13C NMR Spectra of p- and rn-Substituted Phenyl N-Methyl- and Phenyl N,N-Dimethyl- Carbamat es

Chisako Yamagami* and Narao Takao

Takaaki Nishioka and Toshio Fujita Department of Agricultural Chemistry, Kyoto University, Sakyo-ku, Kyoto, Japan 606

Yoshito Takeuchi*

Kobe Women's College of Pharmacy, Motoyamakita-machi, Higashinada-ku, Kobe, Japan 658

Department of Chemistry, College of A r t s and Sciences, University of Tokyo, Komaba, Meguro-ku, Tokyo, Japan 153

-C NMR spectra of p and rn-substituted phenyl N-methylcarbamates, phenyl Nfl-dimethylcarbamates and p and m-suhstituted phenyl propionates were recorded, and their para -C SCS (substituent chemical shW) were analysed by DSP (dual substituent parameters) and DSP-NLR (non-linear resonance) equations. It was found that the 6xed substituent Y, --oCONHCH,, -OCON(CH& and --oCWH,, were all mild in the sense that DSP analysis gave a good correlation, leaving little room for improvement by the DSP-NLR treatment. Further, the three series of compounds gave similar p, and p~ values (para derivatives, 3.2-3.3 and 17.7-18.0; meta derivatives, 5.1-5.2 and 21.8-22.0). Examma * tion of the corresponding analyses of similar compounds indicated that the p, and p~ values and, hence, their ratio p&, =A, depended primarily on the nature of the atom through which the fixed substituent Y (e.g. OK, a-N and a-0) was bonded to the aromatic ring when the Y substituents are mild. The extent of this tendency for compounds with active tixed substituents is also discussed.

INTRODUCTION

As part of our continuing investigations to elucidate the structure-activity relationship of various carba- mates with anticonvulsant activity, bearing a common structure I or I1 with a variable substituent X and a fixed substituent Y associated with their pharmaceuti- cal activities, we previously reported' the Hansch analysis2 of p - and rn-substituted benzyl N,N- dimethylcarbamates 1 and 2. The following correlation

I

X: variable substituent type I

1 Y = p-CHZOCON(CH,)z 3 Y = p-NHCOCHzPh 5 Y = p-NHCOCHZCH, 7 Y = p-OCONHCH, 9 Y = p-OCON(CHJ2

11 Y = p-OCOCH,CH, 13 Y = p-CHZOCOCHzCH3 14 Y = p-CHzNHCOCHzCH, 15 Y=H

Y

6 5

I1

Y: fixed substituent type I1

2 Y = m -CH,OCON(CH,), 4 Y = m-NHCOCH,Ph

8 Y = m-OCONHCH, 10 Y = m-OCON(CH,), 12 Y = m-OCOCH,CH,

6 Y = m -NHCOCHzCH,

* Authors to whom correspondence should be addressed.

0 Wiley Heyden Ltd, 1984

was obtained:

-log ED,, = -0.21 (log P)' +0.7610gP-0.32 go-0.18 HB+2.95,

(1) where ED5, is the anticonvulsant activity, P is the octanol-water partition coefficient, uo is the electronic parameter and HB is the hydrogen bonding parameter.

Since the biological potency of these compounds depends partly on the electronic properties of sub- stituent X, we expected that the 13C NMR chemical shifts of these compounds could be correlated with their pharmaceutical activity. With this in mind, we analysed3 13C SCS (substituent chemical shifts) of C-1 for 1 (para to X) and of C-6 for 2 (para to X) by means of Taft's DSP (dual substituent parameter) and DSP-NLR (with non-linear resonance effect) analyses based on the equation

where uI and uRo are inductive and resonance sub- stituent constants, respectively, and pI and pR are transmission coefficients determined b y the least- squares r n e t h ~ d . ~ It was found that E, which is a constant for each Y group, and characterizes the elec- tron demand exerted by the Y group on the resonance effects of the X substituent, is small (0.06 for 1 and

ccc-0030-4921/84/0022-0439$03.50

ORGANIC MAGNETIC RESONANCE, VOL. 22, NO. 7, 1984 439

C. YAMAGAMI E7 AL.

-0.04 for 2), indicating that there is no 'additional' interaction between X and Y. This was not unex- pected, since the carbamoyl moiety is insulated from direct conjugation with the aromatic ring bearing sub- stituent X by the interposing CH,.

This observation prompted us to investigate the DSP and DSP-NLR analysis for p- and rn-substituted phenylacetanilides (3 and 4) and propionanilides (5 and 6), where the aromatic ring with the variable substituent X is bonded directly to the nitrogen of the amide moiety without interposing methylenes (hereaf- ter designated as an a - N series: in this sense, 1 and 2 can be designated as an a-C series). The DSP correla- tion is excellent ( f= 0.06),5 and there is little room for improving the correlation by DSP-NLR analysis. In fact, the DSP-NLR analyses of 13C SCS of C-1 (3 or 5) and C-6 (4 or 6) gave very small E values (0-0.16).5 Since there are considerable differences between the a -N and a-C series as regards the structure and degree of conjugation, the failure to differentiate between them by means of E values is annoying, since DSP and DSP-NLR analyses are generally regarded as a most reliable method for the correlation of 13C SCS to the substituent constants.

This investigation had several purposes. Firstly, it is important to compile 13C chemical shift data of phar- maceutically useful compounds where the fixed sub- stituent is attached to the aromatic residue via oxygen (i.e. the a-0 series). Secondly, it will be interesting to analyse their 13C SCS by means of DSP and DSP- NLR analyses. Thirdly, it is important to find some means of differentiating between the a-C, a - N and a -0 series based on 13C SCS since these series have various pharmaceutical activities. Thus, 1, 2, 3 and 4 have anticonvulsant activities, 3 and 4 belong to a well known class of herbicides while 7-10 are, in general, acetylcholine esterase inhibitom6

For this purpose the 13C NMR spectra of a series of p - and rn -substituted phenyl N-methylcarbamates (7 and 8) and phenyl N,N-dimethylcarbamates (9 and 10) were determined. For the sake of reference, p - and m -substituted phenyl propionates (1 1 and 12) are also included. Furthermore, p-substituted benzyl propionates (13) and N-benzylpropionamides (14) were included as further examples of the a - C series.

EXPERIMENTAL

The preparation of compounds 7-10 has been previ- ously des~ribed.~?' Compounds 11 and 12 were pre- pared by the reaction of the corresponding phenols and propionyl chloride, while 13 and 14 were pre- pared from benzylamines and propionyl chloride.

The 13C NMR spectra of these compounds were recorded at 50.3MHz on a Varian XL-200 spec- trometer in 1Omm tubes at ambient temperature (25 "C). A pulse width of 5 ps (corresponding to a flip angle of ca 30") was used. The spectral width was 13 000 Hz with 16 000 data points. The chemical shifts were measured in CDC13 solution (0.1 M) with tetra- methylsilane (TMS) as the internal standard.

RESULTS AND DISCUSSION

13C Chemical shifts

The assignment of the 13C signals is straightforward in all cases. The signals due to the carbamoyl moiety were easily detected from their chemical shifts. Com- pounds 9 and 10 gave two methyl signals owing to the restricted rotation about the amide double bond. The assignments of signals due to the aromatic carbon nuclei were made based on the splitting pattern under off-resonance decoupling conditions, and of the SCS for monosubstituted benzenes.' Assignments for spectra of propionates 11 and 12 were carried out in a similar manner.

The 13C chemical shifts of 7 and 8 (40 compounds are shown in Table 1 and those of 9 and 10 (22 compounds) in Table 2. Table 3 lists the chemical shifts of 11 and 12 (12 compounds). In order to assess the extent of X-Y interaction, the C-1 SCS of 7, 9, 11 and the C-6 SCS of 8, 10, 12 have been plotted against the p-C SCS of monosubstituted benzenes 15 (SCS,): The results are given in Table 4.

For entries belonging to the I1 group, the slopes are almost unity. For those belonging to I, however, the slopes are considerably different from unity, indicat- ing, as expected, the presence of X-Y interaction. The nature of this interaction is not necessarily straightfor- ward since the intercepts also vary, suggesting that dual parameter analysis is necessary.

DSP and DSP-NLR analysis of "C SCS

In carrying out the DSP and DSP-NLR analyses of a variety of compounds, it was noted that the correlation is slightly affected by the number and the nature of the substituents selected. Hence, for a proper comparison among a variety of compounds, an identical set of substituents is preferably employed for all correla- tions.

Preliminary calculations indicated that in this par- ticular investigation where fixed Y substituents are employed, six X substituents, viz. OCH3, CH3, C1, F, CN and NOz, are sufficient, in the sense that the inclusion of further substituents does not affect the correlation to any significant extent. In certain cases cyano derivatives are not available and, hence, corre- lations were carried out for only five substituents.

The parameters obtained from the DSP and DSP- NLR analyses of C-1 (i.e. para to X) for 7 and 9, and C-6 (i.e. para to X) for 8 and 10 are shown in Table 5. The results of similar anslyses for 11 and 12, and for the a - C and a - N series (1-6, 13 and 14) are also included.

The DSP analysis of 7 and 9 gave very small f values. Hence, there is little room for improving the correlation and, indeed, the E value obtained by the DSP-NLR analysis is smaller than that for 1 with an interposing CH, between the carbamoyl and aromatic residues. This corresponds to the fact that the electron-donating potency of the a-oxygen is cancel- led by the electron-withdrawing carbonyl group to

440 ORGANIC MAGNETIC RESONANCE, VOL. 22, NO. 7, 1984

13C NMR SPECTRA OF SUBSTITUTED PHENYL CARBAMATES

~~ ~ ~ ~~~~~~

Table 1. 13C chemical shifts for p- and m-substituted phenyl N-methylcarbamates"

X

H p-Me p-Et p-Pr p-tert-Bu P-F p-CI p-Br P -1 p-OMe p-OEt P-OBU p-SMe p-S0,Me p-COMe p-COEt p-CN p-CHO ~ 4 0 2

m -Me m -Et m-Pr m -iso-Pr m -tert-Bu rn -F m-CI m -Br rn - I m -CF, m -0Me m -0Et m-0-iso-Pr m-OBu m -CN m -COCH, m -COEt m -CHO m -NO, m -SO,NMe, m -N Me,

c-1

151.10 148.84 148.93 149.03 148.69 146.91 149.58 150.13 150.96 144.64 144.48 144.43 148.89 155.26 154.92 154.70 154.47 155.93 155.99

151.02 151.12 151.02 151.10 150.89 152.20" 151.59 151.61 151.36 151.22 152.08 152.00 152.01 152.02 151.25 151.32 151.31 151.71 151.46 151.32 152.13

c-2

121.60 121.32 121.35 121.25 120.90 1 22.9gb 122.92 123.37 123.76 122.46 122.40 122.40 122.11 122.32 121.46 121.45 122.38 121.99 121.95

122.25 120.98 121.57 119.59 118.61 109.61' 122.22 125.09 121.15 1 22.03k 107.59 108.08 109.30 108.10 125.27 121.46 121.16 122.33 117.22 121.19 105.73

Aromatic

c-3

129.27 129.78 128.61 129.19 126.16 1 15.85' 129.28 132.27 138.28 114.35 114.91 1 14.92 128.11 129.05 129.87 129.52 133.53 131.16 125.12

139.43 145.76 144.25 150.47 152.81 1 62.Wg 134.46 122.20 93.39

131.79' 160.39 159.73 158.68 159.98 11 3.24 138.39 138.23 137.67 148.72 136.34 151.67

carbons

c-4

125.26 134.84 141.19 139.65 148.01 159.93d 130.57 118.23 89.05

156.94 156.27 156.51 134.84 136.94 134.07 133.87 108.87 133.41 144.72

126.11 124.87 125.47 121.47 122.30 11 2.24h 125.49 128.43 134.39 122.03"' 111.25 111.75 1 12.93 111.79 128.91 125.20 124.82 126.65 120.14 124.25 109.430

c-5

129.00 129.05 128.96 129.05 128.73 129.95' 129.95 130.30 130.81 129.84 129.65 129.60 129.59 129.59 130.20 129.49 129.45 129.96 129.81 129.87 129.53

C-6

118.54 11 8.77

118.92 118.61 117.28' 1 19.93 120.44 121.15 125.16 113.83 113.64 113.52 113.58 126.53 126.50 126.24 127.78 128.00 125.98 109.600

i 1 8 . n

OCONHCH:, G=O NHCHJ Substituent

155.27 155.49 155.50 155.50 155.46 155.20 154.83 154.76 154.67 155.70 155.68 155.73 155.15 153.98 154.37 154.41 153.88 154.13 153.72

155.38 155.34 155.39 155.41 155.40 154.64 154.66 154.64 154.65 154.62 155.14 155.13 155.13 155.18 154.22 154.92 154.91 154.70 154.16 154.45 155.47

27.70 27.70 CH, 20.82 27.71 CH, 15.62, CH, 28.25 27.70 CH, 13.79, CH, 24.56, ArCH,, 37.43 27.71 CH, 31.43, CMe, 34.40 - 27.74 27.73 27.73 27.73 27.73 OCH, 55.60 27.71 CH, 14.84, OCH, 63.55 27.72 CH, 13.84, CH, 19.23,31.31, OCH,68.07 27.73 CH, 16.67

27.74 CH, 26.58 C=O 197.01 27.75 CH, 8.26, CH, 31.74, C==O 199.68 27.76 CN 118.44 27.75 k O 191.00 27.80

27.71 CH, 21.32 27.71 CH, 15.25, CH, 28.64 27.70 CH, 13.82, CH, 24.32, ArCH, 37.82 27.72 CH, 23.85, CH 33.94 27.70 CH, 31.24, CMe, 34.72 27.73 27.71 27.74 27.74 27.75 CF, 122.64" 27.71 CH, 55.38 27.71 CH, 14.75, OCH, 63.59 27.70 CH, 21 99, OCH 70.06 27.73 CH, 13.85, CH, 19.24,31.26, OCH, 67.83 27.78 CN 118.01 27.74 CH, 26.72, C=O 197.26 27.76 CH38.17,CH,31.93,C==O 199.89

27.80 27.76 N(CH,), 37.98 27.72 N(CH,), 40.49

27.77 ~ ~ ~ 4 4 . 6 9

27.77 c=o 191.35

a In ppm downfield from TMS (solvent, CDCI,). 3J(CF) = 8.6 Hz. 'J(CF) = 23.6 Hz. 'J(CF) = 244.4 Hz.

",J(CF) = 10.7 Hz. ' 'J(CF) = 24.7 Hz. g'J(CF) = 247.7 Hz.

'J(CF) = 21.0 Hz. ' ,J(CF) = 9.6 Hz. 'J(CF) = 3.5 Hz. ' 3J(CF) = 3.7 Hz. "J(CF) = 32.4 Hz.

,J(CF) = 3.7 Hz. " 'J(CF) = 272.6 Hz. O Assignments interchangeable.

make the substituent as a whole extremely mild. This Brownlee and Sadek," who analysed 15 p-substituted is in agreement with our recent observation that 3 and phenyl acetates (11). Their results are also included 5 also gave very small E value^.^ Further, 11 gave a in Table 5. They ascribed the mildness of the nearly identical correlation with that for 7 and 9, indi- -OCOCH, moiety to resonance stabilization within cating that N-methylamino or N,N-dimethylamino the group itself. Our results further suggest that the moieties exert no additional interaction with a remote lone pair of the nitrogen bonded to the - 0 C w X. moiety does not contribute to the resonance to any

A similar result has already been reported by significant extent.

ORGANIC MAGNETIC RESONANCE, VOL. 22, NO. 7, 1984 441

C. YAMAGAh41 ET AL.

~ ~-

Table 2. =C chemical shifts for p- and m-substituted phenyl N,N-dimethylcarbamatesa

Aromatic carbons OCON(CH& X c-1 c-2 c-3 c-4 c-5 C-6 c==o N(CHd2 Substituent

H 151.55 121.76 129.21 125.14 154.93 36.48.36.68 p-Me 149.29 121.45 129.69 134.67 155.16 36.41,36.67 CH, 20.82 p-Et 149.42 121.46 128.54 141.03 155.16 36.42.36.67 CH, 15.64,CH228.25 p-Pr 149.46 121.37 129.14 139.49 155.18 36.43,36.67 CH,13.78,CH224.57,ArCHz37.44 p-iso-Pr 149.45 121.39 127.10 145.63 155.12 36.42.36.65 CH324.08,CH33.58 - P-F 147.35b 123.13" 115.79 159.92" 154.94 36.42,36.72 p-CI 150.03 123.12 129.23 130.49 154.57 36.46,36.75 p-OMe 145.12 122.56 114.29 156.85 155.34 36.42,36.70 CH, 55.60 p-COMe 155.33 121.71 129.83 134.10 154.06 36.54,36.76 CH326.59. P-n 196.98 P-CN 154.90 122.68 133.50 108.89 153.60 36.54.36.82 CN 118.48 p-CHO 156.35 122.27 131.11 133.40 153.86 36.56,36.79 C=O 191.06 p-NO, 156.42 122.24 125.05 144.77 153.44 36.57,36.85

m-Me 151.48 122.39 139.34 125.99 128.95 118.70 155.08 36.04.36.67 CH,21.30 rn -Et 151.52 121.13 145.65 124.74 128.99 118.90 155.06 36.42,36.65 CH, 15.28, CH, 28.63 m -F 152.45' 1O9.8lg 162Sh 112.15' 129.87' 117.50k 154.33 36.46,36.74 m -Cl 152.02 122.45 134.44 125.45 129.90 120.1 5 154.36 36.47,36.76 rn-OMe 152.53 107.69 160.40 111.26 129.55 114.00 154.81 36.47,36.70 CH,55.38 m-CN 151.67 125.52 113.20 128.86 130.13 126.76 153.91 36.50,36.82 CN118.04 m-COMe 151.77 121.64 138.40 125.11 129.41 126.68 154.55 36.48,36.76 CH326.69,M197.17 m-CHO 152.14 122.57 137.64 126.55 129.90 127.98 154.35 36.50,36.78 C=O191.36 m-NO, 151.89 117.44 148.70 120.09 129.74 128.26 153.84 36.53,36.85 m-NMe, 152.57 105.91 151.65 109.50 129.43 109.63 155.16 36.44,36.64 N(CH3),40.50

a In ppm downfield from TMS. 4J(CF) = 3.9 Hz. ,J(CF) = 8.5 Hz. ,J(CF) = 14.7 Hz. 'J(CF) = 242.7 Hz. ' 3J(CF) = 11.1 Ht. 'J(CF) = 24.1 Hz. 'J(CF) = 246.0 Hz.

"J(CF) = 20.9 Hz. 1 3J(CF) = 9.7 Hz. ' 4J(CF) = 3.4 Hz.

~ ~ -~

Table 3. -C NMR chemical shis for p and m-substituted phenyl propionates"

X c-l c-2 c-3 C-4

H 150.74 121.55 129.38 125.68 p-OMe 144.26 122.27 114.40 157.14 p-Me 148.49 121.21 129.88 135.29 P-F 146.53b 122.91' 116.01d 160.14" p-CI 149.23 122.93 129.42 131.07 p-CN 154.04 122.71 133.63 109.62 p-N02 155.50 122.42 125.19 145.23

m-OMe 151.71 107.54 160.44 111.59 m-Me 150.68 122.14 139.53 126.51 m -F 151 .60' 109.70° 162.89" 11 2.79' m -CI 151.19 122.27 134.64 126.02 m-NO, 151.04 117.37 148.75 120.68

a In ppm downfield from TMS (solvent, CDCI,). 4J(CF) = 3.5 Ht. ,J(CF) = 8.5 Hz. ,J(CF) = 23.8 Hz.

" 'J(CF) = 244.4 Hz. '3J(CF)=11.3H~.

,J(CF) = 24.1 Hz. 'J(CF) = 246.7 Ht.

i 'J(CF) = 20.9 Hz. i 3J(CF) = 9.7 Hz. ' 4J(CF) = 2.8 Hz.

c-5 C-6

129.76 1 3.76 129.09 118.48 130.13 117.35k 130.12 119.96 129.99 128.10

CH,CH,

172.95 9.09 173.33 9.09 173.19 9.10 173.01 9.02 172.72 9.01 172.06 8.90 171.96 8.87

172.88 9.06 173.03 9.10 172.63 8.99 172.66 9.00 172.28 8.92

CH&H, Substituent

27.76 27.67 OMe55.54 27.74 Me20.87 27.64 27.69 27.74 CN 11 8.26 27.74

27.76 OMe55.38 27.76 Me21.30 27.71 27.68 27.64

442 ORGANIC MAGNETIC RESONANCE, VOL. 22, NO. 7, 1984

13C NMR SPECTRA OF SUBSTITUTED PHENYL CARBAMAES

Table 4. p-C SCS of compounds 7-12 vs SCS, (15)” Type Y (entw) a b r

I OCONHCH, (7) 0.82 -0.14 0.997 OCON(CH,), (9) 0.81 -0.08 0.999 OCOC2H5 (1 1) 0.81 -0.16 0.997

OCON(CH,), 1.04 0.26 0.999 OCOC2H5 (12) 1.03 0.23 0.999

II OCONHCH, (8) 1.03 0.20 0.999

a p-C SCS = aSCS, + b ( r = correlation coefficient).

It is interesting that for both types I and I1 com- pounds, the pR and pI values depend primarily on the nature of the a-atoms. The variation of the p values with the nature of the a-atom depends on the general structure I or 11. Thus, for system I both pI and pR values decrease in the order

Although p-C SCS is involved, the correlation for I1 (X and Y are rnetu) is expected to give smaller E

values because there is no direct mesomeric interac- tion between X and Y. For the compounds investi- gated, both pR and pr values are also basically depen- dent on the nature of the a-atoms in system 11. The relative magnitudes of the p values are, however, considerably different from those of I. For pR, the whole series gave similar values to that of the refer- ence compounds 15 (pR = 22.1, recalculated for the same set of substituents from the data in Ref. 4) while pI decreases in the order

a-O>a-N>a-C (4)

which is contrary to that observed for pI and pR of type I.

Relative transmittance of polar and resonance effects

The relative transmittance of the polar and resonance effects, A = pR/pI, as an indicator of the relative impor- tance of the resonance effect compared with that of the polar effect, has been partially de~cribed.~

Our observation that for 1-14 the p values depend primarily on the nature of the a-atom necessarily leads to the conclusion that A may also be dependent on the nature of the a-atom. The A values for both DSP and DSP-NLR analyses are listed in Table 6. The direction of the change in A values is reversed between I and 11. In system I1 the origin of this order is ascribed to the difference in pI, while in system I the origin is more complex since both pR and pI change according to the nature of the a-atom.

For system I the order of A is a-O>a-N>a-C, which reflects the magnitude of interaction between the a-atom and the aromatic ring. Whatever the origin of this order, A values seem to be a convenient meas- ure of differentiating between the a-0 , a-N and a-C series of system I.

For system I1 the pR values are nearly constant. Hence, the order of A is contrary to that given in Eqn

’

(4).

DSP and DSP-NLR analysis of compounds with active substituents

We have so far examined compounds with a carba- mate, amide or ester moiety, or those with an addi- tional interposing methylene as a fixed substituent Y. These substituents are mild in the sense that the E

values in the DSP-NLR analyses are small. It will be interesting to see whether the observed general trends for the A values are common to compounds with a fixed substituent Y, such as NH, or OH, which are active in the sense that they can interact either

Table 5. DSP and DSP-NLR correlations with mild substituents Y DSP

Type Series Y Entry ns pI pR Ah

I a-C CHZOCON(CHJ2 1 sd 6.1 23.0 3.8 CH20COC2H, 13 6 6.0 22.8 3.8 CH2NHCOC2H5 14 5 6.5 23.1 3.6

a - N NHCOCH2Ph 3 sd 4.4 19.3 4.4 NHCOC,H, 5 sd 4.4 19.4 4.4

a-0 OCONHCH, 7 6 3.4 17.9 5.3 OCON(CH,), 9 6 3.3 17.8 5.4 OCOC,H, 11 6 3.2 17.8 5.5 OCOCH, 11 15 3.2 17.1 5.3

f C PI

0.03 6.0 0.03 6.0 0.03 6.3 0.04 4.3 0.02 4.3 0.04 3.3 0.05 3.3 0.04 3.2 0.12 3.2

-- DSP-NLR

PR Ah

23.5 4.0 23.1 3.9 23.9 3.8 19.7 4.6 19.5 4.5 18.0 5.4 18.0 5.5 18.7 5.4 17.5 5.5

E

0.09 0.05 0.12 0.08 0.03 0.03 0.04

-0.02 0.06

f C

0.03 0.02 0.03 0.03 0.02 0.04 0.05 0.05 0.05

__ Ref.

3 This study This study

5 5

This study This study This study

10

II a-C CHZOCON(CH,), 2 Sd 4.0 21.3 5.4 0.01 3.9 21.4 5.4 0.02 0.01 3 a-N NHCOCHzPh 4 sd 3.9 21.6 5.5 0.02 4.0 21.6 5.5 (~l<0.01 0.02 5

NHCOC,H, 6 6d 3.9 21.7 5.5 0.02 4.0 21.6 5.4 -0.02 0.02 5 a-0 OCONHCH, 8 6 5.1 21.9 4.3 0.03 5.1 22.0 4.3 0.01 0.03 This study

OCON(CH,), 10 6 5.2 21.9 4.2 0.03 5.2 21.9 4.2 (~l<0.01 0.03 This study OCOC2H5 12 5 5.1 21.8 4.3 <0.01 5.1 21.8 4.3 (~(<0.01 0.04 This study

a n = 6: X = OMe, Me, F, CI, CN and NO2. n = 5: X = OMe, Me, F, CI and NOz. A = pR/pI. f = SD/RMS, where SD is the root mean square of the deviations and RMS is the root mean square of the experimental values. Recalculated for n = 6.

ORGANIC MAGNETIC RESONANCE, VOL. 22, NO. 7, 1984 443

C. YAMAGAMI ET AL.

~

Table 6. X values for I and I1 x

Series I 11

a-C 3.9 5.4 a - N 4.6 5.5 a-0 5.4 4.3

through the .rr-frame or through the a-frame with the variable substituent X.

The results of DSP and DSP-NLR analyses for p-substituted benzylamines (16), p- and rn-substituted benzyl alcohols (17 and 18) and toluenes (19 and 20) are given in Table 7. For the a-N series, p- and rn- substituted anilines (21 and 22) and p-substituted di- methylanilines (23) are included and, in addition, p- and rn-substituted phenols (24 and 25) and anisoles (26 and 27) are also included for the a - 0 series. The SCS values necessary €or the correlations were taken either from the literature4 or from our own unpub- lished results."

3 L

L-2

I

Y+' ')" k z z 2 ' 6 5

I1

X: variable substituent Y: fixed substituent type I type I1

16 Y=CHZNH, 18 Y = CH,OH 17 Y = CH,OH 20 Y=CH, 19 Y =CH, 22 Y=NH, 21 Y=NH, 25 Y=OH 23 Y = N(CH& 24 Y=OH 26 Y=OCH,

27 Y=OCH,

Although the entries 16, 17 (a-C series) 21, 22 ( a - N series) and 25 ( a - 0 series) gave pI and pR values close to those for the 1, 13 (a-C series), 3-6 (a-N series) and 8, 10 and 12 ( a - 0 series), respectively,

these vary more than those for compounds with a mild Y (Table 5 ) , and a serious deviation was observed for 20, 23, 24 and 27. Further, in these cases the f values are larger than those of 1-14.

With an active substituent Y, the DSP-NLR analysis improves the correlation to a considerable extent. All the entries in Table 7 except for 18 and 27, have larger E values than 15 ( E = 0.10, recalculated for the same set of substituents from the data in Ref. 4). In addition, the E values vary, and no apparent relation- ship seems to exist between E and the nature of the a-atom.

The general trend of the order of A observed for type I, i.e. a -0 > a -N > a -C, is, however, still observ- able except for 23 and 24. The values themselves are fairly close to those in Table 6. Hence, the h value is also a meaningful parameter for compounds with an active Y substituent.

Much the same is true for type I1 compounds. Thus, compounds with such active substituents as NH, (22) or OH (25) follow the general trend observed for compounds with a mild Y substituent to a fairly good extent.

CONCLUSIONS

DSP and DSP-NLR analyses of para C (to X) in p- and rn-XC6H4Y (I and 11, respectively) systems has revealed that A values, as well as p1 and pR values, are very sensitive to the nature and position of the Y substituent, even when compounds with a mild fixed substituent is involved, but E values are small and insensitive to the structural change.

When there is an active fixed substituent Y the above tendency is less clear, and there are a few exceptions, such as 23, which give values completely out of the range for the other compounds.

A parameter such as A may be of some value in a Hansch-type analysis of the activity-structure relation- ship, and further studies are being carried out in our laboratories.

Table 7. DSP and DSP-NLR correlations for compounds with active snbStit0ent.s Y OSP DSP-NtR

Type Series Y

I a-C CHZNH, CHZOH CH3

N(CH3)zb

OCH,

a-N NHZ

a-0 OH

Entry ne PI PR

16 5 5.6 22.6 17 6 5.9 22.7 19 6 6.6 24.2 21 6 4.8 19.1 23 6 1.8 13.1 24 6 4.7 18.6 26 6 3.6 16.7

xa f a PI PR x=

4.1 0.04 5.3 23.9 4.5 3.8 0.04 5.7 23.7 4.2 3.7 0.05 6.1 26.2 4.3 4.0 0.05 4.4 20.8 4.7 7.3 0.06 1.6 14.1 8.9 3.9 0.09 4.2 20.8 4.9 4.8 0.07 3.2 18.3 5.8

E __ 0.21 0.16 0.32 0.35 0.31 0.46 0.37

f=

0.03 0.04 0.04 0.04 0.04 0.07 0.05

II a-C CHZOH 18 5 3.7 21.3 5.8 0.01 3.6 21.7 6.0 0.06 0.01 CH3 20 6 4.8 21.4 4.5 0.03 4.6 22.2 4.8 0.13 0.02

a - N NH2 22 6 4.0 20.2 5.1 0.04 3.8 21.0 5.5 0.15 0.03 a-0 OH 25 6 5.3 21.5 4.1 0.02 5.1 22.2 4.4 0.12 0.01

OCH, 27 5 6.1 22.5 3.7 0.01 5.9 23.1 3.9 0.09 0.01

a See footnotes to Table 5. Recalculated for n = 6 by using the data from Ref. 4.

~ ~ ~ ~ ~~ ~~~~~ ~~ ~ ~~ ~~ ~

444 ORGANIC MAGNETIC RESONANCE, VOL. 22, NO. 7, 1984

13C NMR SPECTRA OF SUBSTITUTED PHENYL CARBAMATES

REFERENCES

1. C. Yamagami, C. Sonoda, N. Takao, M. Tanaka, J. Yamada, K. Horisaka and T. Fujita, Chem. Pharm. Bull. 30. 4175 (1982).

Reson. 21, 570 (1983).

R. W. Taft, J. Org. Chem. 45, 2429 (1980).

Bull. 31, 4172 (1983).

Pestic. Biochem. Physiol. 7, 107 (1977).

2. E.g. C. Hansch, Acc. Chem. Res. 2, 232 (1969). 3. C. Yarnagarni, N. Takao and Y. Takeuchi, Org. Magn.

4. J. Brorninow, R. T. C. Brownlee, D. J. Craik, M. Sadek and

5. C. Yamagami, N. Takao and Y. Takeuchi, Chem. Pharm.

6. T. Nishioka, T. Fujita, K. Kamoshita and M. Nakajima,

7. T. Fujita, K. Kamoshita, T. Nishioka and M. Nakajirna, Agric.

8. T. Nishioka, T. Fujita, K. Kamoshita and M. Nakajima, J.

9. D. F. Ewing, Org.. Magn. Reson. 12, 499 (1979). 10. R. T. C. Brownlee and M. Sadek, Aost. J. Chem. 34, 1593

11. C. Yamagami, N. Takao and Y. Takeuchi, unpublished

Biol. Chem. 38, 1521 (1974).

Org. Chem. 40. 2520 (1975).

(1981).

results.

Received 7 October 1983; accepted 23 December 1983

ORGANIC MAGNETIC RESONANCE, VOL. 22, NO. 7, 1984 445