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. ...
...

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 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..."
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 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

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 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

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 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)

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 (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]
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