A strange, possible, amphetamine synthesis (by Chem Guy) Okay this synthesis involves the decarboxylation and methylation of phenylalanine in one step. The basic equation is: C6H5-CH2-CHNH3-COOH + CH3COONa --{electroysis @ Pt anode}--> C6H5-CH2-CHNH2-CH3 + H2 + CO2 The problem that I find with this is the solublity of phenylalanine... What does phenylalanine, or it's salt dissolve in? Where could I find that... ________ From "Synthetic Organic Electrochemistry", by Albert J. Fry, yr 1972 Library of Congress # QD273.F78, page 273 "8 OXIDATION PROCESS ... 8.1 CARBOXYLIC ACIDS It has been known for conciderably more than a century that electrochemical oxidation of salts of carboxylic acids results in dimeric products [6]: 2 RCO2(-) --{O}--> 2 CO2 + RR This reaction is known as the Kolbe reaction after the early investator who, though not it's discoverer, studied it in sufficent detail to outline its scope. Perhaps no other organic reaction has been studied as intensively as has the Kolbe reactioon; indeed, investigation into its sublter aspects have continued right up to the present day. While some mechanistics details still remain unclear, the preparative methodology and mechanism are sufficently well established that synthetic applications are straight forward. ... 8.1.1 The Kolbe and Related Reactions Mechanism Weedon has discussed optimal experimental procedures for the Kolbe reaction [1]. ... Apparently, a film of absorbed intermeditates inhibits oxidation of the solvent and permits a potential to be attained where the Kolbe reaction can then occur. This feature is of interest synthetically because it results in considerable experimental simplifications. Since anodic potential control (to avoid oxidation of the solvent) is rendered unnecessary by this absorption process, one may use constant-current, rather than controlled-potential, electrolysis. As Weedon has pointed out, the experimental apparatus for the Kolbe reaction can be quite simple, merely a beaker containing both the solution and a pair of platinium electrodes connected to a source of direct current (see Chapter 9) [1]. ... Synthetic Scope and Limitations Kolbe dimers are formed in 50-90% yeild when the intermeditate radical is either primary [1] or is substituted by electron-withdrawing groups [15], that is, RC*H2 or RC*HX or RC*X2_____________(X = COO2R', CONR2', etc.) When the [alpha] position of the acid containsa substituent capable of stablizing a carbonium ion (X = alkyl, alkoxyl, halogen, aryl, etc.), yields of the Kolbe dimer are very low ( 0-10% ). In such cases, the intitially formed radical is oxidized further to a carbonium ion: RCO2(-) - e(-) --{ -CO2}--> R* --{ - e(-)}--> R(+) --> products ... There are a few other other cases where the Kolbe yields are low. Aryl [16] and [alpha], [beta]-unsaturated acids [17] afford little or no dimer, for example. The isolation of benzene from the oxidation of benzonic acid [16], ... Other than these, there are really very few restrictions on the nature of the R group in a carboxylic acid (RCO2H) that is to be submitted to the Kolbe reaction. ... ... A valuble extension of the Kolbe reaction was first reported by Wurtz [23]. He found that oxidation of a mixture of two different carboxylic acids results in a mixture of three possible coupling products: RCO2H + R'CO2H --{ -e(-)/ -CO2}--> RR + RR' + R'R' The fact that the three are formed in more or less statistical ratio need not be a detterent, for the proper choice of the molecular size of R and R' the products can be made to differ substantially in physical properties, thus making separation easy, and use of a large excess of the cheaper acid increases the relative yield of the desired mixed product RR'. ... (One common application of this crossed Kolbe coupling is the oxidation of a carboxylic acid in the presense of a large excess of acetate ion, thus resulting in efficent conversion of the acid RCO2H to the alkane RCH3 in one step [10-12]. This reaction would be useful for the introduction of a labeled methyl group.) The crossed Kolbe coupling reaction has the dual advantage of being able to accommodate a wide variety of functional groups and of enabling quick assembly of molecular subunits whose coupling by other routes might be lengthy. ..." [1] B. C. L. Weedon, Advan. Org. Chem., 1, 1 (1960) [6] H. Kolbe, Ann., 69, 257, (1849) [10] W. J. Koehl, Jr., J. Org. Chem. 32, 614 (19670. [11] W. A. Bonner and F. D. Mango, J. Org. Chem., 29, 430 (1964). [12] H. Breederveld and E.C. Kooyman, Rec. Trav. Chim., 76, 297 (1957). [13] G. W. Kenner, M.A. Murray, and C. M. B. Tylor, Tetraherdon, 1, 259 (1957) [15] L. Eberson, Acta Chem. Scand., 17, 1196 (1963); L. Eberson and B. Sandberg, Acta Chem. Scand., 20, 739 (1966); but see L. Eberson and S. Nilsson, Acta Chem. Scand., 22, 2453 (1968). [16] F. Ficher and R. E. Myer, Helv. Chim. Acta, 17, 535 (1934); F. Ficher and H. Stenzl, Helv. Chim. Acta, 22, 970 (1939). [17] J. Petersen, Z. EleKtrochem., 18, 710 (1912); P. Karrer and M. Stoll, Helv. Chim. Acta, 14, 1189 (1931). [23] A. Wurtz, Ann. Chim. et Phys., 44, 291 (1855); A. Wurtz, Jahresberichte, 575 (1855). ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ From "The Journal of Organic Chemistry", Vol. 29, yr 1964, page 430 Title "Kolbe Electrolyses of 3-Phenyl- and 3,3-Diphenylpropanonic Acids" "EXPERIMENTAL ... ... The electrode unit consisted of two platinium foil electrodes (1.25 X 1.25 cm.) spaced approximately 2 mm. apart and joined to wires sealed into a tapered glass head (...) equipped with a gas exit tube. The cell compartment (30 mL), fitted to recieve the electrode unit, was equuipped with a water jacket for thermosating. The electrolysis appartus was energized by a 12-V Heathkit battery eliminator. ... Electrolysis of 3-Phenylpropanonic Acid in Acetic Acid.- A solution of 3-phenylpropanonic acid (2.89 gr.) [0.01927 mol], and sodium acetate (1.43 g.) [0.0174 mol], in acetic acid (25 mL) [assume Glacial acetic acid- .425 mol @ 17 mol/L] was electrolyzed as above for 21 hr. (0.2 amp., 8 f./mol). ... The observed retention times showed that n-propylbenzene and 2-phenylethyl acetate were present..." ============================================================ Osmium: Solubility of phenylalanine in water is 10-50mg/ml, but this figure should be much higher in acidic or basic solutions. ------------------------------------------------------------ From "Topics in Currnet Chemistry" Volume 152, Electrochemistry IV, edited by E. Stekhan, LoC# QD1. F58 v.152 page 93 "The yield and selectivity of the Kolbe electrolysis is determined by the reaction conditions and structure of the carboxylate. ... Experimental factors that influence the the outcome of the Kolbe electrolysis are the current density, the temperature, the pH, additives, the solvent, and the electrode material. High current densities and high carboxylate concentrations favor the formation of dimers. This is due to a high radical concentration at the elctrode surface that promotes dimerization. Furthemore, at high current densities the so called critical potential of about 2.4 (vs NHE) is reached [28] above which the Kolbe dimerization proceeds smoothly. ... There is, however, no need for potential control in Kolbe electrolysis as the critical potential is already exceeded at 1 to 10 mA/cm^2. This is much below the usually applied current density, which should be as high as possible, normally equal to or greater than 250 mA/cm^2. ... ... A nuetral, or even better a weakly acidic medium seems to be prefferable for the Kolbe reaction. This is achieved by nuetralizing the carboxylic acid to an extent of 2 to 5%, in some cases up to 30%, by an alkali metal hydroxide or alkoxide. ... The endpoint of the electrolysis is indicated by a change of the electrolyte to an alkaine pH. ... In aqueous solution an elevated pressure favors the Kolbe-coupling against non-Kolbe products [37]. ... Temperature has some effect on Kolbe electrolysis. Higher temperatures seem to support disproportionation against the coupling reaction and intramolecular additions to double bonds against a competing inter- molecular coupling (Chap. 6). ... Additives can strongly influence the Kolbe-reaction. Foreign anions should be definitively excluded, because they seem to disturb the formation of the necessary carboxylate layer at the anode. Their negative effect increases with the charge of the anion. ... Foreign cations can increasingly lower the yield in the order of Fe(+2), Co(+2) < Ca(+2) < Mn(+2) < Pb(+2) [22]. Alkali and alkaline earth metal ions, alkylammonium ions and also zinc or nickel cations do not effect the Kolbe reaction [40] and are therefore counter ions of choice in preparative applications. Methanol is the best sutied solvent for Kolbe electrolysis [7, 43]. ... The following electrolytes with methanol as a solvent have been used: MeOH-sodium carboxylate [44], MeOH-MeONa [45, 46], MeOH-NaOH [47], MeOH-Et3N-pyridine [48]. The yield of the Kolbe dimer decreases in media that contains more than 4% water. In aqueous solutions especially, the current yield is distinctly lower; furthermore, solublity problems can occur when the salt-deficit method is used. In aqueous solution, alpha-amino- or alpha-phenyl subsituted carboxylates lead mainly to decomposition products, whilst in dry methanol or methanol-pyridine, coupling products were obtained with alpha-phenyl- and alpha-acetylaminocarboxylates [49]. ... As anode material, smooth platinum in the form of a foil or net seems to be most univerisally applicable [32, 33]. ... ... The nature of the cathode material is not critical in the Kolbe reaction. ... ... In summary the following general experimental conditions should be applied for a sucussful dimerization of carboxylic acids: An undivided beaker type cell can be used equipped with a smooth platinum anode and a platinum, steel or nickel cathode in close ditance; a current density of 0.25 A/cm^2 or higher should be provided by regulated power supply, a slightly acidic or nuetral electrolyte, prefferable methanol as solvent and a cooling device to maintain temperatures between 10 to 45 C should be employed. With this simple procedure and equipment yields of coupling product as high as 90% can be obtained, provided the intermediate radical is not easily further oxidized (see Chap. 7)." ============================================================ Phenylalanine Properties: Phenylalanine, dl- CAS# 150-0-1 Phenylalanine, l- CAS# 63-91-2 From- http://ntp-server.niehs.nih.gov/htdocs/CHEM_H&S/NTP_Chem6/ Radian63-91-2.html [for l-phenylalanine] *SOLUBILITIES: WATER : 10-50 mg/mL @ 25 C (RAD) DMSO : <1 mg/mL @ 25 C (RAD) 95% ETHANOL : <1 mg/mL @ 25 C (RAD) METHANOL : Very slightly soluble [031,295] ACETONE : <1 mg/mL @ 25 C (RAD) TOLUENE : Not available OTHER SOLVENTS: Ether: Very slightly soluble [043] Alcohol: Very slightly soluble [043,295] Dilute mineral acids: Very slightly soluble [295] (But in solutions of pH less than 2, very soluble) From- www.chemfinder.com [for L-phenylalanine] water solutblity: 1-5 g/100 mL at 25 C @ http://esc.syrres.com/interkow/webprop.exe?CAS=63-91-2 [for L-Phenylalanine] Water Solubility: Value : 2.69E+004 mg/L Temp : 25 deg C Type : EXP Ref : YALKOWSKY,SH & DANNENFELSER,RM (1992) End of Properties- ============================================================ Here is a wonderful article that i just found that sheds new prespective on the particulars of the crossed Kolbe coupling scheme. Here is the text, i only included the bulk of the article, not the experimental section _______________________________________________________ Journal of the Chemical Soceity, 2854 (1951) Linstead, Shephard and Weedon: 634. Anodic Syntheses. Part V.* Electrolysis of N-Acylamino-acids. A Novel Alkoxylation Reaction . By R. P. LINSTEAD, B. R. SKEPHMID, and B. C. L. WEEDON. Electrolysis of N-acyl-glycines and -DL-[alpha]-alanines in methanol gives N-methoxymethyl- and N-l'-methoxyethyl -amides respectively in good yields. Analogous reactions occur in both ethanol and isopropanol. Under similar conditions N-acyl derivatives of 6-aminohexanoic acid, [gamma]- aminobutyric acid, and [beta]-alanine undergo the normal Kolbe reaction giving the corresponding derivatives of polymethylenediamines in ca. 20— 40% yields. THE Kolbe synthesis of compounds of the type R*R by electrolysis of the acids R-CO,H is known to be accompanied by side reactions, a number of which were described by Kolbe himself (Annaltn. 1849, 69, 257). The extent to which by-products are formed is governed both by the experimental conditions and to a marked degree, by the structure of the acid, to a electrolysed. A survey of the literature reveals that presence of substituents [alpha] to the carboxyl group has the most pronounced influence, as would be expected, and may result in the Kolbe coupling reaction being largely or completely suppressed. Thus although normal coupling occurs with alkyl hydrogen malonates (Brown and Walker, ibid., 1891, 261, 107; Hickling and Westwood, /., 1938, 1039) and, to a smaller extent, with [alpha]-phenyl- (Fichter and Stenzl, Helv. Chim. Ada, 1939, 22, 970) and [alpha]-aryloxy-acetic acids (idem, loc. cit.; Fichter and Kesten-holz, ibid., 1942, 25, 785), and a few [alpha]-alkyl-acids, little or no coupling has been reported for [alpha]-aklyl acids, for [alpha]-methoxy-, [alpha]-hydroxy-, [alpha]-halogen-, a-keto, a-cyano-, and [alpha]-amino- acids most (for a review see Brockman, " Electro-Organ c Chemistry," New York, 1926) or for di-or tri-phenylacetic acid (van der Hoek and Nauta, Rec. Trav. Mm., 1942, 61, 845; Riccoboni, Gazzetta, 1940, 70, 748). However as the experimental conditions employed in much of the early work in this field cannot now be regarded as the most suitable for coupling, further study seemed desirable. Moreover an investigation of the competing reactions might well reveal new and valuable synthetic processes. With these considerations in mind an exploratory investigation of the electrolysis of a number of substituted acids has been put in hand. The results with N-acylamino-acids are reported in the present communication. Fichter and Schmidt (Helv. Chim. Acta, 1920, 3, 704) demonstrated that electrolysis, in aqueous solutions, of [alpha]-amino-acids or their N-acyl or N-sulphonyl derivatives led to complete disruption of the molecule and not to coupling of the Kolbe type. In the application of the Kolbe reaction to fatty acids the use of methanolic either than aqueous solutions has frequently been found advantageous, and the present work hits been confined to non-aqueous solutions. These have yielded results quite different from those reported by Fichter. Electrolysis of N-benzoylglycine in methanol furnished in good yield (61%) a neutral product which, on the basis of the analytical results and the formation of bisbenzamidomethane (II) and formaldehyde on treatment with mineral acid, is formulated as N-methoxymethyl-benzamide (I; R = Ph). This structure was confirmed by treatment of N-hydroxymethyl-benzamide with methanolic hydrogen chloride (cf. UiS.P. 2,364,737; B.P. 557,932), which gave in 30% yield a product identical with that prepared anodically. (I) R-CO-NH-CH2-CO2H --> R-CO-NH-CH2OMe (III) R-CO-NH-CHMe-CO2H --> R-CONH-CHMe-OMe (II) (Ph-CO-NH)2CH2 Anodic methoxylation also took place readily with N-acetyl- and N-carbobenzyloxygylcine, giving N-methoxymethylacetamide (I; R = Me) and -benzylurethane (I; R = PhCH2O) in 78 and 74% yield respectively. Similarly N-acetyl- and N-benzoyl-DL-[alpha]-alanine gave the N-l'-methoxyethyl- amides (III; R = Me and Ph) in 85 and 91% yield respectively. The use of solvents other than methanol was also briefly investigated, and by electrolysis of N-benzoylglycine in ethanol and isopropanol, and of N- benzoyl-DL-[alpha]-alanine in ethanol, the corresponding ethoxy- and isoopropoxy-alkylamides were obtained (56—70%). [Page 2855] These reactions can be generalised as follows : X-NH-CHR-CO2H + R'-OH ——> X-NH-CHR-OR' + CO2 where X is acyl, R hydrogen or methyl, and R' alkyl. The alkoxyalkyl-amides (acylaminoethers) so produced are of a rare type hard to prepare in other ways. The yields are high aid the products easily obtained as crystalline solids or colourless distillable liquids. Electrolysis of N-phenylacetylglycine in acetic acid solution yielded N- (acetoxymethyl) phenylacetamide (IV) (38%), previously prepared by the action of lead tetra-acetate on phenylacetylglycine (Sus, Annvlen, 1949, 564, 137). From a few of the electrolyses in alcohols described above, small amounts (<15%) [alpha]-diamine derivatives, the products of normal coupling, were also isolated. Ph-CH2-CONH-CH2-OAc (IV) Ph-CO-NH-CH2-N(CO)2(C6H4) (V) When N-methoxymethylbenzamide (I; R = Ph) and the corresponding ethoxy- and isopropoxy-compounds were heated with phthalimide, N-phthalimidomethylbenzamide was obtained. A number of the other l-alkoxyalkyl derivatives described above were also shown to react similarly with phthalimide and were conveniently characterised in this way. The only previous well-authenticated example of anodic alkoxylation was reported by van der Hoek and Nauta (loc. cit.) who isolated methoxydiphenylmethane (36% yield) from the products formed by electrolysis of diphenylacetic acid in a mixture of methanol and pyridine. Anodic alkoxylations, in general, are reminiscent of the formation of alcohols on electrolysis of fatty acids in aqueous solution (Hofer and Moest, Annalen, 1902, 828, 284). The Hofer-Moest reaction is promoted by various inorganic anions and can involve attack at positions both [alpha] and [beta] to the eliminated carboxyl group (Kruis and Schanzer, Z. physikal. Chem., 1942, 191, A, 301). In the present work, however, no evidence was obtained of [beta]-attack on derivatives of DL-[alpha]-alanine. Several plausible mechanisms could be put forward to account for these anodic alkoxylations is but it is not proposed to speculate on these at present. Experiments designed to provide information on this aspect are in hand. It is hoped to determine also the structural features which favour alkoxylation and related reactions. After the study of derivatives of [alpha]-amino-acids, attention was directed to acids with the amino- and carboxyl groups separated from one another. Fichter and Schmidt (loc. cit.) were unable to detect the normal Kolbe reaction on electrolysis of [beta]-alanine or its N-benzo rl derivative in aqueous solution, but, more recently, Ofie (Z. Naturforsch, 1947, 2b, 182, 18 5) has stated that electrolysis in methanol of N-acyl or N-alkylsulphonyl derivatives of amino-acids other than those of the [alpha]-series leads to the corresponding derivatives of diamines by normal coupling. This conclusion was based on the results of electrolysing [gamma]-phthalimido- butyric acid and derivatives of 6- aminohexanoic acid but yields were given in one case only. We find that normal Kolbe coupling occurs in the electrolysis in methanol of a considerable range of acylamino-acids other than those of the [alpha]-series. The reaction X-NH[CH2]n-CO2H ——> X-NH-[CH2]2n-NHX proceeds in about 30% yield where n is 2, 4, or 6. Thus 6-acetamido-, 6-benzamido-, and 6-carbobenzyloxyamino-hexanoic acids yielded the corresponding derivatives of 1 : 10-diamino-decane (31, 23, and 38% respectively). 1 :6-Bis- carbobenzyloxyaminohexane was similarly prepared (35%) from [gamma]-carbobenzyl- oxyaminobutyric acid. Electrolysis of N-benzoyl- and N-carbobenzyloxy-[beta]- alanine furnished the derivatives of 1 : 4-diaminobutane in 20 and 33 % yield. From N-benzoyl-[beta]-alanine a small amount of 2-phenyloxazoline was isolated (in the form of its picrate) as by-product. In general, however, the nature of the side products these reactions remains to be determined. EXPERIMENTAL. ... [truncated for brevity] ============================================================