Analytical Chemistry in Retrospect and Prospect GEORGE D.BEAL Mellon Institute, Pittsburgh, Pa. How to rid oneself of the domination of old ideas and methods becomes a problem, especially when those practices and habits have been impressed by early teaching and have become precepts because of the faithful service given to them by the older persons whom one has admired and emulated. Because of the phenomenal developments in chemistry during the past decade, the present-day analyst has an especially difficult task in deciding what to retain and what to discard in favor of newer methods and physical techniques usually defined as instrumentation.
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HERE comes a time in every man’s life when he finds himself spoken of as “an elderly man.” After that, he is espected to engage in reminiscence to the limit of the patience of his listeners, and to presume to address scientific meetings without having assembled a line of experimental data. Having recently come into that estate, it is my privilege to discuss “Analytical Chemistry in Retrospect and Prospect.” RETROSPECT
There is an old saying that “hindsight is better than foresight,” the thought being better expressed in the definition of snappy comebacks as “things you might have said.” Retrospectively, I am beginning with the status of the AMERICASCHEVICAL SoCIETY with the year in which I first signed an analytical report. That was in 1907, the year when the industrial fellowship plan for research, later to become Mellon Institute, was established by Robert Kennedy Duncan a t the University of Kansas. In that year the Society was boastful of its large membership, reported a t the annual meeting as 3079. There were 22 local section8, and the largest, which was the Yew York Section, had over 400 members, and was entitled to 5 councilors. The papers read a t the two meetings of that year grouped themselves easily into three families: organic, experimental physical, and analytical chemistry. The favored areas in the analytical discipline were the determination or revision of atomic n-eights, mineralogy and metallurgy, physiological, food, and agricultural chemistry, and the problems of the industrial control laboratory. It is little p-onder then that before that time, in my childhood years, when a chemical laboratory looked like no more than a wonderful playground, I thought that all chemists were analytical chemists. In the years that have passed since then, I have only modified this into the belief that all real chemists are analytical chemists. Such, I believe, is a factual definition, for it is the capacity for analysis, by thought a t least, that distinguishes the chemist from the technician. I am sure that I am not the only person who has held such an early belief It was my fortune, while a member of the faculty a t the University of Illinois, to have charge of the industrial inspection trips for students. One of our regular visits was to a plant of a large manufacturer of heavy chemicals. On this particular day my squad kept asking, “When will we see the laboratory?” to be assured by our guide that we could be sure to 8ee it before we left. Finally, a small dingy building v-as pointed out. “Is that the laboratory? The chemical labora-
tory? How many chemists do you have?” “Well over a hundred” was the reply. “But they don’t a-ork there?” “Of course not! Chemists run this plant. We have a few analysts in there for control work.” On the same trip we visited a great steel mill and, of course, there was the same question, “How many chemists do you have?” “Several hundred,” was the reply, “They work all around the plant.” “Well, where are some of them?” “I’m one.” ‘What do you do?” “I am superintendent of the blast furnaces.” As all of these men in production were working to specifications, for which there were numerical expressions, each man, in his chemical thinking, was analytical. ELEGANCE IZT ANALYSIS
The term “elegance” is continually used in pharmaceutical instruction, where it has an especial significance. The pharmacists’ products must be of such an appearance, whether compounded according to a prescription or manufactured in large bulk, as to inspire a measure of confidence in a person who is ill and therefore not capable of normal reactions. This same kind of elegance is part of the stock-in-trade of the real analyst. I t explains, I believe, why many early apothecaries turned to analytical chemistry to satisfy the curiosity in their budding science, and why a good many notable discoveries were made by scholarly apothecaries rather than philosophers. And, of course, the healing art could not be any part of a black art. Observation of the principle of elegance has come to the aid of many an analyst. Elegance exists in the manner of thinking as well as performance. I t is elegance that insists on blank determinations, upon verification of label claims for reagents, and upon confirmation of critical analyses by other available procedures. Charles F. Chandler, who was the teacher of so many budding chemists at Columbia, used an experience of his own almost a century ago to illustrate the importance of elegance in analytical practice and the danger of taking things for granted. With his Ph.D. newly conferred a t Gottingen, and himself employed to teach chemistry at Union College, he was summoned by an up-state New York coroner to examine the organs of a person who had died under such circumstances as to suggest arsenical poisoning. Before beginning his examination, he proceeded to test his reagents and found that all of the sulfuric and hydrochloric acids available contained arsenic, and that his only arsenic-free acid was nitric acid. This, of course, could berve for the tissue decomposition, but not for the Marsh test for arsenic. But by oxidizing sugar with nitric acid, he obtained oxalic acid. This, mixed with a solution of salt from the new salt works at Syracuse, known to be arsenic-free, and distilled, furnished hydrochloric acid, dilute. of course, but arsenic-free, that could be used in the hydrogen generator. As an industrial chemist, he had learned that the zinc from a new source just being developed was arsenic-free. Some of this was secured and a blank test showed that the hydrogen prepared therefrom contained no arsenic. Finally, the corpus delicti, its tissues having been decomposed by the nitric acid, was also found to be arsenicfree. The late George McPhail Smith, my immediate predecessor at Illinois, utilized several weeks of laboratory training in advanced
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V O L U M E 26, NO. 5, M A Y 1 9 5 4 analytical chemistry for the qualitative analysis of complicated mixtures. He pointed out repeatedly during classroom discussions that a truly satisfactory qualitative scheme of separation should require only manipulative refinement to become a sound quantitative procedure. When all of the practical laboratory training in quantitative analysis stresses elegance, which means precision, the theories of analytical chemistry may be presented in the classroom far beyond the practicability of covering them in the laboratory. Sir Edward Appleton, vice chancellor of the University of Edinburgh, 111esented a thoughtful presidential address last year to the British A4ssociationfor the Advancement of Science on the theme, “Science for Its Own Sake.” But whether one practices wience for its own sake or as a means of livelihood, Sir Edward’s remarks are equally applicable. He reminded his audience first of all that scientific activities are twofold. One may gather facts by observation and experiment, and one may go further and seek to understand how the facts fit together. Any order that was discerned among the welter of facts might be expressed as a hypothesis or theory a theory being a hypothesis that had become respectable. To quote him, then: ?;ow, even in this question of making observations, the scientific process is one which requires the fullest and subtlest employment of all our faculties. It demands for example, that we should not only see things, but should notice them; and not only notice, but perceive them. Many a vital discovery has been nothing else than recognizing the unexpected. To encounter nature in this necessary state of awareness is inevitably to find all its forms and movements, from the infinitely small to the infinitely large, full of inexhaustible significance and relevance. But even in experimental work it is the primacy of an imaginative idea of intuition that often starts it off. In simple words, I might say that the important thing in experimenting is to ask nature the right question and in its most direct form. Only then is the answer unmistakable. There is an area of analytical chemistry that resembles the physical and political geography as taught a half-century ago. Geographers were just coming out of the descriptive phase, when a correct recitation in the subject consisted of reciting the physical and political boundaries of a state, naming the capital and other principal cities, and perhaps the rivers and lakes, but not on a utilitarian basis. -411 of this, of course, was worth while, because it provided a number of triangulation points that would serve when and if any effort was made to study the significance of that state to the nation. Similarly. there was a form of descriptive analytical chemistry that served to furnish an ultimate, empirical atlas of the physical components of the world around us. Of course, through these studies were developed the many fine techniques of analytical chemistry. This approach, to determine the composition of natural substances, and, based on that experience, to determine the constants of nature approachable by chemical methods, was the beginning of the science of analytical chemistry. In establishing this background, and in developing and refining procedures down to the present time, analytical chemistry has borrowed extensively from other divisions of chemistry, and from the related physical and biological sciences. I t is good to remember, then, that this is a Conference on rlnalytical Chemistry and Spectroscopy. It might even be suggested that the conference be known as the Bunsen Conference, its coat of arms being a crossed burner and spectroscope upon a laboratory apron. When two scientific disciplines are as closely mingled as ale chemistry and physics in such a gathering as this, an ever-present question is when to reject the old or accept the new. Alexander Pope proposed a judgment in his “Essay on Criticism” when he wrote In words, as fashions, the same rule will hold, .4like fantastic if too new or old: Be not the first by whom the new are tried S o r yet the last to lay the old aside.
793 Pope wrote as a rhetorician rather than aa a researcher, for someone must explore the way, but there are many occasions when practicality diminishes to the vanishing point. How to rid oneself of the domination of old ideas and methods becomes a problem, especially when those practices and habits have been impressed by early teaching, and have become precepts because of the faithful service given to them by older persons whom one has admired and emulated. Sometimes more than habits seem involved when trying to rid oneself of the antiquated and worn out. An rlustralian tribe once held a testimonial dinner for its old chief, and, after much palaver, presented him with a fine new boomerang, perfectly balanced, and beautifully chased and inlaid by the most famous boomerang maker in all of the back country. That was a perfect evening and the old chief felt t h a t he could die of joy. But by the next evening all of his growing sense of frustration had come back in full force, for he had spent the entire day in trying vainly to throw his old boomerang away. PRECISION
What sort of precision does one need apply in exploring a mere idea in analytical procedure? Let us say, for example, that you wish to devise a convenient method of assay for a rubber-base adhesive plaster containing salicylic acid. From your knowledge of the general behavior of such plasters, you are sure that you can disintegrate the base and extract the acid, first with chloroform, then with alcohol and ammonia. Vaguely you recall that salicyclic acid, like many other phenols, has been determined by the volumetric bromination method. But, search as you may, you find no printed reference to such a method. It bothers you; you cannot keep your mind off of it. So you go to the laboratory, because this question has suddenly grown out of all proportion. Your assistant tells you that the job you set for him the other day has reached a critical point where it cannot be set aside without loss, but that he will be glad to check this for you on Monday. You stand on one foot, then on the other, looking around the laboratory. There’s a bottle of thiosulfate solution, there is some reagent potassium bromate, and there’s a bottle of salicylic acid. Why not try it? Reading your mind, he tells you that the thiosulfate hasn’t been standardized for three years, but he will check it for you tomorrow morning. A look a t the bottle of thiosulfate shows that the stopper is tight, and there is no sulfur precipitate on the bottom. Then he points out that the salicylic acid has not been dried, but he will put some in a desiccator and have it, and the solutions, ready in the morning. You see, you’re just the old man who wants to mow the lawn now, when every one knows that the grass ought not to be cut while the sun is beating down, and besides you might have a sunstroke. Well, it is your laboratory, so you make up a bromine solution empirically, and a stock solution of the acid to save time, and you set up two blanks and two aliquot8 of the acid solution and, using the three-year-old normality factor for the thiosulfate solution, you calculate, in about an hour, that if your guesses were all good the laboratory salicylic acid has a purity that is just under 99%. You would have been satisfied, allowing for all tolerance, if you had found 95%. So you tell him that he can check what you have done after he finishes that present job and has prepared, and standardized, new solutions, and done all of the other things you should have done. Then you go back to your desk thinking; “Well, you might as well write up some tentative directions for the assay, for of course you’ll modify them anyway when you get his report.” Just as you go into the office you see in the bookcase, back in the corner, behind the doorframe, one of your old texb books. There, on page 74, are directions for the titration, just as you carried it out. Next day the assistant comes in to tell you that the purity of the dried acid was 99.6% by that method, that the checks were good, and that the data agreed with those obtained by an acidimetric titration; but why did you go ahead as you did?
ANALYTICAL CHEMISTRY
794 There is no one rule that has been followed in the experiment just described. In fact, as far a8 the assistant’s thinking goes, a good many rules for sound analytical laboratory practice have been violated. What you have done is to use in a refined qualitative way Some of the leavings of a good many yeam of experience. Most important was the unconscious use of the mental fling system, reaching into drawers where Gearge D. B e d had been storedfactsaccumuIsted. often h s o h a e a r d l y , through years of teaching and/or practice. System, both mental and physical, is necessary if orderly laboratory work is to he carried out, and the generally uncluttered condition expected in an analytical laboratory is to be maintained. But except in very routine analytical control, one does not follow the textbook. The textbook lists the volumetric solutions required far 8 determination, and gives directions for their preparation and standardization. Therefore, the assistant, being closest to the textbook, follows the orderly rule of the text in having all solutions on hand before an analysis is undertaken. Only experience leads him eventually to realize that the standardizationis onlya blank titration. It is possible to become so much governed by rules and disciplines 8 8 t o make any f o r b of inquiry extremely difficult. This ia most common with students and sometimes years pass before it is replaced by thinking. I remember well the answer given by a student t o a question about the various anionions precipitable as silver salts. After a number of leading questions, including the substance of the previous year’s instruction‘, came the rather hurt reply, “but that was qualitative analysis.” Sometime, I hope, it will become possible to teach analytical chemistry without distributing it between two or three in&uctionaI disciplines. In final application, one’s practical use of analytical chemistry is going to Cover all of the disciplines, inorganic and organic, physical and physiological. The quantitative principles, and the exemplification of elegance, if impressed upon all of the aforesaid courses of instruction, cannot fail to improve that instruction a8 well. DRUG STANDARDIZATION
It will be permissible, I hope, for me to tur‘n in summing up t0 my own favorite area of analytical ehemistrjI , drug standardiza i n a l l.-.,w.anhnro tion, to trace the influence of new science in t1.- a n - l r r t”.--. tory. During this past half-century the analY t ieal chemistry of pharmaceuticals has been particularly susceptiible to progress in the r.l.yyll -lotd ~ winnnn. Uns&nn nf . r n. d. i ,_ - i_ n. mI .l ..._, ~ . ~ -__l_r ~ ” ” .nana w i t h +.he rnmrtin, the analytical chemistry of drugs and pharmaceuticals had undergone just 8.8 much change as had the materia medica. itself. Just as i t is said that the physician who graduated 20 years ago uses almost none of the drugs whose effects he studied a t that time, so the analytical chemist engaged in the standardization of medicinal products now has little use for quite a number of the analytical procedures that were in good standing at that time. The analytical chemistry of drugs a short time ago was still that of inorganic salts, organic bases, acids, alcohols, and esters, with occasional excursions into ketone ttnd terpene chemistry. When the active principles of drugs were isolated with sufficient physical, or chemical, characterization t o indicate that they were chemical individuals of a sufficiently high degme of purity, one might, in the absence of a sharply quantitative chemical reaction -0
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significant of some group present, resort to ultimate analysis for the determination of total nitrogen, sulfur, or a halogen. I n the absence of such characteristics, about the best that could be done in determining the purity of B drug or the concentration of an extract was by means of aome sort of sensoly perception, or what later came to be known as organoleptic tests. Naturally some persons with sharp senses of perception heoame adept, especially with the nose and the palate. The 8ame skill is possessed by coffee, tea, and liquor tasters, but all these reactions are more qualitative than quantitative. The use of sensory methods is not confined to organic compounds. It is still, I suppose, the custom t o pour and chill a test bar from every hlast furnace tap, then examine the broken surface for an indication of quality before sending the teat bar to the laboratory or to use the eye rather than the spectroscope in controllingthe heat in a Bessemer converter. The merging of physiology and chemistry, organic and physical, into pharmacology has continually increased the knowledge of specific drug action so that, with the aid of instrumentation, many methods of bioassay today are approaching the generally satisfaotory pattern of outcome of in uitro chemical assaytys, although heeause of the greater extent of variation between individual determinations more reliance must be placed on statistical analysis in judging the outcome of the several testa. Spectrometric methods of analysis now are adding greatly to the facility with which a pharmaceutical control laboratory can pass quickly on the acceptability of both supplies and products. Such methods of examination are being used to a greater extent also in the different states of manufacturing operations for the control of intermediates. One may go over too wholeheartedly to a new style of quantitative measurements before the background is completely laid for the procedure. Sometimes the theory of the method is enticing, sometimes the drudgery or monotony of an old method is lacking, sometimes i t is just fascinating to work the controls. There is only one way to judge the adequacy or superiority of any method of quantitative analysis, whether gravimetric or instrumental. That criterion will he found in the specification against which the article in question is being assayed, or rather the end use covered by the specification. Except for its academic value, there is no sound reason for trying to introduce a degree of precision unwarranted by the end use. Precision in analyses is essential, and if the mme grade of material serves a number of end u8eq the analysis obviously would be directed toward the most critical need, But I have never been able to justify either the development or use of an analyticalpracedurepurelyasastunt. Cadenzas, I think, are best left to the piano or violin virtuoso. The analytical laboratory is, in my estimation, thesupreme Court of the chemical profession in its relation t o industry. Whenever a court defers to a laboratory i t is invariably an analytical Iabomtory. With the laboratory in the position of a m i m curiae, it behooves the laboratory to apply the same rules of reason that the court8 are expected tc apply. Robert Herrick, whose days were past hefore Alexander Pope , appeared, left this verse that may have suggesseo me rule we mve earlier crec
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Thi New things succeed, as former things grow old But beside this reference to elderly men and elderly methods, Herrick left an even better motto for the analyst: Attempt the end, and never stand t o doubt; Nothing’s so hard but search will find i t out Annsesa delivered a t the Pittsburgh Conference on Analutical Chemistry and Applied SpectroBaow, Pittnburgh. Pa.. March 1,1954.
