4577
Conformational Influence of Nonacyl Groups on Acyl Group Properties in N-Monosubstituted Amides and in Other Carboxylic Acid Derivatives: a 7-Position Proximity Effect John P. Idoux,* James M. Scandrett, and James A. Sikorski Contribution from the Department of Chemistry, Florida Technological University. Orlando, Florida 32816. Received September 9, 1976
Abstract: NMR substituent chemical shifts (SCS) for the acyl methyl protons of 32 N-monosubstituted acetamides, CH3CONHR’, have been measured in CC14. The variation in SCS can be accounted for by steric effects from the R’ group, but not in terms of only the steric substituent constant ESC.That is, groups in the 7 position of R’ (from t h e carbonyl oxygen as position 1) exert an influence not accounted for by EsC.Reevaluation of reaction and nonreaction properties of carboxylic acid derivatives demonstrates that a 7-position proximity effect of general significance operates from the nonacyl on the acyl portion of these molecules and is thus a factor of importance in considering properties associated with the acyl portion. Data demonstrating the interinfluence of proximate groups in some selected noncarboxylic acid systems suggest that a 7-position proximity effect may be operating in those systems as well.
Studies of substituent proximity and steric effects and their influence on molecular properties have provided considerable information concerning the various contributory factors of substituents and many of these studies have produced quantitative relationships which account for the influence of these f a c t 0 1 - s . ~I n~ ~the case of carboxylic acids and esters, Newman4 has demonstrated that the 6-number of a substituent (i.e., the number of atoms in the 6 position from the carbonyl oxygen atom as atom number 1) makes a large contribution to the total steric effect of that substituent and is thus an important factor in considering the esterification of carboxylic acids and the saponification of the corresponding esters. In an attempt to refine the 6-number concept, Hancock and his coworkers5 recognized that the steric 6-number effect was already included in the overall or total corrected6 steric substituent constant EsCfor a particular substituent when in the acyl portion of an ester (R of RC02R’); but was not necessarily correctly included in EsCfor the same particular substituent when placed in the alkyl portion of the ester (R’ of RC02R’). The latter observation arises because in moving a particular substituent from the acyl to the alkyl portion of an ester the 6-number may, depending upon the structure of the substituent, increase, decrease, or remain the same. In order to account for this variability, Hancock and his co-workers5 proposed and demonstrated that the change in 6-number, A6 (Le., the 6number of a substituent in the acyl portion of an ester minus the 6-number of the same substituent in the alkyl portion of the ester) provides the necessary steric 6-number correction to EsCwhen E,C is used for a substituent in the alkyl portion of an ester. Kan’ and independently Hancock and his co-workerss have shown that various 6-number effects are also of importance when considering nonreaction properties such as N M R substituent chemical shifts (SCS) of the methyl protons for acetate esters (CH$OOR’), and more recently the alkaline hydrolysis and N M R substituent chemical shifts (SCS) for thiolacetates (CH3COSR’) have been treated in a similar manner.9 For the SCS data on both the oxygen and sulfur esters, the 6-number effect of the R’group was found to be best represented in terms of the carbon 6-number (i.e., the number of carbon atoms in the 6 position). I n these same cases, the 6-number, the A6 number, and the hydrogen 6-number were apparently not important. While these results are of interest and do provide further demonstrations of the ability of remote substituents to influence properties conformationally and/or sterically, no adequate indication of the nature of these effects
for substituents in the nonacyl portion of a carboxylic acid derivative has been advanced. In particular, if the number of carbon atoms in the 6 position of the nonacyl portion of the molecule is an important factor in considering the SCS’s for the acyl methyl protons in acetates and thiolacetates, it seems reasonable to assume that atoms directly attached to the 6 position might be influential also and in fact might be the primary factor responsible for the origin of the 6-number effect. In order to investigate these points and to provide data on another important class of carboxylic acid derivatives, which, in addition, serve as a simple model peptide bond system, we have prepared an extensive series of N-monosubstituted acetamides (CH3CONHR’) and have determined the N M R SCS’s for the acyl methyl protons of these compounds. The present paper reports the results of this study, evaluates previously reported data on carboxylic acid derivatives in terms of these results, and provides an indication of the origin of 6number effects from the nonacyl portion in carboxylic acid derivatives.
Results and Discussion The chemical shifts in hertz for the acyl methyl protons of the N-monosubstituted acetamides were measured vs. Me4Si a t 37 OC in a 10% CC14 solution. These data are reported in Table 1 as substituent chemical shifts (SCS) where SCS = chemical shift of the acyl methyl protons of CH3CONHR’ minus the chemical shift of the acyl methyl protons of CH3CONHCH3. A positive S C S then represents a downfield shift from the acyl methyl protons of CH3CONHCH3, while a negative SCS indicates an upfield shift. Also reported in Table I are a number of substituent parameters for the R’ group of CH3CONHR’. Inspection of these data indicates that the various upfield and downfield SCS’s are not simple functions of just polar effects (as represented by u*) or steric effects (as represented by EhC)or steric “correction site” parameters (as represented by 6-no., A6, C-6no., or H-7no.). That is, for several of the isomeric alkyl group sets (no. 5-8; 9-14; 15-20; 21-24; 25-26) and for the polar group set (no. 27-32), the SCS’s present an apparent scatter in order and magnitude. In an attempt to quantify these qualitative assessments and to understand the SCS’s for these amides in terms of the variations in structure, we have followed the lead of previous investigators who have studied carboxylic acid derivatives and have subjected some of these SCS data to correlation a n a l y ~ i svia ~ ~the ] ~extended
Idoux, Scandrett, Sikorski
/
Influence of Nonacyl Groups on Acyl Group Properties
4578 Table 1. Substituent Chemical Shifts (SCS) and Substituent Constants for 32 N-Monosubstituted Acetamides, CH3CONHR’ No.
R’ in CH3CONHR’
1
Me Et n-Pr i-Pr n-Bu i-Bu
2 3 4 5 6 7 8 9 IO 11
12 13 14 15 16 17 18 19 20 2 22 23 24 25 26 21 28 29 30 31 32
SCS, Hz’
S-BU t-Bu n-BuCH2 i-BuCHz s-BuCH~ t-BuCHz i-PrCHMe Et( Me)zC 1- Bu(C H 2 ) 2 t-BuCHMe i-Pr(Me)zC s-BuCHMe i-BuCHMe (Et)zMeC (i-Pr)zCH t-Bu(Me)zC s-BuCHZCHMe i-BuCHzCHMe (n-Bu)(Et)CHCHr t-BuCH2(Me)ZC (Me)zNCHzCHz MeOCHzCH2 ClCHzCH2 HlC=CHCHz HSCHzCH2 EtO(CHd3
E,Cc
6-n0.~
A d
C-6no.g
H-7n0.~
0 -0.38 -0.67 - 1.08 -0.70 - 1.24 - 1.74 -2.46 -0.71 -0.66
0 3 3 6 3 3 6 9 3 3 3 3 6 9 3 6 9 6 6 9 6 9 6 6 3 9 3 3 3 2 3 3
0 -3 0 -6 0 3 -3 -9 0 0 3 6 0 -6 0 3 -3 0 -3 -3 6 0 -3 -3 3 -6 -1 -2 -3 0
0 0 1
0 0 3 0 2 6 3 0 2
a*
0 -1.3 -1.5 -2.1 -1.3 -0.2 -1.6 -4.1 -1.3 -1.3 0.2 1.7 1.9 -3.7 -1.7 0.7 -4.8 0.5 -1.5 -4.7 -0.1 -4.3 -1.1 -1.6 -0.6 -6.1 -1.8 -1.3 -0.8 -0.1 1.5 -1.9
0
-0.100 -0.1 1 5 -0.190 -0.125 -0.130 -0.210 -0.300 -0.13 -0.13 -0.143 -0.165 -0.230 -0.3 15
-2.05 -0.6Sd
-0.265 -0.330 -0.243 -0.230 -0.330 -0.260 -0.365 -4.82 -0.229 -0.227 -0.150 -0.334 -3.49d 0.079 0.238 0.385 (0.12-0.20) 0.169
-2 0
0 I 2 1
0 I 1
2 3 2 1 1
3 2 2 1 2 4 3 1
1 2 1
1 5 9 6 3 0 9 6 5 1 6 12 9 1 2
4 0
0 0 0 1 0 1
2 1 0
SCS = chemical shift of the acyl methyl protons of CH3CONHR’ in 10% CC14 minus the chemical shift of the acyl methyl protons of CH3CONHCH3 in 10% CC14. Chemical shift of the acyl methyl protons of CH3CONHCH3 (10% CC14) vs. Me4Si is 115.8 Hz. From ref 2 or from P. R. Wells, “Linear Free Energy Relationships”, Academic Press, New York, N.Y., 1968, Chapter 2, or calculated by Taft’s additivity principle (see ref 2 and/or ref in footnote d , Table I, p 369). See ref 2 and 6. E , from 0.A. Reutov, “Fundamentals of Theoretical Organic Chemistry”, Appleton-Century-Crofts, New York, N.Y., 1967, p 371. ESCcalculated as described in ref 6. 9 e e ref 4. /See ref 5 . g Number of carbon atoms in the 6 position. Number of hydrogen atoms in the 7 position.
Taft equation. The resulting equations, eq 1-4, represent correlations for 14 of the amides in Table I (1 -10, 12, 15,22, 26) for which both polar2 (u*) and steric6 (EsC)substituent constants were available. In each of these equations the additional parameter is a 6-number steric “correction site” constant, R 2 is the square of the correlation coefficient1Ia expressed as a percentage (provides an indication of percent variation in SCS accounted for by the particular relationship) and sIla is the standard deviation from regression. The numbers in parentheses below the various parameters are the significance levels as determined by “Student’s” t test.’Ib This statistic, recommended earlier by other chemists,I2.l3has recently been suggestedI4 as an appropriate goodness of fit criterion for expressing the confidence with which a regression coefficient is known. We endorse these recommendations and have used this statistic here for comparing the significance of the parameter combinations in the various correlation equations.‘
SCS = 0.94 - 4.10u* - 0.24EsC+ 0.83 (6-no.), (>0.500) (0.500) (0.14) R 2 = 74.6%,s = 1.18 SCS = -0.20
(0.016) (0,001) R 2 = 84.3%, s = 0.91
Journal of the American Chemical Society
+
-
SCS = -0.14
2.66u* 0.36ESC- 0.58 (H-6no.L (>0.500) (0.500). (0.025) R 2 = 80.8%, s = 1.02 (3)
+ 9.370* + 0.85E,’ + 1.23(C-6no.), (0.260)
(0.230) (0.006) R 2 = 85.4%, s = 0.89
(1)
(2)
(4)
For example, in eq 1-4, the t test indicates that the least significant variable is u*. Rejecting this variable, eq 5-8 are obtained. SCS = 0.91 - 0.38ESC- 0.74(6-no.), (0.400) (0.003) R 2 = 73.4%, s = 1.09 ( 5 ) SCS = -0.25 0.77ESC 0.32(A6), (0.002) (
