Indian Journal of Chcmistry Vol. 43B, August 2004, pp. 1753- 1757

NMR spectral studies of some N-aroyl hydrazones

A Manimekalai*, B Senthil Sivakumar & T Maruthavanan

Departmcnt of Chcmistry, Annamalai Uni vcrsity . Annamalainagar 608002, India.

e-mail: mckama y l @hot lllail.com

Received II February 2003; accepted (revised) 27 April 2004

IH and DC NMR spcctra arc rccordcd fur somc N-aroy l (bcnzoy l, salicyloy l) hydrazoncs 1-9 derivcd from r(2),c(6)­diphcnylpiperidin-4-onc, t(3)-mcthy l-r(2) , c(6)-diary lpipcri din-4-oncs and 1'(2), c(6)-d iphcny ltetrahydrothiopyran-4-one and analyscd in dctail. Thc study rcvcals that thcsc hyd razoncs cxis t as an equilibrium mixture of amido and imidol forms in solution. Thc obscrvcd chcmical shi ft is thc we ightcd avcragc popu lat ion of amido and imidol tautomeric forms. The clTcct of varying the substitucnts on thc chcmica l shifts has bccn studi cd in dctail.

IPC: Inl.CI. G 01 R 33/46, C 070211100

The development of agents which selectively inhibit the growth of certain types of cell s is an area of much current interest. Aroy l hydrazines and many other hydrazine derivatives have been reported to inhibit many reaction cata lyzed by pyridoxal 5-phosphate as co-enzyme l

. Hydrazides of organi c acids and their ary lidene deri vati ves are considered to function as antitubercul ous compounds2

.3 and the

mode of ac ti on was attributed to the formation of stab le chelates with transition meta l ions present in the cell. Cu(lI) complexes have been reported to produce significant inhibition of tumor growth4

.

Some hydrazides are al so found to exhibit anti­ma lari al act ivit/ while their chelates with Cu(II) have antifungicidal6 effects against a number of pathogeni c fungi. The interest in the study of hydrazones and their derivatives has been growing due to their biological activit/ · 8 espec iall y as potent inhibitors for many enzymes9

. 10, in the treatment of tumor, tuberculosis, leprosy and mental disorder and their use in analyt ical chemi str/ I as metal ex tracti ng agents 12. We report herein the detailed 13C and IH NMR spectral studies of N -benzoy l-r(2 ), c(6)­diphenylpiperidin-4-one hydrazone 1, N-salicyloy l­r(2), c(6)-di phenylpiperidin-4-one hydrazone 2, N­benzoy l-t (3) -meth y 1-1'(2) , c( 6)-diary I pi peridi n-4-one hydrazones 3-5 [aryl = phenyl 3; o-chlorophenyl 4; p-chlorophenyl 5], N-sal icyloyl-t(3)-methyl-r(2), c(6)-diary lpiperidin-4-one hydrazones 6-8 [aryl = phenyl 6; o-chloropheny l 7; p-chlorophenyl 8] and N-benzoy l -r (2 ), c( 6)-di pheny I tetrahydrothiopyran-4-one hydrazone 9.

:-NH-CO--@ 5 Y

Ar Ar

1-9 Compd X Y R Ar

NH H H Ph

2 NH OH H Ph

3 NH H CH) Ph

4 NH H CH3 o-ClC6 H4

5 NH H CH J p-CIC6H4

6 NH OH CH) Ph

7 NH OH CH3 o-CiC '-l4

8 NH OH CH) p-ClC6H4

9 S H H Ph

Results and Discussion

The signals in the IH NMR spectra were assigned based on their positions, multiplicities and areas. The coupling constants about C(5)-C(6) bonds cou ld not be extracted due to slight broadening of the signal H(6) in most of the cases. The broadening is probably due to the amido-imidol tautomerism present in the hydrazones. The signals in the 13C NMR spectra were ass igned based on comparison of these signals with those of appropriate piperidin-4-one oximes 13 and 2,6-diphenyltetrahydrothiopyran-4-one oxime l4

. The JR, 13C and IH chemical shifts are displayed in Tables 1-III respectively. The absence of signals for the

1754

3428 3086 1646 1600

1492 1451

1292 11 37

1030

756 696

Compd

1

2

3

4

6

7

8

9

INDIAN 1. CHEM., SEC B, AUGUST 2004

T able I - IR spectra l data (em-I) of N-aroy l hydrazones 1-9

2 3 4 5 6 7 8 9 Assignmen t 3727 3296 3284 3662 VOII

3059 3208 3302 2924 3026 3023 3 152 3423 VN_II or ring and amide NH 3029 3029 2980 2927 2935 1632 164 1 1663 1628 1607 1624 1632 1598 Amidc I band 1603 1543 1523 1555 1494 1604 1530 1488 Amide II and VC=N

1548 1539 1492 149 1 1489 1488 1452 1474 1492 1450 A romati c C-C skcleta l vibrat ion 1455 1447 1474 1454 1455 145 1

1438 1306 1362 1306 1307 Couplcd vibrations of OH and and and and in plane bendi ng and vc_o 1101 1103 1100 1092 1232 1296 127 1 1235 1237 1230 1230 1358 Am idc III band 1150 1142 1132 11 52 11 55 1163 11 6 1 1076 VC_N ring 1064 1039 1034 1087 1049 1034 10 14 1020 VN_N

754 754 757 820 753 753 825 768 Aromat ic C-H out-or-planc 697 696 708 748 698 754 704 Bcnd ing vibration

T able 11 - I3C NMR chcmica l shifts (ppm) of N-aroy l hydrazoncs 1-9.

Compd aI/ I i syl/ C(4) Alky l C(2) C(3) C(5) C(6)

1 6 1.9 43 .8 a 60.9 = 159 2 61.8 43.7 36.9 60.8 159.24 3 69.3 45.7 a 6 1.0 = 162 12.22

4 63.2 45 .6 34.7 56.5 152.35 11.49 5 67.7 45.0 a 59.5 167.57 11.74 6 68.6 44.7 37 .0 59.9 162.95 12.42 7 62.4 45.0 34.6 55.8 152.99 I 1.1 I 8 68.2 45 .3 37.5 59.8 = 165 12.02

9 50.6 47.6 44.7 49.4 = 158

(a) - ovcrlappcd w ith DMSO signa l

Table 111 - IH NMR chemical shi rts (ppm) of N-aroy l hydrazoncs 1-9.

(// 11 i SY,11 Othcrs

H(2) H(3) H(5) H(6)

4.07 2.86 (cq) 2.95 (eq) 2.29 (ax) 3.95 (l oa,)a = 11 .20 Hz) 2.2 (ring NH)

(12J = 11 .45 Hz) 2.55 (ax) (15a.5e == 13.63 Hz) 8.80 (amide NH)

(haJe = 13.75 Hz) 4.06 2.92 (cq) 3.0 I (cq) 2.33 (ax) 3.95 2. 17 (ring NH)

(h,3 = 10.36 Hz) 2.57 (ax) 8.22 (amide NH) 9.29 (OH)

3.66 2.70 2.91 (cq) 2.34 (ax) 3.99 1.05 (mcthy l)

(h,3 = 8.73 Hz) 2.06 (ring NH) 8.78 (amidc NH)

4.44-4.38 2.77 3. 16 (cq) 2. 1 5(ax) 4.44-4.38 1.1 2 (methy l) 1.97 (ring NH) 8.94 (amide NH)

3.55 2.63 2.99 (eq) 2.29 (ax) 3.92 0.86 (methyl )

(h ,." = 9.73 Hz) (15a,5c = 13.98 Hz) (16a.5a = I 1.54 Hz) 2.5 I (ring NH) 11 .76 (OH) 11 .25 (arn idc NH)

4.37 2.74 3.26 (eq) 2.2 1 (ax) 4.44 1. 10 (methyl) 2.04 (ri ng NH) 11 .06 (amidc NH)

11.53 (OH)

3.60 2.59 2.96 (eq) 2.2 1 (ax) 3.94 0.99 (methyl) ] .99 (ri ng H) 11 .58 (amide NH) 11 .75 (Off )

4.33 3.27-3.24 (eq) 3.27-3.24 (eq) 4.22 8.82 (amidc NH) 2.96 (ax) 2.69 (ax)

MANIMEKALAI el al.: NMR SPECTRAL STUDIES OF SOME N-AROYL HYDRAZO ES 1755

carbonyl group in the region \90-200 ppm in the 13C NMR spectra reveals that all these hydrazones ex ist as an equi librium mixture of amido and imidol forms in so lution as shown be low.

o II

-C-NH-

OH I

-:;;_~=! ... ~ -C=N-

One can visualize amido-imidol tautomerism both in the N-benzoy l- and N-sa li cyloy l derivatives. The two tautomeric forms of N-benzoy l derivatives are shown in Figure 1. The imidol form is expected to be stab ilized to a greater extent than the amido form in so lution due to hydrogen bonding and hence expected to be populated to a greater extent than the amido form. In the N-salicyloyl derivatives, the amido form A (keto form) itself is stabilized due to hydrogen bonding as shown in Figure 2. In the imidol form of salicyloyl derivative B, the OH group of the salicy loyl ring may be oriented towards the amide nitrogen atom which is in contrast to the orientation observed in the amido form A. This orientation is stabilized due to hydrogen bonding between the hydroxyl proton and amide nitrogen atom. Moreover, in this orientation additional stabilization also occurs through add itional hydrogen bonding between the imidol proton and azomethine nitrogen. The observed chemica! shift is expected to be the weighted average population of the amido and imidol forms as shown in Eqn (1).

8 0bs = x 8"l1lido + (1-x) 8il1lidol ... (1)

where x and I-x are the mole fractions of amido and imidol forms respectively and 8"mido and 8ill1idol are the chemical shifts of a particular proton in the amido and imidol forms.

The observed vicinal coupling constants about C(2)-C(3) bond are in consistent with chair conforma­tion with equatorial orientations of aryl and meth yl groups. It is seen from Table II that there is no appreciable change in the chemical shifts of all the carbons by the replacement of N-benzoyl group by N­salicyloyl group in these hydrazones. Comparison of the chemical shifts of 3 with those of 5 reveals that the introduction of ch loro substituent in the para­position of phenyl rings at C(2) and C(6) sli ghtl y shields all the carbons except C(4). Similar compari­son of 6 and 8 however, reveals no appreciable chanoe except C(4) due to the in troduction of chlorine in th~ para-position of the phenyl ring. Hasan el al. 15

have reported that C(4) carbons resonate around the same field in both 1(3), 1(5)-dimethyl-r(2), c(6)­dipheny lpiperidin-4-one (211.1 ppm) and 1(3), 1(5 )­dimethyl-r(2), c(6)-his(p-chlorophenyl)piperidin -4-one (2 10.1 ppm). Therefore, introduction of chloro group in the para-position of the phenyl rings at C(2) and C(6) is not expected to alter the chemical shifts of C(4). However, C(4) carbons are deshielded by 3-5 ppm in 5 and 8 due to the presence of ch loro substituent in the para-position of the phenyl ring. In the arrha-chloro compounds 4 and 7 C(4) carbons are however shielded by "" I 0 ppm due to the presence of artha-chloro substituents. This can be explained as fo llows.

Recently, Manimekalai et a1. 16.17 have attributed the

downfield resonance of C(4) in the azine 10 relative to the hydrazone 11, to the greater electronegativity of nitrogen in the azine compared to the hydrazone. The electronegativity of nitrogen in the imidol form (resembles azine moiety) is expected to be greater

H / '0

A ~N\ ci Az;;:::!J N~ '@ X Ar

Figure 1

B Figure 2

1756 INDIAN J. CHEM., SEC B, AUGUST 2004

than that of the amido form since in the imidol form both nitrogens are in Sp2 hybridi sed state whereas in the amido form one nitrogen is in Sp2 hybridised state and another nitrogen is in Sp3 hybridised state. As the s character increases electronegati vity also increases. Due to hydrogen bonding also the electron density on nitrogen is considerably reduced in the imidol form . Both these factors are probably responsible for the greater electronegativity of nitrogen in the imidol form compared to the amido form. Therefore, C(4) resonance in the imidol form is expected to be considerably greater than that of the amido fo rm.

The contribution of imidol form in the arrha-chloro compounds 4 and 7 is considerably lower when compared with para-chloro compounds 5 and 8. As a result the observed chemical shift of C(4) carbon which is the weighted average population of the amido and imidol forms (Eqn 2) in the a-chloro compounds 4 and 7 are lower when compared with p­chloro compounds 5 and 8. Therefore, the di fferent contributions of the imidol forms are probably re!>ponsible for the differences in the chemical shifts of C( 4) in these compounds.

8obsfC(4)] = x 8"mido[C(4)] + (I-x) 8imidol[C(4)] . .. (2)

It is very interesting to note that the introduction of chlorine in the OJ·tlw-position of the phenyl ring shields C(2) [-6.1 ppm 4, -6.2 ppm 7] , C(6) [-4.5 ppm 4, -4.1 ppm 7] and C(5) carbons [-2.4 ppm 7]. The shielding observed on C(2), C(6) and C(5) carbons can be accounted in terms of the parallel conformation of the aryl rings. The aryl ring lies parallel to the axial hydrogen at C(2)/C(6) and in thi s parallel conformation the chlorine substituent is syn to the hydrogen at C(2)/C(6) as shown in Figure 3.

In this conformation interaction exists between the chlorine and the axial hydrogen at C(2)/C(6) and equatorial hydrogen at C(5). Therefore, C(2)-H/C(6)­H and C(5)-H bonds are polarised and the hydrogens acquire positive charge and the corresponding carbons acquire negative charge. This is the reason for the upfield shifts observed on C(2), C(6) and C(5) carbons due to the presence of a-chloro substituent. Similar explanation has been offered by Pandiarajan er al. 18 in 3-alkyl-2, 6-his(a-chlorophenyl)piperidin-4-ones due to the presence of artha-chloro substituent.

It is inferred from Table III that there is no appreciable change in the chemical shifts of hetero­cyclic ring protons due to the replacement of N­benzoyl group by N-salicyloyl group in these hydrazones. However, a slight shielding magnitude

RII'ON NH=CH-Ar I, 3 5

Ph X Ph

10 11

a) X = NH; R = CH3

b) X = S; R = H

H- -----Cl

H

Figure 3

has been observed on methyl protons in the sa li cy loy l hydrazone 6 due to the replacemen t of N-benzoy l group by N-salicyloyl group.

Comparison of the chemical shi Frs of 6 and 8 reveals that the introduction of chloro subst ituent in the para-position of the phenyl ring causes no appreciable change on the heterocycl ic ring protons but deshi elds slightly methyl protons. It is also observed that the introduction of a rrha-chloro substituent deshi elds benzylic hydrogens [H(2) and H(6)] and Hsc. The deshielding observed on these protons are already accounted in terms of preferred conformation of the ary l rings (Figure 3). Slight deshielding magnitude has been observed on the methyl protons at C-3 due to the introduction of artha-chloro substituent in the phenyl ring .

Experimental Section IR spectra were recorded on a Perkin-Elmer

spectrometer using potassium bromide di sc (pellet technique). IH NMR spectra were recorded on a BRUKER AMX-400 NMR spectrometer operating at 400 MHz. Samples were prepared by dissolving about 10 mg of sample in 0.5 mL of COCl3 or OMSO-ch containing 1% TMS, ten FlO's were accumulated for each sample. The experimental parameters were the following: data points 32 K, number of transcients 32, spectrum width 4000 Hz. I3C NMR spectra were recorded on BRUKER AMX-400 spectrometer operating at 100 MHz and using 10 mm sample tubes. Solutions for the measurement of spectra were prepared by dissolving 0.5 g of the sample in 2.5 mL of CDCb or OMSO-d6 containing a few drops of TMS as internal reference.

MAN IME KALAI el a/.: NMR SPECTR AL STUDIES OF SOME N-A ROYL HYDR AZONES 1757

Bcnzoy lhydrazine and salicy loy l hydraz ine were prepared according to the procedure reported earli er l 9

.

r(2), c(6)-Diphenylpiperidin-4-one and t(3)-methyl­r(2), c(6)-diphenylpiperidin-4-o ne were prepared fo llowing the procedure repo rted by Baliah et apo.

t(3 )-Methy l- r(2), c( 6)-his(o-ch lo rophen y I )pi peridi n-4-one and 1(3)- meth y l- r(2), c(6)-his(p-chlorophenyl)­piperidin-4-one were prepared fo llow ing the proced ure reported by Pandi arajan el al l 8

. cis-2, 6-Diphenyltetrahydrothiopyran-4-one was prepared fo llow ing the procedure reported by Arndt el aP.

The hydrazones 1-9 were prepared by refiu xing appropri ate heterocyclic keto nes (5 mmoles) with benzoy l- or salicyloyl hydrazine (5 mmoles) in ethanol (50 mL) for 4 hr. The solution was poured into crushed ice. The solid product obtained was fi ltered, washed with hot water and then with ethano l. Hydrazones 1, 3 , 6 and 9 were recrysta lli sed twice from benzene. Hydrazoncs 2, 4 and 7 were recrystallised twice from ethanol. Hydrazones 5 and 8 were recrystallised fro m

benzene-petroleum ether (60-80°) mi xture. The yields were in the range 50-60%. Melting points of the hydrazones are 196° (1); 135° (2); 174° (3); 182° (4);

195° (5); 171 ° (6); 169° (7); 159° (8) and 198°C (9).

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G elll , 43B, 2004, 10 18. 18 Pandiarajan K, Sekar R, An<1 nt haral1lan R & Ramali ngam V,

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20 Bali nh V & Noller C R, J Alii G elll Soc, 70, 1948. 3853. 2 1 Arndl F, Nachtwey P & Pusch P, J Chelll Bel'. 58B, 1925,

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