Charles D. Hurd Northwestern University Evanston, Minois 60201
Acid Anhydride Functionality
The term "acid anhydride" must have been conceived originally to represent a compound formally derived from an acid or acids by removal of the elements of water. This concept serves well for the simple carboxylic anhydrides, all of which contain the grouping kG-0-C=O
I
I
but it leads to two comments. (1) Not all organic acids are carboxylic acids, hence not all acid anhydrides would be expected to contain the above grouping; the one from an imidic acid, RC(=NR)-OH, would contain imino rather than 0x0 groups: RN4-0-C=NR
I I (2) Atoms other than oxygen may hold the proton of an organic acid. An example is a thiolic acid, R-COSH. Paralleling the change of RCOOH into (RCO)%O would require change of the thiolic acid into (RCO),S, but this change would require loss of H a rather than H20. The diacyl sulfide does behave typically in the manner of acid anhvdrides and reacts vigorouslv with nucleophiiic reagents. Water, for example, gives rise to RCOSH RCOOH. The structure ( R C 0 ) S cannot be named as a "thiolic anhydride," but if one is broad-minded it may be classified as an acid anhvdride. Indeed, one need not even "be broad-minded decause the compound may he regarded as a formal dehydration product of the two acids RCOSH and RCOOH. From this point of view ( R C 0 ) S becomes an unsymmetrical acid anhydride even though it is a symmetrical acyl sulfide. A specific structure (C5H&O)zS, might therefore be named hexanethiolic hexanoic anhydride although it has never, to my knowledge, been so named till now. In the following presentation, attention will he directed to several different structural 'types each of which may be regarded broadly as possessing acid anhydride functionality, even though most of them are named on a different basis. To keep the presentation within bounds, the discussion will omit reference to anhydrides of inorganic acids and will confine itself to those acid anhydrides wherein the central atom is attached to carbons. As mentioned above, the general anhydride grouping is too limited but if we replaced oxygen by E, an electron-rich element, this generalized structure results:
+
Ek=CeC=E
I
I Ordinarily, E represents 0, S, or N, but in some compounds it may represent C. 454
/
Journol of Chemical Education
In these structures there is polarization to a greater or lesser extent,
>
which tends to make the two C=E groupings diier even in symmetrical structures. For example, infrared spectra of simple carboxylic anhydrides (RCO)*O, show not one but two carbonyl absorption bands, 5.5 and 5 . 7 ~ . It is significant that the 5.5 value approximates the carhonyl reading in spectra of acyl chlorides, RCOCl. Another example showing difference in the two %E groupings is that to only one of them is I imparted the carbonium character that makes for reactivity with a nucleophilic reagent such as ammonia, aniline, water, or an alcohol. Evidence supporting generalized acid anhydride classification will now he presented for structures wherein at least one of the three E's is carbon or nitrogen. Carboxvlates of Phenols and Enols
These compounds characteristically contain the grouping
Phenyl acetate is a simple example,
Many chemists refer to it as an ester, which is understandable since the name follows ester terminology and since there is no suitable acid anhydride terminology that would be distinctive. Classification as an ester is unjustifiable, however, since an ester is supposed to yield an acid and an alcohol on hydrolysis. Phenyl acetate, instead, gives rise to two acids, namely, acetic acid and phenol. Phenols, although recognized as acids, usually are not named as acids. 2,4-Dinitrophenol, which would result on hydrolysis of 2,4dinitrophenyl acetate, is an even stronger acid than acetic acid. Using this classification as acid anhydrides, one has no trouble in correlating the structure of aryl acetates with their facile hydrolysis and their reactivity toward alcohols and amines. The last, for example, has been developed into an effective synthesis of peptides (1)
using m-riitrophenyl phthalimidoacetate as the aryl carboxylate and an amino ester as the amine:
with ethylamine, for example, yields RCH-CO-liHCIHj
I
NH-COCH,
and reaction with an amino ester (as SH2CH,COOEt) leads to synthesis of a peptide, RCH-CO-NHCH?COOEt
I
NH-COCHa
Adducts of Carboxylic Acids to Ketenimines and Carbodiimides
These adduck also contain the p-Nitrophenyl acetate and 2,4dinitrophenyl acetate have recently been found to be good titrants (2) for the enzyme a-chymotrypsin, and other p-nitrophenyl carboxylates were effective titrants for trypsin, papain, and acetylcholinesterase. Enols resemble phenols in being acidic, hence an en01 acetate is also an acid anhydride. 1-Methylvinyl acetate is illustrative. It is synthesized by mercury(11)-catalyzed addition of acetic acid to propyne (3) or bv acid-catalvzed addition of acetone to ketene (4). ... It is an excellent acetylating agent (5) and works with a vigor that resembles acetic anhydride:
+ RCHIOH
CHs=C-0-CO-CHJ
-
+
RCH?O-CO-CHI
CHJ lCH&CO (from CH-C-OH)
I
CHa
As evideuee of its strength, 1-methylvinyl acetate is capable of converting a carboxvlic acid to an acid anhydride: CHz=C(CH~)-0-COCHs
+ RCOOH
-
CHsCOCHs
+
RCO-0-COCH,
The tautomerization of 1-propen-2-01 into acetone that, occurs during such reactions cannot be a large contributor to the driving force since aryl acetates, with no such tautomerization, also are effective acylating agents.
-N=C-O-C=O
I
I
grouplog hut they differ from azlartorlen irr being acyclic. A ketenimine may be prepared conveniently from an amide by changing it to an imidyl chloride with !'CIS, and then dehydrohalogenating the latter with triethylamine (7) Ph?CH-CO-NHBr
-
PhlCH-CCI=N.4r
-
Ph*C=C=P;At
Just as carboxylic acids are changed into acid anhydrides by addition to ketene (8)or isocyanates (9) RCOOH
+ CH,=C=O
RCOOH
+ ArN=C=O
-
RCO-0-COCHx RCO-0-CONHAr
so they add to keteriirni~iesin benzene solution t,o yield related arid anhydrides (10) : RCOOH
+ PhnC=C=NAr
-
RCO-0-C=NAI. CHPh,
Such an adduct, iu reaction with ethylamine, would vield two amides, RCONHEt and Ph2CHCONHAr. i t s high reactivity as an acid anhydride is witnessed by its reaction, if undiluted, with glacial acetic acid to yield acetic anhydride:
Azlactones
+ O=C-XHAr
These compounds (6) result from the irrt.eract,ion of a-amino acids with acet,icanhydride: ItCHCOONa
I
NH~
--
-
no20 KCH-COOH
lo0 RCH-CO,
I I NH-COCH$(-H.OI W=C
OK-.
/
Reaction
Imide 11, although less reactive than I, still has the st,ructure of a generalized acid arihydridc O=C-N-C=O I
l
l
and is reactive toward amines and alcohols; but it does fail to react mith glacial acetic acid (see section on Volume
44, Number 8, August 1967
/
455
imides). It should be noted that when an acid anhydride rearranges to another generalized acid anhydride, the latter is of less energy content than the former. An interesting peptide synthesis has been developed (lo), based on the above reactions. Here, the acid RCOOH used for intial addition to the ketenimine is a protected a-amino acid (as PhCH,OCONHCOOH) . To the adduct, presumably a mixture of both I and 11, is added an a-amino ester (as btyrosine methyl ester). The resultant products are the amide PhzCHCONHAr and the dipeptide derivative
/CO\
+
N-CH-COOH
CJI,,N=C=NCaH,t+
HCOH I
Carbodiimides are usually made by elimination of the elements of H 8 from thioureas Anhydride Intermediates during the Passerini Reaction
such elimination being effected (18) by freshly-precipitated, yellow mercuric oxide, sodium hypochlorite, or sodium chlorite. Carboxylic acids add to them readily, yielding acid anhydrides not unlike those from ketenimines: R'COOH
-
+ RN==C=NR
R'CO-0-C=NR
In this reaction an isocyanide, a carboxylic acid, and an aldehyde or ketone are brought together. The electron-deficient carbon of the isocyanide triggers the reaction by attracting the carboxylic anion. This creates a carbanion which attacks the aldehyde carbonyl:
NHR
Sheehan and Hess (IS), using an amido acid, acylNH-CHR"-COOH, for R'COOH, developed an important peptide synthesis that is based on a reaction of the adduct with an a-amino ester:
Because of the insolubility of dicyclohexylurea, the preferred R group in the carbodiimide was cyclohexyl. Just as with azlactones, the attacking amine always goes to the 0x0 position and avoids the imino position. Mechanistically, these st,epsare indicated, using methylamine:
I
-C=O
+
RNH-CO-NHR
The anhydrides obtained from carbodiimides are more stable than those from ketenimines, but here also the same two concurrent reactions have been observed: (a) further reaction (14) of the original R'COOH with the acid anhydride to produce (R'CO)20 and the urea and (b) rearrangement of the acid anhydride to the imide, here an acylurea, if dioxane or tetrahydrofuran (15) were used as solvents (rather than metbylene chloride or acetonitrile) 456 / Journal of Chemical Education
RN=C:
c
~ ~ RN=C-0-C=O , QH + I R'CH=Ou R'CH-OH
e
x -'
O
~
~
I
Substance I11 is not the final product as should be obvious, since its structure contains an alcoholic hydroxyl group and a generalized acid anhydride function. These two functions react intramolecularly to produce the est,er-amide I V which is t,he product of t,he reaction. RNH-CO
Ugi (16) has ~ummarizedwork in this field. The above considerations make i t logical to inquire if an aldimine might not be used in place of the aldehyde, thereby leading to amides instead of esters. This has indeed been achieved, again starting with an isocyanide and an aldehyde, but changing the carboxylic acid to its ammonium (or alkyla.mmoninm) salt,. The st,eps are 2,sfollows: NH.'
-
R'CHO - R'~H-OH
R'CH
/ \
+ NHa
- Ha0
-
R'CH /
R'EH-NH.
,- ....- .
(9) NXGELI, C., A N D TYABJI,A,, Helu. Chim. Acta, 17, 934 (1934); 18, 142 (1935). C. L., AND MnNK, M. E., J . Am. Chem. Soe., 80, ( I W R~EVENS, 4065, 4069 (1958). H.. Her.. 48. 3XR i l l ) MIIMM.0.. HESRE.H.. L N D VOLQCTAR,I~Z. ,
E.,\ N U CULlrhBOHIY>IIS,fler., 74, 12x5 (1941): (12) SVHMIDT, Ann., 571,83 (1951); 612,11 (1957). i1): SHEEHAN, J. C., .%NU Hesn, (i. P., J . Am. Chrvr. So?, 77, 1067 (1955). (14) (a) SMITH,M. MOFFATT,.I., A N D KHORANA, H., .I. Am. C h . Sac., 80,6206 (1958); (1)) SPHUESSLER, H., AND ZAHN,H., Chem. Ber., 95, 1066 (1962). J. C.. GOODMAN. M.. AND HESB.G. P.. J. Am. (15) SHFIEHAN.
/
. , "
\
(1) B O D ~ S Z KM., Y ,Natwe, 175,685 (1955). (2) BENDER, M. L., AND CO-WORKERS, J. Am. Chem. Soe., 88,
460
.
-
(19RQ\~ - - - ,.
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.
.
Journal o f Chemical Education
. . ,
,
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