piperonal to isosafrole

[hypo]

hi,

another one of lughs articles:

piperonal is converted to methylene-homocaffeic acid and then decarboxylated
to isosafrole in a one pot reaction. the reaction needs to be optimised,
only a part of the acid is decarboxylated.

CHIMIE ORGANIQUE - Safrole and isosafrole. Synthesis of isosafrole.
  Note by Mr. Ch. Moureu, presented by M.H.Moissan.

  One usually supposes that the configurations of safrole resp. isosafrole are:
    { correct pictures of safrole and isosafrole }

  The first of the supposed isomers is thus an allyl derivate and the second one a propenyl derivate of methylenepyrocatechol. The methylenepyrocatechol group (-O-CH2-O-) really exists at the given place in the safrole and in the isosafrole molecules, indeed safrole is the precursor in the industrial production of piperonal { correct picture of piperonal }. The best reason for the forms given to the non saturated radicals is the transformation of safrole boiling at 232° into isosafrole boiling at 248° under the influence of potassium, discovered by Mr. Grimaux and Mr. Ruotte(1), which reminds the transformation of eugenol, an allyl derivate boiling at 247°, into it's propenyl isomer isoeugenol, boiling at 263°.

  The theory was sound, it just needed to be proven by the direct synthesis of safrole or isosafrole. This was the target I aimed at.

  The first compound to obtain was methylene-pyrocatechol { picture of 1,3-benzodioxole } common kernel to the two piperonal isomers. I achieved this by reacting methyleneiodide with the disodium salt of pyrocatechol. It's an oily, colourless liquid with an aromatic smell, boiling at 172°-173° and having a density of 1.202 at 0°.
  (C=68.53 and 68.10; H=5.02 and 5.11; Computed: C=68.80; H=4.91).
Methylenepyrocatechol reacted with allyliodide and zinc powder would certainly give safrole, like veratrol gives methyleugenol (Ch. Moureu). But the low yields obtained in his preparation have not until now allowed me to perform this reaction. On the other hand I synthesised isosafrole.

  If isosafrole really is 4-propenyl-(1,2)-methylene-pyrocatechol, one must be able to obtain it by the action of heat on methylene-homocaffeic acid.
  { picture of caffeic acid with a methylene bridge and a methyl group in alpha to the COOH}

  This compound is easily prepared by heating to reflux a mixture of piperonal, propionic anhydride and dry sodium propionate (Perkin reaction). It is hardly soluble in boiling water and crystallises from alcohol at 80° in little needles with a mp of 198°-199° (C = 64.09 and 63.77; H=5.1 and 5.09; Computed: C=64.07; H=4.85). The silver salt crystallises from boiling water in little white needles with a red touch. (Ag = 34.45; computed: 34.5). The Lorenz derivate (2) melted at 192°-194°

  When one gradually heats methylene-homocaffeic acid, it first melts and then loses, beginning at 270°, carbon dioxide; it distills at a higher temperature, partly unaltered, and leaves an important amount of resinous residue. By the way, the reaction does not run more regularly under vacuum. When one makes an intimate mixture between the unsaturated acid and the theoretical amount of anhydrous chalk and performs dry distillation, by 3g or 4g portions, one obtains some drops of an oil smelling like isosafrole.

  With such small quantities, we were unable to identify the product as being isosafrole. M. Eykmann (1b), in an expose which we got to know only after this work was finished, says having gotten an yellow aromatic oil, of which, due to the small amount of substance, he could not exactly determine the boiling point (240°-245°), and which gave him a vapour density value of 80.25 instead of the theoretical value of 81.

  After being delayed for a long time by the same difficulties as Mr. Eykmann, I was happy to be able to turn around the matter in the following way:

  When preparing the methylene-homocaffeic acid, if one lets communicate the atmosphere of the flask with a vase containing baryte water, one observers in the latter an abundant tarnishing with precipitation of barium carbonate and at the same time notable amounts of isosafrole are formed. The reaction mechanism is easily explained. The reaction temperature is about 200°, and this is hot enough to allow the decomposition of the unsaturated acid; the excess propionic anhydride protects the isosafrole, helps it develop, and hinders resination. Here is by the way how it is convenient to operate:


  A mixture of piperonal (50g), dry sodium propionate (50g) and propionic anhydride (60g) are heated to reflux for four to five hours. The pasty mass is poured into an excess of water and the whole lot boiled for a short time in order to destroy the excess anhydride. One lets cool, decants the clear liquid and sucks the precipitate dry on aspirator. A yellow, reddish oil separates which is removed by washing with alcohol and ether. The solid product, first yellow, is now white; it's methylene homocaffeic acid (32g). The yellow, reddish oil consists nearly entirely of isosafrole. It is steam distilled from an alkaline solution. The distilled isosafrole (19g) is dried over calcium chloride an distilled. After three rectifications, nearly all (16g) comes at 248.5°-250.5°. It has definitely isosafrole odour by which I identified it.


 1) Combustion
                  I.       II.   Computed
    H%........  6.5g      6.5g     6.17
    C%........ 74.32     74.30    74.74

 2) Density at 0°: Synthetic isosafrole (248.5°-250.5°), D=1.135; natural isosafrole (248°-251°), D=1.136
 3) Refraction index at 20°: Synthetic isosafrole, n=1.5743; natural isosafrole, n=1.5733
 4) Like natural isosafrole, the synthetic product gives, on oxidation with permanganate, piperonylic acid (Mr. Ciamician and Mr. Silber) melting at 227° and on oxidation with potassium bichromate and sulfuric acid, a mixture of piperonal and aldehyde.
 5) Finally, synthetic isosafrole gives, when treated with bromine in sulfocarbonic solution, a white compound, crystallising in fine, shiny needles, melting at 109°-110°, identical to the tribromoisosafrole C10H9Br3O2 of Mr. Ciamician and Silber

  Conclusions. - The synthesis of isosafrole starting with methylene-homocaffeic acid shows the it's definition in an non arguable way; it shoes that it truly is propenylmethylene-pyrocatechol. When one proceeds by exclusion, safrole must be allylmethylene-pyrocatechol

(1) Bulletin de la Société Chimique, t. II, p. 465.
(2) Berichte, XIII, 759.
(1b) Berichte, XXII, 2749.

[GC_MS]

Identification by smell? Haha, if you dare to identify a substance these days without an NMR, you're publically shot   .

Nice article hype. The mentioned technique is also known as the PERKIN REACTION. As far as SWIM remembers, it's a technique developed in the late 1800s. It was very popular in the perfume industry (to make adulterated products, or rare substances). SWIM has some old stuff and adds some theoretical comment as a complement to the article:

1. Perkinsche Synthese: Zimtsäure aus Benzaldehyde und Essigsäure (Perkin synthesis method: cinnamic acid from benzaldehyde and acetic acid) [L Gattermann, Die Praxis des organischen Chemikers. 22. Auflage, 1930, pp 222-226]

The Perkin reaction is a consequence of the general condensation reactions of aldehydes, viz. the separation of oxygen and 2 hydrogens from a methylene or methyl group. The latter's reactivities determine the reaction conditions. Aldehyde and aldehyde or ketone -> in cold acid or alkaline environment as catalist. Aldehyde and acid anhydride -> high temperatures, alkali salt (a).
The difference in reaction conditions is based on the reduction of the low reactivity of methyl groups (especially alpha-methyl) in acid anhydride.

2. Phenole mit ungesättigten Seitenketten (Phenoles with unsaturated side chains) [Meyer, Jacobson, Lehrbuch der organischen Chemie. 1923, B II P I pp 430-436]

Anethole is a main component from anis oil (from anis seeds), and can also be found in the oils of star anise, fennel and others. It can be produced synthetically by application of the Perkin reaction on anisaldehyde:

MeO-C₆H₄-CHO + CH₃CH₂COONa --> H₂O + MeO-C₆H₄-CH=CMeCOONa

MeO-C₆H₄-CH=CMeCOOH - CO₂ --> MeO-C₆H₄-CH=CH-CH₃

This reaction is evidence for its molecular structure (...). Isosafrol (b) is produced by heating safrol in a solution of an alcoholic base, or synthetically from piperonal in a similar way as anethole is made from anisaldehyde and isoeugenol from vanillin (!). Furthermore, this synthesis is prove for the location of the double bond in isosafrol.

----

The Perkin reaction was initially used to prove the position of the double bond in the propene side chain on the phenyl (allyl vs propenyl). The method has been used for proving in a simple way the molecular difference between anethole/methyl chavicol, eugenol/isoeugenol, safrol/isosafrol etc. Interesting historical sidenote: the method has also been used for the structural elucidation of asarone. Although they found out that asarone was a propenyl derivative, they still didn't know the exact positions of the 3 MeO- groups on the phenyl ring (at least, in a 1923 book (cf. 2.)   .

Mentioned references:

(a) Kalmin, Helv XI, 977 (1928)
(b) Grimaux, Ruotte, Bull. 11, 465 (1869) - Poleck, Ber. 17, 1940 (1884) - Eykman, Ber. 22, 2749 (1889); 23, 859 (1890); Rec. Trav. Chim. 14, 189 (1895) - Ciamician, Silber, Ber. 23, 1159 (1890); 25, 1470 (1892) - Tilden, Forster, Journ. Soc. 65, 332 (1894) - Angeli, Mole, Ber. 27 Ref, 799 (1894) - Wallach, Pond, Ber. 28, 2719 (1895) - Heffter, Chem. Centr.-Bl. 1896 I, 121 - Moureu, Compt. Rend. 122, 792 (1896)

Note: hypo, is your "Mr. Ch. Mourec" a typing error, and shouldn't it be "Mr. Ch. Moureu"? In that case, might be interesting to check the last reference from (b), if it would be the same person   .
-[ A Friend With W33D Is A Friend Indeed ]-

[hypo]

> Note: hypo, is your "Mr. Ch. Mourec" a typing error, and shouldn't it be "Mr. Ch. Moureu"?

yes, it's Mr. Moureu. i misspellt the poor mans name twice
in the same post (Mourec and Moureau)     .

[hypo]

here is a related synthetic pathway:

aldehyde + bromopropionicacidethylester + Zn --> oxyester (reformatzky)
oxyester + heat - H20 --> unsaturated ester
unsaturated ester --> unsaturated acid
unsaturated acid + heat - CO2 --> propenylbenzene

again, the decarboxylation step is the problematic one.
reference as usual by lugh  

II. On the synthesis of anethole from anisaldehyde and isosafrole from piperonal
coedited by Edgar Evans.

  In numerous cases, the method of synthesis I have recommended (2) has proven worthwhile, starting with the reaction of Reformatzky and Saytzeff (interaction of halogenated acidesters with aldehydes or ketones in presence of zinc). The suggested use of benzene as solvent is very favourable for the yield and the purity of the products. This also proved to be true using aldehydes as reagent. The following outstandingly high yielding reactions exemplify this.

  1. Synthesis of anethole

  10g Anisaldehyde are reacted with 14g bromopropionicacidethylester in 40ccm benzene and 5g grained zinc. One obtains 15g of the oxyester CH3O.C6H4CHOH.CH(CH3).CO2C2H5. From the fraction distilling between 235-245° at 13mm one can easily remove water by heating with twice the amount of potassium bisulfate to 150° for two hours. The thus obtained unsaturated ester CH3O.C6H4CH:C(CH3).CO2C2H5 (boiling point of the major fraction at 170-180° at 25mm) was saponified to the anisyl-alpha-methylacrylic acid CH3O.C6H4CH:C(CH4)CO2, yielding 7.3g. This acid, which after recrystallisation from acetone melts at 157°, was already obtained by W.H. Perkin sen. during his classical work on the aldehyde condensations by heating anisaldehyde with propionaldehyde. Perkin specifies the melting point to be 154° and reports pertaining to the acid (3): "When heated to boiling, it decomposes, yielding anisole, which has the odour of oil of anise and when cooled becomes crystalline."

  Indeed the acid decomposes on slow distillation (to about 50%) to CO2 and anethole CH3O.C6H4CH:CHCH3.

  The anethole, which rapidly solidifies on cooling, could be identified by the boiling point - 232° - and by the melting point of the nitrite derivate: 121°.

  2. Synthesis of isosafrole

  18g piperonal and 21g alpha-bromopropionicacidethylester were dissolved in 4 times the amount of benzene and reacted with 8g zinc.
  One obtained 27g of product boiling between 180-210°, which was heated with potassium bisulfate and saponified like in the previous example. The yield was 16g piperonyl-alpha-methylacrylic acid MD:C6H3CH:C(CH3)CO2H.

  This acid is practically insoluble in acetone, methanol, benzene and ethylacetate and can easily be freed from the red impurities by washing with the mentioned solvents. On strong heating, the acid loses carbon dioxide. But the reaction is not quantitative. Anyway, after washing with alkali and steam distillation, enough product was obtained to identify it as isosafrole MD:C6H3CH:CHCH3 by the boiling point - 244° - and by preparing and recrystallising the nitrite, which melts at 128°.

Notes

2) These Annalen 323, 138 (1902); 317, 316 (1906)
3) Journ. Chem. Soc. 31, 411-413 (1877), for the analysis of the constitution of Perkins acid, see Annalen 255, 294-295

[GC_MS]

Just a small addition: in SWIMs previous reply, he talked about cinnamic acids (Perkin). It is also possible to make cinnamaldehydes, and go for the allyl isomeres (eugenol, safrol, methylchavicol). All depends on the bee: what does he want to do, and fits him best...

(translatiert auf German   )

Ungesättigte aromatische Aldehyde (unsaturated aromatic aldehydes) [V. Meyer and P. Jacobson, Lehrbuch der organischen Chemie, Walter de Gruyter & Co., 1923, B2 P1, p. 487-488]

Cinnamaldehyde Ph-CH=CH-CHO (propenylalbenzene) is an easy to get substance. It is a main component of "Zimmtöls" (a), which can be prepared by distilling the bark of Cinnamonium cassia and Cinnamonium ceylonicum, and by steam distilling the leaves of Cinnamonium cassia (b). The substance can be obtained in high purity by its sodiumbisulfite derivative. It can also be prepared synthetically by condensation of benzaldehyde and acetaldehyde in the presence of a weak alkaline solution:

Ph-CHO + Me-CHO - H₂O -> Ph-CH=CH-CHO

This reaction can also be used for the preparation of homologue substances (c):

NO₂-Ph-CHO + Me-CHO - H₂O -> NO₂-Ph-CH=CH-CHO
Ph-CHO + Et-CHO - H₂O -> Ph-CH=C(-Me)-CHO

Cinnamaldehyde is a transparant, aromatic smalling and volatile oil. It boils at 128-130°C under 20 mmHg and has a density of 1.050 (20°C). Cinnamaldehyde reacts with NH₃ in an alcoholic solution to yield hydrocinnamide (Ph-CH=CH-CH)₃N₂.

(a) "Zimmtöls"... SWIM doesn't know how to translate this well   . "Zimmt" means "cinnamic", so SWIM thinks it should be something like cinnamic oil. A synonym (trade name) is Cassia oil (Cassiaöls).
(b) The books adds a remark here: the commercially available "Zimmtblätteröl" (cinnamic oil from leaves) from the Cinnamonium ceylonicum contains eugenol as main component.
(c) Miller, Kinkelin, Ber. 19, 525 (1886)

---

And where the f*ck is that allyl thing you talked about   ? There is a small, condensed but well written page on Rhodium's site:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/cinnamaldehyde.html

Don't know if you really want to go to the safrol if you can go to isosafrol as well using Perkin, but it could be usefull if you have problems or low yields with piperonal -> isosafrol. Safrol -> isosafrol is discussed ad nauseam on Rhodium and the Hive   .
-[ A Friend With W33D Is A Friend Indeed ]-

[mellow]

Another way of proceeding is to 1) reduce alpha-methyl MD-caffeic acid  to alpha-methyl MD-dihydrocaffeic acid followed by 2) conversion to the amide and finally 3) Hofmann degradation with NaOCl giving MDA. Step 2 may be a bit tricky - it may be best to esterify the acid with alcohol followed by reaction with ammonia to give the amide.

1. MDP.CH=C(Me).COOH ==> MDP.CH2.CH(COOH).CH3
2. MDP.CH2.CH(COOH).CH3 ==> MDP.CH2.CH(CONH2).CH3
3. MDP.CH2.CH(CONH2).CH3 ==> MDP.CH2.CH(NH2).CH3