Introduction mechanism

Attempts to use intermolecular and intramolecular kinetic isotope effects (see section 2.2) to identify a complexation step during ortholithiation have so far been inconclusive. Both intramolecular and intermolecular KIE s for the deprotonation of 152 and 153 by s-BuLi at -78 °C have values too high to measure, perhaps because complexation is fast and reversible but deprotonation is slow.11 

Stratakis111 showed that a similar situation exists for the deprotonation of anisole by BuLi in Et20 or TMEDA. The kinetic isotope effects are much lower, but give no evidence regarding the existence of an anisole-BuLi complex prior to deprotonation. 

Given that BuLi-TMEDA will deprotonate benzene,108 substrate coordination alone should clearly be sufficient to allow the deprotonation of substituted aromatics. And indeed, amine 154, whose aromatic protons are no more acidic than those of benzene, is deprotonated rapidly (much more so than benzene)112 113 and regioselectively (at the 2-position, closest to the directing group).114 

Detailed NMR and theoretical studies have identified and characterised a number of the complexes along this proposed reaction pathway for anisole, 1,2-dimethoxybenzene and N,N-dimethylaniline.115)116 For example, anisole deaggreagates the BuLi hexamer (see chapter 1) to form a tetrameric BuLi-anisole complex 155. Adding TMEDA displaces the anisole from the tetramer and breaks it down further to give a BuLi-TMEDA dimer 156, which deprotonates anisole at 0 °C yielding 157. 

It has usually been assumed that the lithiation step involves loss of TMEDA and re-formation of a BuLi-anisole complex prior to the deprotonation itself. However, the kinetics of deprotonaton step are inconsistent with this proposition both TMEDA molecules remain part of the complex during the deprotonation,117 which may therefore involve no O-Li coordination and be directed purely by the acidifying effect on nearby protons of the a-electron-withdrawing MeO substituent.118 

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Workstations and robotic systems are very expensive, so inexpensive alternatives such as flow configurations have been developed for automated sample preparation. The earliest flow systems for sample preparation were used for GC determination (with flame ionization detector [FID] or electron capture detector [EGD] detection) of organic compounds, which requires no special extraction or derivatization, in environmental matrices [30-34]. Automated GC-MS systems for the determination of volatiles in water or air [35-38] are the most commonly reported. Detailed descriptions of these systems can be found elsewhere in this book. Few continuous flow systems (CFSs) for the automated pretreatment of biological fluids in combination with GC-MS have been developed to date. The intrinsically discrete nature of the GC-MS sample introduction mechanism makes online coupling to continuous flow systems theoretically incompatible for reasons such as the different types of fluids used (liquid and gas) and the fact that the chromatographic column affords volumes of only 1 to 2 j,l of cleaned-up extract. Therefore, the organic extracts from CFSs have traditionally been collected in glass vials and aliquots for manual transfer to the GC-MS instrument (off-line approach) only in a few cases is an appropriate interface used to link the CFS to the GC-MS instrument (on-line approach). These are the topics dealt with below. 

Syringe, (optional, depending on sample introduction mechanism employed with each instrument) gas-tight, 1 to 20 mL capacity with a 1 % or better accuracy and a 1 % or better precision. The capacity of the syringe should not exceed two times the volume of the test specimen being dispensed. 

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