Weygand/Hilgetag Preparative Organic Chemistry

Replacement of oxygen by nitrogen 481
oration of the ether leaves the crude anilide as residue. If the anilide is sparingly soluble
in ether it suffices merely to wash out the aniline formed by means of ether. Yields are around
90%.
This procedure affords iV-phenylsuccinimide from succinic acid.
Water can also be removed from ammonium salts by heating them in highboiling
inert solvents, the water being continuously removed as azeotrope.
Nitrobenzene and xylene have been used for this purpose. Formylations occur
relatively readily and for formylation of, e.g., iV-methylaniline it suffices to
use boiling toluene. 691
There have, of course, been many attempts to moderate the reaction conditions
by various additions and to make the process usable for more sensitive
substances. For instance, adding small amounts of concentrated sulfuric
acid have been recommended for acylation of aromatic amines, or similarly
addition of aluminum chloride. Phosphoric oxide has sometimes been added
to bind the water formed. In other cases it proved valuable to add the anhydride
of the acid in question, but its action is not limited to binding the water because,
being a stronger acylating agent than the acid, it must itself perform much of
the acylation of the ammonia.
iV-Propylacetamide : 692 Acetic acid (30 g) is added slowly to propylamine (25g) in a 250-ml flask
fitted with a reflux condenser; reaction is violent. Acetic anhydride (50 ml) is next added and
the mixture is heated under reflux for 0.5 h, after which the acetic acid is distilled off through
a column. When this has been achieved (70 ml of distillate), distillation is continued without
a column, giving a small forerun and then A^-propylacetamide (34-35 g, about 90%), b.p.
208°/760 mm, 100°/16 mm.
In many cases the catalysts added have, however, a more deep-seated effect:
they form very reactive intermediates with either the acid or the amine —
intermediates that can often be isolated.
For instance, the reaction of amines with carboxylic acids occurs under
appreciably milder conditions if phosphorus trichloride is added; the reaction
does not proceed by way of the intermediate acid chloride, as previously assumed,
but the amine and phosphorus trichloride first form a "phosphorazo compound"
(phosphoramidic imide) which in turn reacts with the carboxylic acid
to give the amide: 693
5RNH2 + PC13 > RN=P—NHR + 3RNH3C1
RN=P—NHR + 2RCOOH > 2RCONHR + [HPO2]
The two steps can be realized separately, 693 * 694 but it is customary to work
without isolating the phosphorazo compound. Recently the method has been
much used for synthesis of peptides from amino esters and iV-protected amino
acids. 694 " 698 Benzene, dioxan, and pyridine are among the solvents used.
The technique will be evident from an example:
691 L. F. Fieser and J. E. Jones, Org. Syn., Coll. Vol. Ill, 590 (1955).
692 K. Heyns and W. von Bebenburg, Chem. Ber., 86, 278 (1953).
693 H. W. Grimmel, A. Guenther, and J. F. Morgan, /. Amer. Chem. Soc, 68,539 (1946).
694 S. Goldschmidt and H. Lautenschlager, Ann. Chem., 580, 68 (1953).
695 S. Goldschmidt and C. Jutz, Chem. Ber., 86, 1116 (1953); 89, 518 (1956); S. Goldschmidt
and G. Rosculet, Chem. Ber., 93, 2387 (1960).
696 O. Siis, Ann. Chem., 572, 96 (1951).
697 W. Grassmann and E. Wunsch, Chem. Ber., 91, 449 (1958).
698 W. Grassmann, E. Wunsch, and A. Riedel, Chem. Ber., 91, 455 (1958).