When Procedures Fail

The majority of the literature on procedural failures comes from within the nuclear power domain (e.g., Marsden, 1996), where research suggests that procedural failures have been involved in around 70% of accidents and incidents within the nuclear power domain (Goodman and DiPalo, 1991 INPO, 1986 Marsden, 1996). Within the petrochemical industry, 27% of incidents involving operators are caused by situations for which there are inadequate or no procedures available (Bullemer and Nimmo, 1994). 

Various researchers have attempted to identify the different problems involved when procedures have been found to fail. For example, in an analysis of procedural failures within the nuclear power domain, Morgenstern, Barnes, McGuire, Radford, 

FIGURE 4.3 Procedure format guidance. (Adapted from Health and Safety Executive, Procedures, HSE Human Eactors Briefing Note No. 4, Health and Safety Executive, London, 2005. Reproduced under the terms of the Click-Use Licence.) 

Language or syntax problans associated with the procedural document 

Incorrect procedure prepared Inaccurate procedure prepared No procedure prepared 

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N-Benzylamides are recommended when the corresponding acid is liquid and/or water-soluble so that it cannot itself serve as a derivative. Phe benzylamides derived from the simple fatty acids or their esters are not altogether satisfactory (see Table below) those derived from most hydroxy-acids and from poly basic acids or their esters are formed in good yield and are easily purified. The esters of aromatic acids yield satisfactory derivatives but the method must compete with the equally simple process of hydrolysis and precipitation of the free acid, an obvious derivative when the acid is a solid. The procedure fails with esters of keto, sul phonic, inorganic and some halogenated aliphatic esters. 

In the first phase, the performance of the instrumentation used for the method is demonstrated. Based on the analysis of standards, results from the participating laboratory should meet the system suitability requirements of the method. Successful completion of this phase will qualify the analyst, his or her equipment, and the laboratory for the trial. Failure in the first phase does not usually cause a method to fail the trial. However, it can slow the process. When a procedure fails during the first phase of a trial, the sponsor may need to write a cautionary note in the SOP discussing recommended or inadequate types of instruments. To correct the problem, the participating laboratory analyst can substitute equipment that gives adequate performance alternatively, the sponsor must find a different laboratory to participate in the trial. 

Philip et al. demonstrated that the mass of a polyvinyltoluene microsphere with a nominal diameter of 2.35/rm was 6.979 0.177pg (1 pg = 10 g). The microspheres examined had charges equivalent to 39-71 elementary charges. This procedure fails, however, when the number of charges is large. 

When the above procedures fail to give a clean product then dissolve the NaBH CN (lOg) in tetrahydrofuran (80ml) and add N MeOH/HCl until the pH is 9. Pour the solution with stirring into dioxane (250ml). The solution is filtered, and heated to reflux. A further volume of dioxane (150ml) is added slowly with swirling. The solution is cooled slowly to room temp then chilled in ice and the crystalline dioxane complex is collected, dried in a vacuum for 4h at 25°, the 4h at 80° to yield the amorphous dioxane-free powder is 6.7g with purity >98% [JACS 93 2897 797/]. The purity can be checked by iodometric titration [AC 91 4329 1969]. 

The p-anisyloxymethyl group520 (abbreviated AOM) played an important role in the synthesis of Calicheamicinone reported by Clive and co-workers.521 Its removal from the sensitive multifunctional substrate 285 1 [Scheme 4.285] was accomplished with CAN in a mixture of pyridine, methanol and water. The excellent yield (89%) attests to the mildness of the conditions. Attempts to apply the same conditions to the deprotection of an AOM group from 286 1 [Scheme 4.286]522 failed but the deprotection was successful if it was conducted in the presence of 2,6-pyridinedicarboxylic acid N-oxide — conditions previously used to convert a phenol methyl ether to a quinone.523 AOM ethers undergo easy reductive cleavage to the corresponding methyl ethers with borane in toluene — a reaction that could have synthetic value when simple O-methylation procedures fail. 

A -Cycloalkene-lA ioiits. a,couple intramolecularly to cyclic ene-l,4-diones in the presence of Cu(acac)2 in benzene at 60°. Other copper catalysts are unsatisfactory. The procedure fails when n is S or 6, but is satisfactory V ien n is 4 and >6. Both cis- and trans-isomers are formed, with the latter predominating exeept when n is 4. The products are reduced by sodium dithionite to cycloalkane-1,4-diones, which can be cyclized by NaOH to fus d-ring cyclo-pentenones when n is 7, 9,10, and 16. 

Before describing these enzymes (see the examples in Table 1), it is necessary to make a broad division of metal interactions in enzymes. In one case, the metal ion is firmly attached to the protein so that like a nonmetal of an amino acid it does not exchange within days. In snch a sitnation, the isolation of the metallo-protein, correctly named, can be followed through all steps of purification until further purification procedures fail to alter the stoichiometry of the metal/protein, and this is a whole number. At the same time, if the metallo-protein is an enzyme, activity will become optimal. This approach to metallo-enzymes was first developed by Professor B. L. Vallee of Harvard. A different extreme is one in which the metal ion is loosely attached to the protein when isolation procedures may well result in an apoprotein, and if it was an enzyme, it would then be devoid of activity. The problem in such a case is to know which metal ion was intrinsically involved in activity in vivo. Now a great number of metal ion/protein interactions are intermediate in character between extremes so that purification results in the discovery of fractional stoichiometry and can be beset by contamination. Confusion is increased because many enzymes have several metal ion centers when it may require astute experimentation to reveal the nature of the original metal ion complement. We must be aware of both binding constants of metal ions to proteins of different kinds and of their rates of exchange so as to establish their nature correctly as it is related to function (1-4). 

Treatment of enones with basic tert-butyl hydroperoxide provides an alternative route for epoxidation of enones when the alkaline hydrogen peroxide procedure fails. For example, the enone shown below did not react with alkaline hydrogen peroxide but underwent chemo- and stereoselective oxidation with tert-h xty hydroperoxide in the presence of the base trimethylbenzylammonium hydroxide (Triton-B). To avoid a 1,3-diaxial interaction with the angular methoxymethyl substituent, the hydroperoxide anion attacked the enone from the a-face of the molecule. 

When the electrode resistance is very large, e.g., with an ion-selective microelectrode, the method described above does not work. An alternative approach consists of fitting the experimental concentration profile calculated from the tip potential to the theoretical profile predicted for the substrate geometry and activity. When the system investigated is at steady state, there is a unique relationship between tip potential and tip-substrate distance and an absolute distance scale can be determined. However, the procedure fails when the system is not at steady state because most ISE are unable to follow rapid changes in concentration. 

In 1901, Koenigs and Knorr published an efficient method for the preparation of alkyl and aryl O-glycosides [89]. The Koenigs-Knorr reaction has for a long time been the best method achievable for the synthesis of O-glycosides. This method has been widely studied and improved in the years [31,90,91], and although valuable alternatives are now established, it still is the method of choice when more sophisticated procedures fail. 

The major decision in the design of a suitable adsorption chromatographic system is the selection of the correct solvent. Most samples can be separated on any of several, general purpose adsorbents (most often silica). Similarly, little thought is generally required in the adjustment of the remaining separation variables bed dimensions, sample size, solvent flow rate, or temperature. In many laboratories more or less standard separation schemes are used, and only the solvent is varied to meet the specific requirement of individual samples. This is especially true of thin-layer separations, where standard silica plates and fixed sample sizes are the rule. Only when such standardized procedures fail is serious attention paid to separation variables other than the solvent. 

These aqueous solutions, when rendered alkaline with ammonia or sodium carbonate (sodium hydroxide when phenolic alkaloids are known to be absent), may yield the basic constituents in filterable form. However, experience has shown that it is more convenient to recover these by extraction with ether or chloroform. Chloroform is to be preferred for it extracts all alkaloids except the quaternary bases (curine), which in any case must be recovered in the form of an insoluble complex salt. This procedure fails when the alkaloids are unstable under the conditions of the experiment, and is conspicuously unsuccessful mth the ergot bases. It is also probable that some alkamine esters suffer change under the conditions imposed. 

There were several cases when this original procedure failed, but it was discovered that if the silane units are treated with a fluorinating agent such as TBAF or CsF, the Ar or SiR 3 unit is replaced with F. Subsequent treatment with hydrogen peroxide or a peroxy acid gave the alcohol. This sequence is often called the... 

The greatest potential for this system is as part of a program of preventive maintenance. Currently, in most operating rooms, endoscopes are removed from service and sent for repair when they fail in clinical use. This causes operative delay with attendant risk to the patient and an increase in cost to the institution. The problem is difficult because an endoscope maybe adequate in one procedure but fail in the next which is more exacting due to clinical variables such as large patient size or bleeding. Objective assessment of endoscope function with the EndoTester may eliminate some of these problems. 

Reactions.—Alkyl nitriles undergo a-ethoxycarbonylation with lithium di-iso-propylamide and ethyl chloroformate in THF at — 74 C, providing a useful procedure when others fail. Monoalkylation of alkylnitriles takes place almost exclusively at the a-position using potassium on graphite in the presence of an alkyl halide. This method appears to be superior to other alkylation procedures. 

Recently, a new intramolecular hydroxyl sulfide (325) catalyzed MBH reaction, using alkyl halides or epoxides 327 as electrophiles and lactams or lactones 326 as substrates, was performed successfully under the basic conditions (Scheme 2.178). However, the procedure failed for aldehydes when a conventional acid (TiCU)-catalyzed procedure was used. ... 

Fume hoods should be regarded as backup safety devices that can contain and exhaust toxic, offensive, or flammable materials when the containment of an experiment or procedure fails and vapors or dusts escape from the apparatus being used. Note the following ... 

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