1844
Journal of the American Chemical Society
/
100.6
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March 15.1978
Kinetics and Mechanism of Amide Acetal Hydrolysis. Carbon-Oxygen vs. Carbon-Nitrogen Bond Cleavage in Acid Solutions Robert A. McClelland Department of Chemistry, University of Toronto, Scarborough College, West Hill, Ontario, Canada MI C 1 A4. Received May 31, 1977 Abstract: Amide acetals ArC(0Me)zNMez competitively cleave the carbon-oxygen bond and carbon-nitrogen bond in acid
solutions. The latter is favored for species with electron-donating substituents in Ar, and is also more favored in D20 solutions. In neutral and basic solutions only C - 0 cleavage is observed. The relative amount of this cleavage also increases with increasing concentrations of added buffers. Kinetic studies are also reported, and a mechanistic scheme is proposed in which the Nprotonated amide acetal is responsible for C-N cleavage, with the neutral substrate accounting for C-O cleavage. This latter process occurs in a noncatalyzed (or water catalyzed) reaction and in a hydronium ion catalyzed reaction and is also catalyzed by the acid component of added buffers. The general question of the acid partitioning in species of this general type is considered, in terms of whether basicity or cation stability is the dominant factor. This depends apparently on the degree to which other groups present can stabilize an adjacent cationic center, and how this affects the position of the transition states. The failure to observe significant C-0 cleavage in tetrahedral intermediates related to the amide acetals is attributed to additional stability associated with the 0 - H group, although other factors such as zwitterion formation or electron-pair orientation may also be involved. It is suggested that acidic partioning of carbinolamines and related species also falls into the general pattern. Species of the type I are the postulated intermediates of several important acyl transfer, or related, reactions. N u OH '
OR
1
0
R -C-N
I
t
OH (R)
C-NN/ I "R' OR
I
I1
I
R-
'
R
would result in a dialkoxycarbonium ion and an amine; the ion is not stable in aqueous solution,27but is instantly hydrolyzed to ester and alcohol. Carbon-oxygen fission would produce an alcohol and imidatonium ion; in nonbasic media, this ion is reasonably stable,28 particularly when R = aryl. In consequence it is possible to distinguish the primary dissociations in neutral and acidic solutions, either on the basis of the
merous examples are now available which suggest that when formed in acidic solutions these species break up with cleavage of the carbon nitrogen bond considerably favored over cleavage of a carbon oxygen bond. This conclusion is reached, for example, in considering the nature of the rate-determining step in ester ammonolysis,1~2the nature of the products obtained on imidate ester h y d r o l y s i ~ , ~or- ~the failure to observe significant l80exchange with amides concurrent with their acid h y d r ~ l y s i s . ~(In - ~the ~ last case, this observation can be used I R as evidence that I is not involved in the r e a ~ t i o n , ~ ~ ' a~ ~ ' ~ - ' ~ claim disputed by recent e ~ i d e n c e . ~ Predominance ~ ~ ' ~ ~ ~ ~ ) of ester:imidatonium ion ratio or on the basis of the amine:imC - 0 cleavage has been observed in certain systems, but these idatonium ion ratio. have all involved molecules with a phenyl or acyl group subResults obtained in 0.1 molar acid solutions are given in stituted on oxygen or n i t r ~ g e n . ' ~ - ~ * Table I, and show that the situation is not as expected,29since The favoring of amine loss is normally attributed to the great both types of cleavage are observed. Three general trends can basicity of the nitrogen as compared to oxygen. Basicity, be discerned in the data. In the series ArC(OMe)2NMe2, C-0 however, is not the sole factor which determines the direction cleavage increases with increasing electron withdrawal of the of tetrahedral intermediate b r e a k ~ p . For ~ ~ example, ,~~ phenyl substituent. On addition of increasing amounts of dimeacetate, when compared with alkyl esters, displays considerably thoxyethane (DME), C - 0 bond cleavage increases. On less carbonyl-180 exchange relative to hydrolysis in acid.24The changing from H20 to D 2 0 , C-0 cleavage decreases. tetrahedral intermediate in this system must lose phenol The pH dependence is shown in Figure 1. In acid solution preferentially over water, and yet this involves the less basic the product ratio remains constant up to a pH of -3. At this site. point the amount of C-0 cleavage increases, until by pH 7 As a further illustration of the complexity of these systems imidatonium ion is essentially the only product. In carrying out we report here that amide acetals (11),25 species which can be this study, it became apparent that the product ratio is also considered as models for I,26 competitively cleave in both diinfluenced'by the added carboxylic acid buffers employed. The rections in acid. An analysis of the factors affecting this results for acetic acid buffers are summarized in Figure 2, and competition is further reported, including a description of the show the general trend of an increasing amount of imidatonium catalytic requirements of the two modes of cleavage. This leads ion with increasing buffer concentration. Table Sl 30 summato a fuller understanding of the interplay of the various factors rizes product data employed in constructing Figures 1 and which influence the partitioning in I and I1 and indeed in 2. species of this general type where a choice between nitrogen In basic solution amide acetals still rapidly hydrolyze but or oxygen loss exists. neither ion is stable. The evidence is consistent however with the trend observed in the product-pH profile continuing, that Results is, complete C - 0 bond cleavage. For example, HC(OMe)2Products. The question of concern is which bond does cleave ~' NMe2 produces in base essentially 100% H C O N M ~ L that initially in amide acetal hydrolysis. Carbon-nitrogen fission is, with the C - N bond still intact. The benzamide acetals SI
0002-7863/78/1500-l844$01.00/0 0 1978 American Chemical Society
McClelland
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1845
Kinetics of Amide Acetal Hydrolysis 80,
I
1
I
1
I
,
Figure 1. lmidatonium ion product in the hydrolysis of 4-MeC6H4C(OMe)2NMez as a function of pH. Points above pH 2.5 were obtained in buffer solutions, and represent extrapolations to zero buffer concentration.The curve is based on the best fit of eq 2 to the experimental data, with k O K s H + / k N = 1.2 X IO-', k H -k K S H + / k N = 0.36. 0
Table I. Primary Cleavage in RC(OMe)2NMe2 Hydrolysis in 0.1 N HCI (DCI) Solutions % imidatonium
Solvent
4-MeCiH4
H2O H20 H20 D20 H20 H20 H2 0 H20 D2O 80% H20,20% DMEd 60% H20,40% DME 40% H?O. 60% DME 25% H;O, 75% DME
ion
(C-0 cleavage) >95b 946
0.2
0.I
[CH,COOH] + [CH, COO-]
Figure 2. lmidatonium ion product in the hydrolysis of 4-MeC6H4C(OMe)2NMe2 as a function of buffer concentration. The points are experimental; the curves are based on eq 2. 1
+I
80,b 84C 50,b 47c 65 41,b 4OC
I
ArC(OMe);! NMe,
I
KINETICS
4-NO2CsH4
-
30%
OME
15b
23,b 2 l C 9' 40C
C6Hs
60 80C
90C
C - 0 cleavage is also observed with HC(OEt)>NMez and HC(O-i-Pr)zNMez. By NMR. By UV. Dimethoxyethane.
-3
c I
-4
L
-
7 5 % DME
4-NOzCsH4 -75%
1 10
1
4
7
DME
l 13
PH
produce esters with only small traces of amide. This, however, is also the result of hydrolyzing imidatonium ion28932under the same conditions. Kinetics. T h e amide acetals prove, in general, to be extremely labile, with a half-life of kN, but this is not always true (Table I). The plateau region in acid arises when the substrate becomes fully protonated. This plateau will occur regardless of the nature of the reaction in acid. In the case of C - 0 bond cleavage in strong acid, the reaction is kinetically [ H + ] independent since the substrate must be deprotonated first. The rate data of Figure 3 have been fitted to the first term of eq 2 and furnish values of ko, KsH+, and kH+ which are given in Table 11. These constants behave much as expected, for example, in their substituent and solvent dependency. This
+
1 March 15, 1978
Table 11. Specific Rate Constants and Dissociation Constants for ArC(0Me)zNMez in Dimethoxyethane-Water
Ar 4-NOzCsHd 4-NO2C6H4 C6H5
Solvent 30% DME 75% DME 75%DME
n
75ohDME
ko, s-'
0.13 0.00038 0.0057 -1.5
k ~ +M-' , s-' 1.2 x 104 5.0 X lo2 5.2 X lo3
-1.3
PKSH+ 4.0
2.3 3.3 +1.3
table makes amide acetals out to be quite weak as nitrogen bases. This is somewhat misleading however, being due to the substituent and solvent requirements necessary to obtain the kinetic data. Interestingly, extrapolation of these data to water suggests that a p K s ~ of + 5-6 applies for nitrogen protonation of species such as PhC(OR)2NR2'. This is very much in the range estimated by GuthrieZ6on the basis of structural considerations. It can be commented here that in its C - 0 cleavage reaction the amide acetals display similar catalytic behavior to that shown by certain ketals and ortho esters where highly stabilized oxycarbonium ions are p r o d ~ c e d . These ~ ~ , ~are ~ also characterized by a general acid catalyzed hydrolysis and also often have a significant neutral hydrolysis rate. In such a comparison, the amide acetals must be considered to produce a considerably more stabilized cationic species, so stable in fact that the neutral hydrolysis has a half-life of
