Substitute Materials

According to the Hazardous Substances Ordinance it has to be checked if hazardous compounds may be replaced by less hazardous compounds. On this page you will find some examples. All hints are given to the best of knowledge but no responsibility is taken for the given information. Especially everybody still remains responsible for what he is doing with chemicals.

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Some years ago it was a big discussion that in toast slices which have been roasted too dark carcinogenic and mutagenic acrylamide is found. You may argue about the hazardous potential of a wrong prepared breakfast. But to prepare an acrylamide gel it is more safe to use a ready-to-use-kit instead of mixing the powder.

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The hazardous potential of benzene is well known. If only a solvent is needed benzene in most cases can be replaced by toluene. Those who are insisting to use benzene should be able to give good reasons for that.

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You will not observe any difference. Benzyl bromide is as horribly lacrymating as benzyl chloride. The surprising difference is, that both compounds have an official ("harmonised") EU classification where benzyl chloride is carcinogenic but the bromide is not even suspected to be carcinogenic.

Therefore it is a good idea to replace the chloride by the bromide. The bromide is even more reactive than the chloride but therefore it also decomposes more rapidly. But since also the chloride is often used only "freshly distilled" this is no disadvantage. On the contrary you may make use of the fact that the bromide has a melting point of -1°C and therefore will become a stable solid in the freezer.

If a very pure quality is needed, a simple distillation is not successful for both compounds. The bromide is purified by washing with concentrated sulfuric acid, water, 10% sodium carbonate or hydrogen carbonate solution, then again with water and finally dried over calcium chloride or magnesium chloride. The vacuum distillation is performed with exclusion of light. (W.L.F. Armarego, D.D. Perrin, Purification of Laboratory Chemicals 4th Edition 1996, Butterworth-Heinemann)

It has to be accepted that a molar equivalent of the bromide is 10 times more expensive than the chloride. But since modern laboratory experiments are mostly performed as small scale reactions this should be not much of a problem.

Benzyl bromide can be prepared in a student's lab course by radicalic bromination of toluene. If the yield is similar to values described in literature the overall costs for this experiment are similar to the cost of benzyl bromide purchaised from a distributer. Even if the yields are lower this could be still a win-win-situation since the students anyway have to prepare compounds in their lab courses and a useful compound of course is better than a compound prepared for the trash bin.

Since the benzyl bromide is highly lachrymating the students need a good advice, if they have to prepare or use this compound. A German example is found at FU-Berlin (Experiment 2-3).

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The moisture indicator of the well known blue gel contains a cobalt compound. Since cobalt ist suspected to be carcinogenic also blue gel is placed in an unfavourable light. A discussion if cobalt which is well shielded in the gel is still hazardous has no value since there is a simple heavy metal free alternative available for the same price. So there will be no disadvantage. All what has to be done is to change the habits. The term "orange gel" today is not yet established. Other trade names are: "Silicagel orange" or "Silicagel rubin" (Fluka).

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Chloroform is a very good solvent. But on contact with air phosgene is formed which is the reason why chloroform is distributed with stabilisators like 1 % ethanol. It is not stable against base and may then perform vigorous reactions with acetone. In Germany chloroform is one of the few examples which is not labelled as to be carcinogenic but nevertheless has to be considered as to be carcinogenic. The reason is that on one hand chloroform has a harmonised EU-classification that it might be carcinogenic but in the TRGS 905 it is stated to be carcinogenic. Although the carcinogenic activity seems to be low, the corresponding regulations - for example the Hazardous Substances Ordinance apply.

In most cases it is easy to use dichloromethane instead. But in NMR-spectroscopy deuterated chloroform is the standard solvent and should remain in use there. This should be also possible for small amounts of non deuterated chloroform needed for checking the solubility of samples used in the NMR-spectroscopy.

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Chromiumtrioxide is carcinogenic for human beings. Other chromium(VI)-compounds are at least carcinogenic in animal experiments. Most hazardous is the inhalation of dusts. Chromium(III)-salts are not carcinogenic, but have to be disposed separately as heavy metal waste. There are no general recommendations to replace the chromiumtrioxide. But often there are alternatives for specific synthetic problems, for example the oxidation of alcohols by SWERN-Oxidation. Even course books sometimes state some alternatives.

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Today there is no need to use chromo-sulfuric acid any more since there are a lot of suitable detergents available for cleaning purposes where the succesful cleaning may still be enhanced by treating in an ultrasonic bath. Another easy alternative is a freshly prepared mixture of sulfuric acid and hydrogen peroxide. However, on cleaning of glass frits vigorous reactions have been reported. Therefore use this mixture carefully.

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The preparation of crystal violet is a very popular experiment in the organic chemistry education because the strong dying effect enforces very clean working conditions. Unfortunately in the meantime the starting material michlers ketone has been classified to be carcinogenic. But instead of crystal violet ethyl violet can be prepared in exactly the same way (see FU Berlin experiment 6-10). Both educts michlers ethylketone und Diethylaniline are not carcinogenic.

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Diazomethane is carcinogenic. Furthermore it may explode on contact with rough (ground connections) or sharp (crystals) surfaces.

Trimethylsilyldiazomethane is said to be more safe in use than diazomethane. It is distributed as a ready-to-use-solution in hexane or diethyl ether - so there is no need to prepare the active compound like the preparation of diazomethane. Especially this derivative does not tend to explode. On the other hand this compound is also carcinogenic and very toxic when it is inhaled. Furthermore it is very expensive. The price for 25 ml of a solution in diethyl ether is about 40 €. In the online-version of Org.Synth. a synthesis for the compound is described.

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Strong methylating agents generally tend to be carcinogenic. Substitutes are less carcinogenic if they are less powerful methylating agents. Often powerful methylating agents are needed. So it will not work to perform every methylation with dimethyl carbonate.

Therefore it is a matter to balance the concrete synthetic problem. In this respect intention should also paid to the question if it is meaningful to exchange "sure"-carcinigenic dimethyl sulfate by iodomethane which is only suspected to be carcinogenic but highly volatile (bp. = 42 °C).

Alkylsulfonates are well known alkylating agents. Most known are tosylates (4-toluenesulfonates). Furthermore there are also brosylates (4-bromobenzenesulfonates), nosylates (4-nitrobenzenenesulfonates) and mesylates (methanesulfonates). However these compounds have no 'harmonised classification'. Therefore the classifications of the hazardous potential may vary from manufacturer to manufacturer.

Methyltosylate is easily obtained. The price is a little bit lower than of iodo methane if molar amounts are compared. Above all it has a much higher boiling point (292 °C) and only moderate toxic potential. From a security standpoint it is therefore far superior to iodomethane.

Methylmethansulfonate is also carcinogenic. From a security standpoint it is therefore no suitable substitute. Other methylsulfonates are difficult to get, have a high price or are commercially unavailable.

Some years ago dimethylcarbonate has been advertised as a suitable substitute. Dimethylcarbonate is even a little bit cheaper than dimethylsulfate. But the alkylating power is only poor. Therefore rigorous reaction conditions are needed and there are substrates which will not react at all. You have to search the literature to find out what will work. If you cannot get any information, you can try it out. Since the job is to perform the reaction with less hazardous compounds this is a good task for students in the lab courses.

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Ethidium bromide is used for staining DNA. It does not have a harmonised classification. The German "Senatskommission zur Prüfung gesundheitsschädlicher Arbeitsstoffe" of the DFG has classified ethidium bromide to be suspected to be carcinogenic and mutagenic. Suppliers try to lower the hazardous potential by offering the compound as pills or as a ready-to-use-solution. It is well known that dissolved ethidium bromide may penetrate latex gloves. Therefore nitril gloves have to be used.

Substitutes are already described in the WIKIPEDIA-information on ethidium bromide. The company BIOTIUM is offering the substitutes "GelRed" and "GelGreen".

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There have been several successfull attempts to exchange hexamethylphosphoramide against the two urea derivatives  1,3-Dimethyl-2-imidazolidinone (DMEU) and  1,3-Dimethyltetrahydro-2(1H)-pyrimidinon (DMPU). A systematic survey is given by D.Seebach in

  • D.Seebach,R.Henning,T.Mukhopadhyay, Chem.Ber. 115,1705-1720(1982)

Users of the substitutes are found in

  • C.J. Gilmore, D.D. MacNicol, A. Murphy, M.A. Russel, Tetrahedron Lett. 24,3269-3272(1983)
  • U. Schöllkopf, R. Lonsky, Synthesis, 675-676(1983)
  • A.R. Bassindale, T. Stout, Tetrahedron Lett.,26,3403-3406(1985)
  • U. Schöllkopf, R. Lonsky, Synthesis, 675-676(1983)
  • T. Mukhopadhyay, D. Seebach, Helv.Chim.Acta,65,385-391(1982)

Some aspects make the changeover easier. It is quite difficult to purchase hexamethylphosphoramide and if there is a supplier, the price is higher than of the substitutes. Nevertheless is a question of the concrete synthetic problem if a substitute does work.

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Methoxymethylchloride is used to introduce the MOM-protecting group. The compound is known to be very carcinogenic for human beeings, where it is still a question if present traces of bis(chloromethyl)ether are the reason of the carcinogenic potential or are only enhancing the carcinogenic effect. (See details). The compound has a very low boiling point of 59 °C and is therefore very volatile.

Methoxymethylchloride is not commercially available and has therefore to be prepared by the users. The 100 years old traditional synthesis using hydrogen chloride, formaldehyde and methanol gives significant amounts of bis(chloromethyl)ether as a by-product which cannot be completely removed by distillation. If it is necessary to use methoxymethylchloride it is better to use a modern synthesis which will not yield bis(chloromethyl)ether as a by-product, for example by using acid chlorides and dimethoxymethane as starting compounds. See

  • R.J. Linderman, M. Jaber, B.D.Griedel J. Org. Chem 59,6499-6500(1994)
  • M. Reggelin, S.Doerr Synlett 1117(2004)

Even pure methoxymethylchloride develops slowly bis(chlormethyl)ether if it is left standing alone.


  • (2-Methoxyethoxy)-methylchloride (MEM-Cl) is also carcinogenic. There is no reason to think oneself safe because there is only rare information about the compound available. Since the compound has so far only be used in small scale reactions in scientific labs no official body had the focus on the hazardous potential. But there are two sure advantages. The compound has a high boilng point (50 - 52 °C / 13 mm) und it is commercially available.
  • (2-Chloromethoxyethyl)-trimethylsilane (SEM-Cl) is not carcinogenic. This compound is also commercially available, but the price is high (ca 40 €/g).

In a complex synthetic problem customised protecting groups are needed. General hints for a substitution are therefore not possible. Careful search of the literature is needed. (for example T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, Whiley)

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N-Nitroso-N-methylurea is used to prepare diazomethane. It is carcinogenic and often it is also self prepared. If a substitution of diazomethane is impossible then at least Diazald (N-Methyl-N-nitroso-4-toluenesulfonic acid amide) may be used as a substitute. 100 g Diazald are commercially available for 60 €. Even isotope labelled diazald is available. The aldrich company offers a lot of references how to use the diazald.

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Phenolphthaleinis an every purpose - indicator and has also been used in schools. Unfortunately 2009 it has got a harmonised classification and is now carcinogenic and probably mutagenic and toxic to reproduction. In fact only very little of the indicator is needed to prepare a suitable solution and it may be that the final concentration is less then 1 %  and therefore the solution is no more carcinogenic concerning hazard regulations. But there must be anybody who has to prepare this solution!

Those who do not need a color change from colorless to red but can accept also a color change from colorless to blue may use thymolphthalein as an alternative which is not classified to be a hazardous compound. The color change is on a similar pH-range (9,4 - 10,6 instead of 8,2 - 10,0) and since only very small amounts are needed it will be of no consequence that the price is 3 times higher. Thymolphthalein at the moment is not classified to be carcinogenic. It is likely that this fact will not be changed in the future because it is well known that alkyl side chains - which make the difference between phenolphthalein and thymolphthalein - are pushing back the carcinogenic activity.

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