums on the methyl end where the desaturase enzyme would act, preventing the introduction of a double bond. Combined together, the labeling studies with precursors and intermediates indicate... 

This text will, therefore, emphasize the broad principles of systems of chemicals manufacture rather than intimate and encyclopedic details that are often difficult to understand. As such, the book will allow the reader to appreciate the chemistry and engineering aspects of important precursors and intermediates as well as to follow the development of manufacturing processes to current state-of-the-art processing. 

S. Zochling, and M. Murkovic, Formation of the heterocyclic aromatic amine PhIP Idenfication of precursors and intermediates, Food Chem., 2002, 79, 125-134. 

The presence of even traces of ethanol in the synthesis batch, stemming from an incomplete hydrolysis of Si(OEt)4 during the ageing period results in a drastical reduction of the ZSM-20 crystallization rate zeolite Beta is then readily formed and achieves a fast growth at the expense of the ZSM-20 "Figure 3".This goes in line with the higher yields of Si-richer Beta observed when this zeolite is intentionally prepared in presence of ethanol (311.This was attributed to the lower solubility of silica in EtOH (311. but it is also probable that the whole system (nature and solubility of ZSM-20 aluminosilicate precursors and intermediates) is perturbed (321. 

The aim of this chapter is to show some representative examples in which aliphatic nitrocompounds are the key starting materials for the synthesis of different targets in a one-pot process. Thus, the availability of a variety of nitroalkenes and nitro-alkanes, their chemical versatility and their reactivity make these compounds highly powerful precursors and intermediates in environment-friendly organic synthesis. 

The facile dissociative adsorption of CO on transition metals at low temperatures has been demonstrated by XPS or pulse techniques for Ti, V, Cr and Mn (96] and at elevated temperatures for Ni, Co and Ku with Fc as the borderline case [96, 97J. A more detailed study by Somorjai for Pt (111) surfaces showed that dissociation occurs at the step sites only, and once these are filled, carbon monoxide is absorbed moiccularly [98]. All of the XPS studies on chemisorption on iron, except at very low temperatures, are indicative of dissociative surpikm being the first step in Fischer-Tropsdi reactions (99 101). However, photoelectron spectroscopy has so far not delineated a logical sequence of precursors and intermediates 1102. ... 

The Ostwald step rule, or the mle of stages, postulates that the precipitate with the highest solubility (i.e., the least stable solid phase) will form first in a consecutive precipitation reaction. This mle is very well documented mineral formation via precursors and intermediates can be explained by the kinetics of the nucleation process. The precipitation sequence results because the nucleation of a more soluble phase is kinetically favored over that of a less soluble phase because the more soluble phase has the lower solid-solution interfacial tension (7cw) than the less soluble phase (equation 50). In other words, a supersaturated solution will nucleate first the least stable phase (often an amorphous solid phase) because its nucleation rate is larger than that of the more stable phase (Figure 13.26). While the Ostwald step mle can be explained on the basis of nucleation kinetics, there is no thermodynamic contradiction in the initial formation of a finely divided precursor. 

Some measure of the concentrations of unstable species can be obtained from the shape of appearance potentid curves, although usually it is not possible to distinguish clearly the contributions from precursors and intermediates. It is also necessary to make assumptions about ionization cross-sections. However, in suitable cases some information may be obtained. Foner and Hudson , for example, made the reasonable assumption that the ionization cross-sections of and... 

Once a decision has been made to identify an unknown, the next logical step is to evaluate all known process-related impurities, precursors, intermediates, and degradation products. By observing the relative retention times (HPLC) of all known process-related impurities, precursors, and intermediates (if available), one can quickly determine whether or not the impurity of interest is truly unknown. If the relative retention time of the unknown impurity matches that of a standard, the unknown can be identified using HPLC with ultraviolet (UV) photodiode array detection as well as mass spectrometry (MS) detection. The identity can be considered confirmed by correlating the retention time, UV spectra, and mass spectra of the unknown impurity with that of the standard. The time and energy saved by analyzing data that may be already available can be considerable. 

Fig, 6,19 Scheme of isotopic correlations between monoterpenes from Coriandrum sativum L. All identified compounds are characterised by their relative amounts, as determined by GC, and by their S C-values, obtained by GC-C-IRMS. The probable common precursors and intermediates are displayed in square brackets, and the calculated turnover rates in a given direction in % at the arrows. Modified with kind permission from [327]... 

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