Grantville Gazette Volume 27
Page 20
Higher aliphatics. In general, the alkanes can be obtained from petroleum, if the gas guzzlers let us. Straight chain, even carbon number aliphatics are available from selected fats and oils. The gaps might need to be filled in synthetically.
Cyclic Aliphatics. In modern practice these are mainly obtained from petroleum. Some crude oils are naturally rich in cyclic aliphatics, and others can be processed to produce them. Coal tar benzene could be hydrogenated to produce cyclohexane.
Carbocyclic Aromatics. Benzene, naphthalene (two fused rings) and anthracene (three fused rings) will almost certainly be obtained by coal pyrolysis, just as in the nineteenth century.
We know that "light benzoils" (probably benzene, toluene and xylene, "BTX") are being produced in Magdeburg at the end of 1633, and aniline (aminobenzene) is being produced at Essen in winter 1633-34. Since DDT was made in mid-1633, that implies that there was some coal tar production earlier, perhaps in or near Grantville. Nothing was said specifically about the polyaromatics (those with multiple rings), but they're in coal tar, too. In modern practice, "BTX" are obtained mainly by catalytic reforming of petroleum, rather than from coal tar.
Biological feedstocks are not especially good sources of the simple aromatics that are the most versatile building blocks. The simplest are benzyl alcohol, found in Peru balsam and storax; benzaldehyde, obtainable by decomposing amygdalin, itself extracted from almonds or apricot kernels; and benzoic acid (from gum benzoin). (EB11) However, we can isolate biologically active compounds from biofeedstocks and then use them outright, or "tweak" the structures a bit ("semisynthesis").
Heterocyclics. Heterocyclic chemistry is simply too complex to be more than touched upon in this article. In general, the simple heterocyclic rings are synthesized by simple addition or by condensation (a combination of addition and elimination; there is loss of water, alcohol or hydrogen halide) of linear building blocks.
A few heterocylic aromatics warrant special note. Thiophene (4C, 1S) occurs in coal and oil, and can be synthesized from acetylene and sulfur. Furfural comprises the furan (4C, 1O) ring, and is produced from agricultural waste (EA/Furfural). Pyrrole (4C, 1N), pyridine (5C, 1N), quinoline (2 fused rings, 1N), and acridine (3 fused rings, 1N) can be obtained from coal tar or bone oil.
There are numerous biomolecules that comprises heterocycles—notably nicotine (pyridine and pyrrolidine), the amino acids histidine (imidazole), tryptophan (indole) and proline (pyrrole), the purine nucleic acid bases guanine and adenine, and the pyrimidine nucleobases thymine, cytosine and uracil—but the additional substituents on these molecules limit their use as building blocks.
Organic Chemical Timeline
So, what additional organic chemicals will we want, early on? The "wish list" for the chemists will be compiled from encyclopedias, textbooks, and even product labels.
Wanting a chemical, of course, isn't the same as knowing how to make it. We know from the review of organic chemicals in canon (Part 3) that the chemists have succeeded in synthesizing DDT, chloramphenicol and sulfanilamide (Figure 4-2). So the chemists are clearly capable of synthesizing compounds with a mono- or disubstituted benzene ring. And I don't think it's too big a jump to trisubstituted benzenes, although figuring out the correct order of substitution is more involved.
It's less clear that they will be able to do much with heterocyclic compounds. From M&B, they will learn a bit about the synthesis and derivatization of pyrrole, thiophene, furan, pyridine, quinoline and isoquinoline. CCD reveals that purine (fused imidazole-pyrimidine) can be prepared from uric acid (in turn derived from guano!), and carbazole from the anthracene cake of coal tar.
EB11 has essays on at least the following heterocyclics: xanthone, pyrazoles, pyrimidines, purin(e), pyrrol(e), acridine, thiazoles, triazoles, quinazolines, tetrazoles, quinoxalines, phthalazines, adenine, phenazine, piperazin(e), piperine, indulines, azoximes, imidazoles, indole, oxazoles, pyrazines, pyridine, quinoline, safranine, thiophen(e), tropine and triazines, and the precursor pyrogallol (catechol). These may give information on how they are synthesized and used. McGHEST similarly covers furan, purine, indole, pyridine, pyramidine, and pyrrole. Some of the heterocyclic compound entries (e.g., imidazole) in Merck Index provide synthesis guidance. The richest source of heterocyclic chemistry tips is the Named Organic Reactions section of Merck Index (MI), which includes the Biginelli pyrimidine synthesis, the Bischler indole and triazine syntheses, and much more.
Synthesizing a heterocyclic ring from the basic building blocks will usually involve a minimum of three steps, one for the ring forming itself and the others to make the reactants. In the Debus synthesis of imidazole, the ring is formed by the reaction of a diketone (R-C(=O)-C(=O)-R) with an aldehyde (R'C(=O)-H) and ammonia. But you would need at least one step to make the aldehyde from our building block alcohols or carboxylic acids, and several to make the diketone (e.g., alcohol to ketone to isonitrosoketone to diketone; EB/Ketones).
If the heterocyclic ring is itself substituted then you need to figure out whether to introduce the substituent before, during or after ring formation. Because of all of the complications, I have only listed a few heterocyclic compounds.
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There are three bases for listing an organic chemical in the timeline (Table 4-4):
—it is explicitly referred to as isolated or synthesized in a story, i.e., a canonized chemical;
—it is an "essential precursor" in the manufacture of a canonized chemical by the inferred synthetic route; or
—it is a chemical which this author predicts would have been made at that stage, because it is both industrially important and reasonably obtainable.
By way of example, DDT is a canonical chemical; chlorobenzene, benzene, trichloroacetaldehyde, acetaldehyde, and ethyl alcohol are essential precursors to DDT; and monochloro- and dichloroacetaldehyde are predicted chemicals because if you can make trichloroacetaldehyde, you can make those, too. Of course, ethyl alcohol and benzene also would have qualified as predicted chemicals, based on their availability in wine and in coal tar, respectively.
In placing a chemical which is neither canonized, nor an essential precursor, on the timeline, I have taken into account whether a natural source or synthesis or natural source is likely to be in the books, when the compound was first isolated or synthesized in the old time line, and whether the method of procuring it is likely to run into any kind of problem, e.g., it is found in some exotic plant, or it needs a complex catalyst, or high temperature or pressure.
Precisely when a proposed chemical appears in the timeline depends not only on when it could be made, but also what demand for it would exist. This is, of course, something about which reasonable minds will differ. Based on canon, there is going to be early demand for pharmaceuticals, pesticides, dyes, explosives, and, a bit later, plastics. In turn, that means early demand for the organic building blocks from which those end-products are created. On the other hand, chemicals specific to the automotive industry are going to lag behind, which is why I left isobutylene and MTBE off the timeline.
Dyestuffs
Dyers classify dyes by mode of fixation to the fiber. Acid dyes contain sulfonic or carboxylic acid groups, whereas basic dyes provide amino and imino groups. Either can be used to (reversibly) dye protein fibers (wool, silk, leather), but acid dyes are preferred. For acid or basic dyes to be fixed to cellulose fibers (cotton, paper), you need a mordant. The mordants known to the down-timers include alum, tannic acid, and urine.
Direct dyes are those able to bind cellulose (via hydrogen bonds) without the aid of a mordant. That's great news, as mordants are expensive and mordanting takes days or weeks, but the binding is reversible and so the direct dyed-cottons bleed when washed. A few down-time dyes are direct (turmeric, saffron, annatto, and safflower), but they are faded by light. Direct dyes are preferred for paper. (Roberts 167).
Ingrain (azoic) dyes are really pigments (water-insoluble colors) that are formed within the interstices of the fibers
by the reaction of two intermediates. The first synthetic azoic dye was vacanceine red (summary synthesis, EA/Dye). With vat and sulfur dyes, a pigment is converted into a dye and then, after permeating the fibers, reverts to a pigment. Indigo is a vat dye.
The reactive dyes (commercialized 1956) are potentially the most useful, because they have reactive groups (see McGHEST/"Dye" and EB15/reactive dye for examples) that react with the hydroxy or amino groups in the fiber to form wetfast covalent bonds. Pretty much any chromogen can be connected by a bridging group to a reactive group to form a reactive dye. Unfortunately, EA/Dye warns that the original process (1894) was "very complex and of little value industrially" and it wasn't until 1953 that these problems were overcome. I am not sanguine that the brief descriptions in Grantville literature are sufficient to sidestep a half-century of false starts.
Dyes have uses outside the textile industry; to color other products, and as inks, pH indicators, or clinical laboratory stains. In the Gram stain protocol, bacteria are stained with Crystal Violet (Gentian violet) and counterstained with safranin or basic fuchsin. And several dyes have activity against microbes or parasites.
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Even a synthetic duplicate of a natural dye can be a success in the marketplace. It takes "on average, 440 grams of fresh dye plant to achieve the same tinctorial effect as one gram of synthetic dye." That makes it expensive to use natural dyes even when the plants are grown right at home. If they are cultivated someplace faraway, then the shipping costs may also be significant. In the late twentieth century, synthetic dyes were perhaps a hundred times cheaper than their natural counterparts. (Kirk-Othmer 673). If the synthetic dye provides a new hue, a greater intensity, or superior dyeing ability, or wash- or lightfastness, all the better.
The Merck Index has structures for at least 150 dyes. So how will Stoner decide which dyes to make first? Here I will look at color, ease of use, and ease of synthesis.
The palette available pre-Ring of Fire in the major Old World civilizations included the following (note that the same source can produce different colors depending on how it was handled):
Black: no good dyes. Best is logwood (banned in England 1581-1673). You could combine blue, red and yellow (expensive), or use a vegetable dye like walnut (more gray than black).(Finlay 107).
Brown: walnut, some barks
Red: kermes, Spanish Red (cochineal), brazilwood; madder, orchil
Orange: safflower (mostly Asia), madder, red sandalwood (Saunders).
Yellow: weld (Reseda luteola) (best), Dyer's Greenweed (!), buckthorn berries, saffron, European dogwood, turmeric, safflower, fustic
Green: usually a two-pot color (blue plus yellow).
Blue: woad, indigo
Purple: New World Royal Purple (purpura), orchil (lichen), brazilwood, woad + madder.
So blacks and greens would be particularly attractive to Stoner. By September 1633, he had the only "waterproof green dye" in the world, and it was being used on the USE's paper money. (Flint and Dennis, 1634: The Galileo Affair, Chapter 8). Even in 1911, green printing inks were mixtures (EB11/Ink). So was his green a single dye? And was it organic or inorganic? The early 20c "chrome green" currency ink was made from chrome yellow and Prussian blue.
The ease of synthesis depends on the chemical structure of the dye, and that also affects the dye's properties. Chemists classify dyes by their chromogen, the structure that is the principal determinant of their ability to absorb light. The substituents can affect the hue and intensity of the color, as well as how the dye is fixed to the fiber.
The most important chromogen in the modern world was azo (-N=N–) (EA/Azo Dyes) , and preparation of azo compounds is discussed in all introductory organic chemistry textbooks, as examples of the use of diazonium salts. See also EB11/Azo Compounds. Most of the azo dyes also include benzene or naphthalene rings. Anthraquinones ranked second in importance and they are derived from anthracene. The triphenylmethanes, with three benzene rings, are also of great interest because of their brightness. There are other chromogens, too.
Coal tar benzene, toluene, xylenes, naphthalene, anthracene, phenanthrene, and pyridine are converted to various intermediates such as aniline (also found in coal tar), anthraquinone, beta-naphthol, and "H acid," and ultimately to the dyestuff. Useful background on the synthesis of the major chromophores, and intermediates used in dye manufacture, can be gleaned from EB11 (triphenylmethane, benzophenone, anthraquinone, aniline, indulines, nitrobenzene, quinoline, benzene, quinones, xanthone, naphthylamines, etc.); EB15 (dye, azo dyes, pigment); EA (dye); McGHEST, etc.
Mauveine (OTL's first synthetic dye, 1856) was obtained by heating crude aniline with potassium bichromate and sulfuric acid. It was fortunate that toluidine was present in the crude aniline. (EB11/Safranine; EA/Dye)
The dyes for which there is at least "final step" synthetic information in Grantville literature (Merck Index 1968 unless otherwise stated) are as follows:
The list above is just a "first cut"; it leaves out some very important dyes because I haven't found synthesis information, and it includes dyes with serious disadvantages.
Pharmaceuticals
Many useful pharmaceuticals come from natural sources. There are four ways in which the organic chemists can promote public health:
(1) assay the level of the active ingredient in extracts so we know how potent they are, and can use them accordingly.
(2) isolate the active ingredient so we have it in pure form.
(3) synthesize the active ingredient so we have it in pure form, independent of the natural source.
(4) synthesize analogues of the active ingredient which are safer or more potent than the naturally occurring compound.
This section mostly covers the simpler compounds on WHO's "essential medicines" list (320 compounds!) and some "obsolete" pharmaceuticals that will be of value in the new timeline because they are easier to synthesize.
In the seventeenth century, infectious diseases killed more than half of the population, so I will focus on antimicrobial and antiparasitic agents.
Antimicrobials. We have chloramphenicol, at least one sulfanilamide, and penicillin in canon.
Aplastic anemia is the bete noir of chloramphenicol, and there has been modern experimentation with analogues to avoid it. Thiamphenicol, florfenicol and azidamphenicol are in MI. However, there is no synthetic guidance, and in OTL they weren't synthesized from chloramphenicol (see appendix).
As mentioned in EA "Sulfonamides," sulfanilamide was the first of a series of drugs.
MI provides synthetic guidance for sulfacetamide, sulfadiazine, sulfadicramide, sulfaguanidine, sulfamidochrysoidine, sulfathiourea, sulfadiamine, sulfonylbisacetanilide, sulfoxone (anti-leprotic) and the heterocyclics sulfamerazine, sulfamethazine, sulfamethizole, sulfamethoxazole, sulfamethoxypyridazine, sulfapyrazine, sulfapyridine, sulfaquinoxaline, sulfasomizole, sulfathiazole, sulfisoxazole. See also M&B 757; Solomons 937ff.
I am not sure which penicillin is the one that's being produced in Cologne in 1635. Most likely, it is Penicillin V (phenoxymethylpenicillin), but Penicillin G (benzylpenicillin) can also be produced by fermentation. (Vardanyan 430ff).
Unfortunately, the Penicillium mold is slow growing and finicky, and the concentration of penicillin in the fermentation broth of even a "high yield" strain is low, making the drug difficult to extract. (Sheehan 85). For these reasons, the total synthesis of penicillin remained a goal. However, it was a rather elusive one; penicillin has what Woodward called a "diabolical concatenation of reactive groups." Even with an MIT laboratory working on the problem, it was 14 years from the structure being determined to it being first synthesized (Sheehan 1959), and the synthesis was never commercially competitive with fermentation methods.
So the best we can do is to semi-synthesize penicillin derivatives. MI reveals that the key intermediate is 6-aminopenicillanic acid (6APA); it can be used to make benzylpenicillin, methicillin, and ticarcillin by a single step acylation reaction the Grantvi
lle chemists should be able to figure out. The catch is finagling the fermentation to produce 6APA.
The aminopenicillins amoxicillin and ampicillin are more difficult to make because you need a protecting group. Cloxacillin is also in doubt because the added moiety (an isoxazole) is itself more complex than anything made by the chemists in canon.
Several other major antibiotic classes (cephalosporins, polypeptides, tetracyclines, macrolides, aminoglycosides) are, like the penicillins, complex chemicals produced in the twentieth century either as fermentation products or by semisynthesis. It is not very likely that lightning will strike twice and we will luck upon a production strain for one of these antibiotics in a high school lab refrigerator, as we did with penicillin. Hence, it is unpredictable when we will first see one of these antibiotics; it depends on the fortuitous discovery of a suitable organism. The cephalosporins, for example, were first identified as antibacterial agents in studies of a culture of Cephalosporium acremonium from a Sardinian sewer.
The nitrofurans weren't major antibacterial agents in this time line (4 million prescriptions in 1989—Kirk-Othmer 2:870), even though they have the advantage that they attack multiple bacterial metabolic systems and hence the evolution of resistant bacteria will be slow. We have significant synthetic guidance; MI gives the precursors for at least nitrofurantoin, nitrofurazone, and nitrofurtimox, and we should be able to figure out nifuratel, nifurazone and nifuraldezone by analogy. Bear in mind that some of these precursors are themselves complex; the first NTL nitrofuran drug would probably be nitrofurazone.