B. V. Tronov

On the Origin of Optically Active Compounds in Nature

The successes of organic chemistry at the present time leave no doubt whatever that any substance, however complex it may be, including any organic substance, can be prepared artificially. Any compound produced by plant or animal organisms can, by one laboratory method or another, be synthesized from substances of mineral origin. Thus the idealistic doctrine of the so-called “vital force,” under whose influence organic compounds were supposedly formed in organisms, must now definitively fall away. Living matter possesses a special form of motion, is subject to special laws in its development, and represents a qualitatively distinct form of matter; nevertheless, it did originate from dead matter and only at a certain moment of development, upon reaching a definite complexity of structure, did it change its form of motion.

At present we still do not know how to synthesize protein substances, which constitute the basis of life, the protoplasm of living cells (according to Engels¹: “life is the mode of existence of protein bodies, the essential element of which is the constant exchange of substances with the external nature surrounding them, and which ceases with the cessation of this exchange of substances, bringing about the decomposition of the protein”). However, this is due only to the fact that the structure of proteins is too complex; when we determine their structure, then, of course, we shall be able to synthesize these substances, and “if it ever becomes possible to compose protein bodies chemically, they will undoubtedly exhibit the phenomena of life and will carry out—however weak and short-lived they may be—an exchange of substances” (Engels).

In the present state of organic chemistry it can already be said with confidence that the synthesis of protein is a question of time. As to how long this time is, Engels wrote: “Until we can even think of the artificial production of protein,—that is, probably, for the next hundred years,—it is ridiculous to complain that all our attempts, etc., have failed.”

The period indicated by Engels, perhaps, cannot be considered too short, since in the 40–50 years that have passed since then the chemistry of protein substances has advanced very far, and the synthesis of compounds with a structure as complex as that of natural proteins now appears to be an entirely attainable task.

However, in the question of the synthesis of proteins and even of the synthesis of many more

of simple compounds there is one area where chemists have made little progress from the dead point. This is the synthesis of optically active substances. Optically active, i.e. rotating the plane of polarization of light, is any substance whose molecule has an asymmetric structure (without a plane of symmetry). As many such compounds as desired can be prepared synthetically. But if we obtain some optically active substance—for example, prepare lactic acid from propionic acid through $\alpha$-chloropropionic acid:

\[ \mathrm{CH_3 \cdot CH_2 \cdot COOH + Cl_2 \longrightarrow CH_3 \cdot CHCl \cdot COOH + HCl,} \]

\[ \mathrm{CH_3 \cdot CHCl \cdot COOH + HOH \longrightarrow CH_3 \cdot CHOH \cdot COOH + HCl} \]

or malic acid from succinic acid through monobromosuccinic acid:

\[ \mathrm{COOH \cdot CH_2 \cdot CH_2 \cdot COOH + Br_2 \longrightarrow COOH \cdot CHBr \cdot CH_2 \cdot COOH + HBr,} \]

\[ \mathrm{COOH \cdot CHBr \cdot CH_2 \cdot COOH + HOH \longrightarrow COOH \cdot CHOH \cdot CH_2 \cdot COOH + HBr,} \]

then we always obtain a mixture of two optical antipodes, two isomers that rotate the plane of polarization by equal angles in opposite directions. Thus, instead of an optically active substance, we obtain a racemic compound, which does not act on polarized light.

Meanwhile in nature, in animals and plants, substances with an asymmetric molecular structure are almost always encountered precisely in optically active form, and not in the form of a racemic compound of the right and left antipodes.

How is this to be explained? How is one to explain, for example, that in the muscles of animals lactic acid is produced precisely in the dextrorotatory form, that glucose in the organism of plants and animals is likewise found exclusively in the form of the dextrorotatory antipode, fructose—in the levorotatory form, and so forth?

Obviously, the question of the possibility of synthesizing any organic substance in the laboratory can be finally resolved only when chemists learn either to separate racemic compounds into their constituent antipodes, or to conduct the synthesis itself asymmetrically, i.e. in such a way that only one of the optical isomers is formed.

A racemic compound can be separated into its optically active components by the following methods indicated by Pasteur:

1) By crystallization. Sometimes, under certain conditions, the right and left isomers separate out in the form of crystals that differ from one another in shape, the so-called enantiomorphic crystals. These crystals are related to one another as an object and its mirror image (like the molecules themselves of optical antipodes). Thus tartaric acid itself cannot be separated by crystallization into right and left tartaric acids, but its double sodium-ammonium salt, at a temperature below $28^\circ$, precipitates from an aqueous solution in the form of crystals $\mathrm{C_4H_4O_6Na(NH_4)\cdot 4H_2O}$, distinct for the right and left acids. Pasteur separated these crystals from one another by direct mechanical means and obtained from them optically active acids.

2) Optical isomers are completely indistinguishable from one another in almost all physical and chemical properties. They have identical melting and boiling points, refractive index, surface tension, specific gravity; in the same direction and at the same rate they react with almost all substances, etc. The difference manifests itself: in the rotation of the plane of polarization of light, in crystalline form, and in those processes in which the given compound encounters another optically active substance. For example, optically isomeric acids are esterified at the same rate by such alcohols (inactive ones) as methyl or ethyl alcohol, but are esterified differently by menthol, which rotates the plane of polarization. Inactive lactic acid with an optically active base (for example, the alkaloids strychnine, quinine, morphine, etc.) gives a mixture of salts (of the right- and left-handed acids) having different solubilities in water. Obviously, such a mixture can be separated by crystallization.

3) Biochemical method. Since animal and plant organisms themselves consist of optically active substances, it is natural that organisms react differently toward one and the other optical antipode. Therefore very often one or another microorganism consumes for its nourishment only one of the optical isomers. For example, the molds Penicillium glaucum extract from a solution of tartaric acid the right-handed tartaric acid, leaving the left-handed one. Racemic lactic acid can likewise be separated into stereoisomers with the aid of molds.

By all these methods, having a racemic compound, one can obtain either both optical antipodes or only one. However, everywhere we in one way or another make use of the aid of organisms. In the first method, man himself has to select crystals of different forms; in the third method microorganisms act; finally, the second method requires some already prepared optically active substance, and this substance must again have been obtained with the aid of organisms.

Experiments in the direct synthesis of only one of the optical antipodes have given the following results:

If one takes (Marckwald¹) the salt of methyl-ethylmalonic acid (which has no asymmetric structure) with the optically active alkaloid brucine, then on heating \(CO_2\) is split off and the brucine salt of methyl-ethylacetic acid is formed:

\[ \begin{aligned} &\begin{array}{c} CH_3 \\ CH_3 \cdot CH_2 \end{array} \!\!>\!C\!\!< \begin{array}{c} COOH \\ COOH \end{array} \;(\text{brucine}) \;\longrightarrow\; CO_2 + \begin{array}{c} CH_3 \\ CH_3 \cdot CH_2 \end{array} \!\!>\!C\!\!< \begin{array}{c} H \\ COOH \end{array} \;(\text{brucine}). \end{aligned} \]

Salts of the right- and left-handed acids are formed with unequal ease, since they are not optical antipodes.

The splitting off of carbonic anhydride from camphorcarboxylic and bromocamphorcarboxylic acids under the catalytic action of quinine and other optically active bases likewise proceeds at different rates for the optical antipodes². If one adds hydrocyanic—

acid in the presence of cinchona or cinchonine, then predominantly one of the stereoisomers is obtained (Bredig and Minaev¹).

McKenzie² synthesized, by similar methods, 29 optically active substances.

In all such cases, indeed, the synthesis of an optically active compound takes place, but again with the participation of an already prepared substance with right or left rotation. Thus the question of how the first substance arose in nature, rotating the plane of polarization in one direction or the other, remains unresolved here as well; for, as one of the later defenders of the hypothesis of a “vital force,” Japp,³ put it, “an optically active molecule, like a living being, is born of another optically active molecule.”

The failure of many attempts to synthesize an optically active substance without any participation of organisms or of compounds produced by organisms compelled some scientists until very recent times to think that in organisms there operate certain special “asymmetric forces,” i.e. something like the vital force of the former vitalists. Pasteur, who first drew attention to the optical activity of substances of organic origin, wrote⁴ that “this property is perhaps the only sharp boundary that can at present (these words refer to 1860) be drawn between the chemistry of dead and living nature.” Here there is the reservation “at present,” but some of the later investigators, such as Japp (see above), expressed themselves in this sense more definitely.

Materialistically minded chemists must, of course, seek natural causes, of a wholly material order, for the origin of optically active organic compounds from mineral substances.

In the literature there are indications of the following possible explanations:

1) The thought was expressed⁵ that initially, somewhere, a mixture of enantiomorphic crystals was formed by spontaneous resolution of a racemate. This mixture could have been scattered by a whirlwind, and one crystal reached our planet. However, the probability of such an event is exceedingly small. Japp compares it with a text of Hamlet being produced from type thrown at random.

2) Pasteur himself⁶ thought that the asymmetric factor in the synthesis of organic compounds in nature might be, for example, the rotation of the Earth or the Earth’s magnetic field. Experiments carried out by Pasteur and others (e.g., Boyd⁷) in conducting reactions in rotating tubes or in a magnetic field gave no results.

Recently N. M. Kizhner returned to the idea of the influence of the magnetic field.¹ Defending the hypothesis of the mineral origin of petroleum, he points out that optically active compounds could have appeared in petroleum precisely owing to the earth’s magnetic field.

3) The photochemical hypothesis has met with greater recognition. Van ’t Hoff² already considered circularly polarized light (the same should also hold for elliptic polarization) a possible cause of the formation of asymmetric molecules in nature.

Indeed, Cotton³ observed that such light is absorbed unequally by solutions of two colored antipodes (copper-alkali salts of tartaric acids). And since light is absorbed differently, there must also be a difference in its chemical action.

Attempts to use this for the synthesis of asymmetrically constructed compounds in optically active form have, finally, in the very last years led to some success.

The action of light with wavelength 2800 Å on an alcoholic solution of racemic $\alpha$-bromopropionic ester gave mixtures with very small (up to $0.05^\circ$) right or left rotation, depending on the direction of polarization of the light.⁴ A more noticeable difference in the angles of rotation ($+0.78^\circ$ and $-1.04^\circ$) was obtained⁵ in the photochemical decomposition of diethylamide of $\alpha$-azidopropionic acid

$$ \mathrm{CH_3-CH-CO.N(C_2H_5)_2} $$

$$ \begin{array}{c} \phantom{\mathrm{CH_3-}}\;|\\ \mathrm{N}\\ /\ \backslash\\ \mathrm{N=N} \end{array} $$

An optically active substance was obtained by the action of circularly polarized light on humulene sesquiterpene nitrosite.⁶

Byk⁷ long ago showed that sunlight at the surface of the earth sometimes does indeed become elliptically polarized. Such polarization occurs, for example, when the light of the sky (partly plane-polarized) is reflected from the surface of water. Owing to the earth’s magnetic field, the polarization proceeds asymmetrically, which, of course, could have caused asymmetric synthesis.

Recently this explanation of the formation of optically active compounds in nature has been considered the most probable.⁸

I wish to point out still another possibility of asymmetric synthesis, a possibility which, in my opinion, must inevitably have led in nature to the formation of optical antipodes.

¹ Journal of the Russian Physico-Chemical Society.

² Van ’t Hoff, “Die Lagerung der Atome im Raume,” 2nd ed., 36. 1894.

³ Cotton, “Ann. ch.” (7), 8, 347. 1896.

⁴ W. Kuhn, Braun, “Naturwissenschaften” 14, 227. 1929.

⁵ W. Kuhn, Knopf, “Naturwiss.” 18, 183. 1930.

⁶ Mitchell, J. ch. soc. 1930, 1829.

⁷ Byk, Z. ph. Ch. 49, 662. 1904.

⁸ A. Semenov, “Uspekhi khimii,” II No. 2, p. 235. 1933.

Let us examine why an optically active substance cannot be prepared in the laboratory by ordinary physical and chemical methods.

If we take, for example, propionic acid and act upon it with a molecule of chlorine, then α-chloropropionic acid of asymmetric structure will be obtained and, consequently, an optically active one. We cannot, however, observe this, since in practice we always deal with a very large number of molecules. In each molecule of propionic acid both hydrogen atoms of the secondary link occupy exactly the same position and can be replaced by chlorine with equal probability. Therefore, for example, with 1 million molecules we shall obtain about 500,000 molecules of the right-rotating isomer and about 500,000 of the left-rotating one. There will probably be an excess of a few molecules of one, but this excess cannot be detected by present-day means of investigation.

It is as though such an experiment could be carried out in the following way. Let us take, say, 1 gram-molecule (74 g) of propionic acid and evaporate it in a volume of 1 cubic meter. Let us take 1 cubic centimeter of this vapor and expand it again to 1 cubic meter, i.e., a million times. Repeating this operation only 4 times, we shall obtain, in a volume on the order of 1 cubic centimeter, one molecule. Now let us act upon 1 cubic centimeter of this mixture with chlorine. We shall indeed obtain one molecule of chloropropionic acid, which must necessarily be optically active. Thus the problem of asymmetric synthesis could, as it were, be solved without particular difficulty.

But even here nothing will come of it, since again we cannot observe a single molecule of chloropropionic acid by any methods known at present. In order nevertheless to use this method, it would be necessary either to improve our instruments and methods to a very great degree, or to look for some such large molecules somewhere with which one could deal individually. It is to this aspect of the question that I wish to draw attention.

Strictly speaking, crystals belong to molecules of exceedingly large size. A diamond crystal, for example, consists of carbon atoms bonded to one another as they are bonded in saturated hydrocarbons. All the bonds in a diamond crystal are the same; consequently, in essence the whole of it must be regarded as one molecule, even if this molecule should reach a weight of several grams. A quartz crystal consists of atoms of silicon and oxygen, likewise joined, in a very large number, essentially into one molecule. This crystal is constructed asymmetrically and therefore proves to be optically active, i.e., it represents an example of the appearance in nature of an optically active substance, formed, moreover, certainly without the participation of any special forces.

Among organic compounds, protein substances have a very large molecular size; these are precisely the basis of life, and with their help, evidently, the synthesis of all other organic compounds takes place in organisms. For the molecular weight of proteins, values of the order of 15000–30000 were formerly found, i.e., not very large. In recent years Svedberg¹) has proposed a method of ultracentrifugation. In his apparatus the centrifugal force exceeded the force of gravity by 8000–10000 times. With such—

¹) The Svedberg. Nature, 123, 871. 1929.

The molecules of protein substances, as it turned out, are deposited at a noticeable rate, and, by measuring the speed of their deposition, one can determine the molecular weight. For most proteins, values from 35,000 to 210,000 have been found, but in some cases (hemocyanin) the molecular weight reaches 2–5 million.

Thus, the more refined the methods for determining molecular weight become, the larger the figures obtained for the molecular weight of proteins. What, then, is the limit of this increase? It must also not be forgotten that in all determinations one has been dealing with dead protein, no longer manifesting the phenomena of life. And one must expect that living protein will prove still more complex.

I consider it quite probable that the protoplasm of the living cell represents (like a crystal) essentially a single molecule, in which all the atoms are connected in the way they generally are in chemical compounds—by valence and complex bonds (between which there is no fundamental difference).

The origin of living organisms, with this understanding of their structure, must be explained as follows:

In obedience to the laws of mechanics, physics, and chemistry, atoms form among themselves the most diverse combinations. Some—very few—of these combinations, of course only with a sufficiently complex structure and owing to this complexity, acquire peculiar properties; they become capable of such phenomena of exchange of substances with the surrounding medium and of such unlimited reproduction as characterize living beings. In addition to the former mechanical, physical, and chemical regularities, in the motion of such systems of atoms there begin to appear further peculiar biological regularities, which, for the given stage in the development of matter, become the leading ones. Thus there must have occurred (and now, perhaps, sometimes continues to occur) a transition to a qualitatively different form of matter, to living matter.

Each of the lumps of protein that became living beings represented, in the chemical sense, one molecule. Given their very great complexity, these molecules must practically always have had an asymmetric structure, and, consequently, their further complication, the further synthesis of organic substance, must also have proceeded asymmetrically. Obviously, even when a part of the substance of a living cell is isolated from it already in the form of a dead molecule of some organic compound, this compound must, as a rule, be isolated (in the presence of asymmetry) in the form of a right- or left-handed optical isomer. Here we have a synthesis carried out by a single molecule and, consequently, this synthesis must lead to the predominant formation of one optical antipode.

Comparing the various explanations of the origin in nature of optically active compounds, one may say that both the magnetic and the optical explanations are, of course, possible. Thus optically active substances could have arisen. According to the chemical hypothesis proposed here, these substances inevitably had to arise, provided only that the protoplasm of the living cell is indeed a single molecule. And this must be considered very probable for every living cell (if not for every living organism), and still more probable for those still acellular and threadlike in their dimensions lumps of protein with which life on earth began.

1. A. Sementsov, “Uspekhi khimii,” II, No. 2, p. 228. 1933. ↩↩↩

2. McKenzie. J. ch. soc. 85, 1249. 1904; 87, 1373. 1905; 89, 365, 688. 1906; 91, 1215. 1907. ↩↩

3. Errero. Nature, 58, 616. 1898. ↩

4. Japp. Nature, 58, 452. 1898. ↩

5. L. Pasteur. Ostwald’s Klassiker, No. 28, p. 33; A. Sementsov, “Uspekhi khimii,” II, No. 2. ↩

6. L. Pasteur. Revue scientifique, (3) 7, 3. 1884. ↩

7. Dissertation. 1896; A. Sementsov, “Uspekhi khimii,” II, No. 2. ↩