Phenylethylamine crystallization

The purity of (/-a-phenylethylamine-/-malate is not readily determined by its melting point or specific rotation, but rather by its massive crystalline form and solubility. The acid and neutral /-base-/-acid salts are much more soluble, and usually do not crystallize at all. 

Kagan and coworkers determined and studied in detail the crystal structure of a 1 1 molecular complex between (i )-methyl p-tolyl sulfoxide (10) and S)-N-(3,5-dinitrobenzoyl)-l-phenylethylamine (11). They suggested that amide 11, which had been used as a chiral solvating agent for sulfoxides, might find use as a resolving agent for these compounds. ... 

Thus, when acid 76 was crystallized as a salt with (S)-(-)-l-phenylethylamine ([S]-PEA), the X-ray structure showed that the conformational enantiomer 76a was trapped in the crystal, displaying O - H and O - Ht distances of 2.47 A and 3.41 A, respectively. The conformation of 76a placed the carbonyl oxygen and Hj, closer to the ideal values mentioned in Figure 7.26 as compared to H. A significant preference for Hj, was demonstrated after photolysis at 0 °C and diazomethane workup, when ester 77a (B) was obtained in 65% ee after 90% conversion. Figure 7.27 illustrates the minimal atomic displacements required for reaction by comparing the X-ray structure of the reactant with that of the product, and with a structure obtained at 50% conversion. Better chemical results were obtained by photolysis of 76a with (/ )-CEA, which gave 90% ee of ester of 77a (B) after diazomethane workup. 

As mentioned above (Scheme 3), condensation of triallylborane and 3-methoxybut-l-yne led, after treatment with methanol, to 7-(l-methoxymethyl)-3-methoxy-3-borabicyclo[3.3.1]non-6-ene. Hydroboration-isomerization of the latter with a THF solution of diborane gave a THF complex of 2-methyl-1-boraadamantane 15 in 85% yield. Treatment of the latter with (S)-(—)-phenylethylamine gave a mixture of diastereomeric complexes ( ) 57 isolated as white, well-shaped crystals (Scheme 19) <2003MC121, B-2003MI97>. 

Single crystal-to-single crystal reactions are quite rare in solid-state organic photochemistry, and we were fortunate to discover a second example in the Yang photocyclization of the 1-phenylethylamine salt of 2-methyl-2-benzoyl-p-carboxylic acid 39 [37]. 

The first S3mtheses of optically active p-BL involves more step sequences, including fractional crystallization of the diastereomeric salts formed from (f ,5)-p-bromobutyiic acid and (/ )-a-phenylethylamine. Ring-closure to respective lactones was achieved by infernal Sa 2 attack of the neighboring carboxylate anion on the sam-rated carbon to yield samples of the desired stereochemistry up to an enantiomeric... 

MAO A and B differ in primary structure and in substrate specificity [5,7]. The two isozymes, located on the mitochondrial outer membranes, have 70% homology in peptide sequence and share common mechanistic details. It is now recognized that these are different proteins encoded by different genes, but probably derived from a common ancestral gene. Crystal structures for both MAO A and B complexes with inhibitors have recently been reported [8]. Serotonin is selectively oxidized by MAO A, whereas benzylamine and 2-phenylethylamine are selective substrates for MAO B. Dopamine, norepinephrine, epinephrine, trypt-amine, and tyramine are oxidized by both MAO A and B in most species [9]. In addition, MAO A is more sensitive to inhibition by clorgyline (1), whereas MAO B is inhibited by low concentrations of L-deprenyl ((f )-( )-deprenyl) (2) [5,6cj. Development of inhibitors that are selective for each isozyme has been an extremely active area of medicinal chemistry [8]. 

The presence of a polar axis confers anisotropic activity to organic crystals (Curtin Paul, 1981 Desiraju, 1984b). Common polar (noncentrosymmetric) space groups adopted by organic crystals areP2i2i2i and P2i- While chiral crystals must have polar directions, polar crystals need not be chiral. Anisotropic reactivity is seen for instance in the reaction of ammonia with p-bromobenzoic anhydride, which crystallizes with a polar axis the polar axis directs the reaction, p-bromobenzoic anhydride is chiral as well as polar. Chirality of the crystalline anhydride has been exploited to resolve a racemic gaseous amine the chiral crystal preferentially reacts with one of the enantiomers of the amine. Thus when p-bromobenzoic anhydride crystals are exposed to vapours of racemic phenylethylamine, the resulting amide contains one of the enantiomers in excess. 

A mixture of 2-naphthol 1 (0.72 g, 5.0 mmol), benzaldehyde 2a (0.64 g, 6.00 mmol), and (/ )-(+)-1-phenylethylamine (0.64 g, 5.25 mmol) was stilled at 60 °C for 8 h under nitrogen atmosphere. Following the progress of the reaction by TLC and 1H NMR, it was seen that the formation of the product occurs during the first 4 h but the initial dr of (R,R)-3n (2.6 at 2 h) increases over time (99 at 8 h) with the formation of a solid and crystalline reaction mixture. The reaction mixture was dispersed at room temperature with EtOH (5 mL). The white crystals separated were collected and washed with EtOH (3x3 mL). The crystal-... 

Sakai, K. (1999) Application of habit modification of diastereomeric salt crystals obtained from optical resolution via crystallization manufacture of enantiomerically pure 1-phenylethylamine,./. Org. Synth. Chem. Jpn, 57, 458-465. 

The ionic chiral auxiliary approach was also applied to the enantioselective photocylization of tropolone. Irradiation of salt crystals of tropolone ether carboxylic acid 29 with several chiral amines afforded the enantiomerically enriched secondary products 31 [52]. The best results were obtained with optically pure 1-phenylethylamine and l-amino-2-indanol, which gave optical yields in the 60-80% ee range depending on the extent of conversion. 

When salt crystals of the aryl 1-phenylcyclopenty 1 ketone carboxylic acid 40 with chiral amines such as (+ )-bomylamine or (—)-1-phenylethylamine were irradiated, the optically active exo- and endo-oxetanes 41 or 42 were formed in low to moderate enantiomeric excesses (Scheme 10) [57]. The formation of the oxetanes is believed to occur through Norrish type 1 cleavage and hydrogen abstraction, producing an alkene and an aldehyde, followed by a Paterno-Buchi reaction within the crystal lattice cage. In contrast, solution photolysis of 40 in acetonitrile afforded product 43 as the only isolable product via a typical Norrish type I a-cleavage followed by radical coupling. 

Highly enantioselective Norrish/Yang photocyclization of cw-4-terf-butyl-1-benzoylcyclohexane 47 was also achieved in salt crystals using chiral amines like R)- + )-l-phenylethylamine or (—)-norephedrine [61,63]. Furthermore, cis-9-decalyl aryl ketones 49 in their salt crystals with chiral amines such as (/ )-( + )-bomyl amine or ( )-( — )-1 -phenylethylamine underwent highly regio-, dia-stereo- and enantioselective Norrish/Yang photocyclizations to give the cyclobutanol 50 alone in > 98% ee [64]. 

Solid-state photolysis of salt crystals of a-mesitylacetophenone-/ -carbox-ylic acid 55 and optically pure amines such as (S)-( — )-phenylethylamine or ( R,2S)-( —)-norephedrine caused 8-hydrogen abstraction from the methyl group, and then cyclization to produce the corresponding 2-indanol derivative 56 in excellent yield and high enantiomeric excess (Scheme 12) [68]. 

Irradiation of the salt crystals of benzocyclohexadienone carboxylic acid 72 with optically pure amines caused enantioselective oxa-di-ir-methane photorearrangement to give the chiral product 73 [82]. The best results were obtained with (S)-( —)-1-phenylethylamine in around 80% ee (Scheme 16). The other amines gave optical purities of 20-50% ee. 

Figure 4.2. Crystal structure of less soluble (R)-l (R)-l-phenylethylamine. (a) Hydrogen-bond sheet viewed down the b axis. (b) Edge-on view of the hydrogen-bond sheets and their packing.

Figure 4.5. Schematic representations of the crystal structures of the less and more soluble salts of enantiopure 1 with 1-arylethylamines in success, (a) Less soluble salts, which are stable from the viewpoint of hydrogen-bonding and van der Waals interactions. (,b) More soluble (R)-l (S)-l-(m-methoxyphenyl)ethylamine, in which a stable hydrogen-bond sheet is formed while the close packing of the sheets is not achieved, (c) More soluble (R)-l (i )-l-phenylethylamine, in which a stable hydrogen-bond sheet is not formed while the close packing of the sheets is achieved.

The crystal structures of the diastereomeric salts of 1-phenylethylamine with chiral carboxylic acids are subsequently reported by other groups (Table 4.7). The comparison of the crystal structure of JAGHEE with that of JAGHII also indicates that columnar hydrogen-bond networks are formed in these crystals, respectively, and that the difference between them can be found in the relative orientation of the substituent on the chiral carbon of the carboxylate moiety in the supramolecular column. 

Z. Bocskei, C. Kassai, K. Simon, E. Fogassy, D. Kozma, Racemic compound formation-conglomerate formation. Part 3. Investigation of the acidic salts of a-phenylethylamine by achiral dicarboxylic acids. Optical resolution by preferential crystallization and a structural study of (R)-a-phenylethylammonium hydrogen itaconate, J. Chem. Soc. Perkin Trans. 2 (1996) 1511-1515. 

K. Saigo, H. Kimoto, H. Nohira, K. Yanagi, M. Hasegawa, Molecular recognition in the formation of conglomerate crystal the role of cinnamic acid in the conglomerate crystals of 1-phenylethylamine and l-(4-isopropylphenyl)ethylainine salts. Bull. Chem. Soc. Jap. 

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