Indian Journal of Chemistry Vol. 438, September 2004, pp. l983-1989

Kinetics of base catalysed 0-acylation of hydroxamic acids

A S Burungale", S L Padwalb, S P Bondageb, R D Ingleb & R A Maneb*

"Yashvantrao Chavan Institute of Science, Satara 415 001, India

bDepartment of Chemistry , Dr. Babasaheb Ambedkar Marathwada University , Aurangabad 431004, India.

Received 17 September 2002; accepted (revised) 13 May 2004

The kinetics of 0-acylation of hydroxamic acids using acetic anhydride as an acy lat ing agent in non-aqueous medium, acetonitrile/dioxane has been invest igated. The kinetic measurements have been carried out using spectrophotometric technique. The effect of tertiary amines, pyridine/triethylamine on the rate of acylation has been reported. The 0-acylation is found to be first order with respect to hydroxamic acids and first order with respect to acetic anhydride. Hence overall order of reaction is found to be two, which is in good agreement with the rate law. The effect of substituents on the rate of acylation, Hammett linear free energy relationship and the thermodynamic parameters are evaluated. The reaction products have been isolated and characterized. The probable mechanism of the acylation is proposed and rate expression is derived.

IPC: Int.C1.7 C 07 C 259/00

Several aspects of hydroxamic acids such as their synthesis, photochemical formation, physical and chemical properties, ionization and structure, analy-tical and therapeutic applications have been reviewed from time to time1.2.

Complexation of metal ions by hydroxamic acids is the basis of number of analytical determinations and hence hydroxamic acids are widely used for quantitative determination of Fe(III), vanadium3 etc. The use of hydroxamic acids as precursor of Lassen rearrangement4 is well investigated. The intermediates required for the Lassen rearrangement to convert carboxylic acids or their derivatives to respective amines are their corresponding 0-acyl/0-tosyl hydroxamates (derived from their respective acids or their derivatives).

Literature reveals that considerable efforts have been made on the kinetic study of acid or base catalysed hydrolyses of various hydroxamic acids3·5 . There are a few reports on the kinetics of Lassen rearrangement6 but there is scanty information on the kinetics of formation of 0-acyl hydroxamates (key reactants required for Lassen rearrangement) from corresponding hydroxamic acids.

In view of the above observations and considering the sy nthetic utility of 0-acyl hydroxamates, it was therefore decided to carry out the kinetic study of 0-acylation of hydroxamic ac ids to optimize the acylation parameters.

Materials and Methods Hydroxamic acids used in the work were benzo-

hydroxamic acid (BHA), p-methyl benzohydroxamic acid (p-Me-BHA), p-methoxybenzohydroxamic acid (p-OMe-BHA), p-chlorobenzohydroxamic acid (p-Cl -BHA) and phenylaceto-hydroxamic acid (Ph-Ac HA). These were prepared by following Uchino's method7

and their authenticity was confirmed by comparing their physical constants with those reported in the literature8. Solvents and catalysts were obtained from S.D. fine chemicals of HPLC/AR standard and were further purified by literature procedures9·10. The acetic anhydride (AR), ferric nitrate (AR) and hydrochloric acid (AR) used in this work were of Merck make.

Stoichiometry and product analysis

Reaction mixture containing hydroxamic ac ids (25 mmoles) and acetic anhydride (25 mmoles) was allowed to react in non-aqueous medium, acetonitrile I dioxane using pyridine/triethylamine as catalyst at 303 K with constant stirring for 3 hr to complete the course of the reaction. Then the reaction solvent was removed under vacuum and the residue was poured on ice cold water. The cold reaction mass was neutralized using acetic acid and the obtained solid was filtered, washed with water, dried and finally crystallized from aqueous alcohol. The yields of the 0-acyl hydroxamates obtained are in the range 80-85% at 1:1 stoichiometric condition . The 0-acyl

hydroxamates derived from BHA, p-Me-BHA,

1984 INDIAN J. CHEM., SEC 8, SEPTEMBER 2004

p-OMe-BHA, p-Cl-BHA and Ph-Ac HA were found to melt at 126°C, 130°C, 136°C, 125°C and 152°C, respectively. The melting points of these hydroxa-mates are in good agreement with those reported in the literature 11 . 15.

Kinetic measurements

The reaction mixture for the kinetic runs was pre-pared by quickly mixing the solutions of the hydro-xamic acids, catalyst and acetic anhydride, prepared in non-aqueous solvents acetonitrile/dioxane. The acy lation reaction was followed spectrophoto-metrically by measuring the concentration of the hydroxamic acids , after known time intervals . The method was used as hydroxamic acids form quanti-tative complexes with ferric nitrate in hydroch loric acid medium at pH 2. The optical densities of the complexes were then measured at Amox 520 nm by fo llowing literature procedure 16. The measurements

were carried out at equal concentrations of the hydroxamic acids and acetic anhydride at differen t temperatures in acetonitrile/dioxane in the presence of pyridine/triethyl amine. Also kinetic measurements were recorded at unequal concentrations of hydrox-amic acids and acetic anhydride in the non-aqueous solvents in the presence of pyridine.

Results

The stoichiometric study indicates that one mole of the hydroxamic acids reacts with one mole of acetic anhydride. The reaction rates were determined at different concentrations of hydroxamic acids by keeping concentration of acet ic anhydride constant (Table 1) . Similarly, the rates were determined at different concentrations of acetic anhydride by keeping concentrations of the hydroxamic acids constant (Table II). Rate constants were calculated using second order rate law and the rate constants

Table I - Rate constants for reaction of hydroxamic acids with acetic anhydride in acetonitrile I dioxane medium at 303 K usi ng pyridine at constant [acetic anhydride] and vary ing [hydroxamic acid].

[Acetic anhydride= 0.0025 mdm-3]

Acids k, clm3 mo1" 1 sec- 1 at vary ing [Hyclroxamic acid]. mol dm·3

0.0025 0.00225 0.002 0.00175 0.0015 Acetonitrile Dioxane Acetonitrile Dioxane Acetonitrile Dioxane Acetonitril e Dioxane Acetonitrile Dioxane

BI-IA 0.190 0.392 0.189 0.383 0.190 0.377 0.180 0.365 0. 177 0.375 ± 0.002 ± 0.002 ± 0.002 ± 0.001 ± 0.001 ± 0.001 ± 0.001 ± 0.002 ± 0.00 1 ± 0.001

p-Met hyl 0.140 0.299 0. 140 0.294 0.139 0.283 0. 135 0.284 0.133 0.273 BI-IA ± 0.003 ± 0.001 ± 0.002 ± 0.002 ± 0.001 ± 0.002 ± 0.002 ± 0.002 ± 0.002 ± 0.002 p-OMc BI-IA 0.120 0.264 0.121 0.266 0.116 0.253 0. 114 0.251 0.112 0.245

± 0.001 ± 0.004 ± 0.001 ± 0.003 ± 0.001 ± 0.002 ±0.00 1 ± 0.001 ± 0.00 1 ± 0.003 p-CI BI-IA 0.098 0.218 0.098 0.204 0.098 0.196 0.093 0.191 0.094 0.182

± 0.002 ± 0.001 ± 0.001 ± 0.001 ± 0.001 ± 0.001 ± 0.002 ± 0.002 ± 0.00 1 ± 0.003 Ph.Ac I-lA 0.124 0.123 0.119 0.118 0. 114

± 0.002 ±0.001 ± 0.001 ± 0.002 ± 0.002

Table II - Rate constants for reaction of hydroxamic acids with acetic anhydride in acetonitrile I dioxane medium at 303 K using pyrid ine at constant [hydroxamic acid] and varying [acetic anhydride]

[Hyuroxamic ac id= 0.0025 Mol dm.3 J

k, dm3 mo1" 1 s- 1 at vary ing [acet ic anhydride] mol dm-3

Hydroxamic 0.0025 0.00225 0.002 0.00175 0.00 15 acids Acetonitrile Dioxane Acetonitrile Dioxane Acetonitrile Dioxane Acetonitrile Dioxane Acetonitrile Dioxane

BHA 0.190 0.392 0.188 0.382 0.186 0.375 0.18 i 0.37 1 0. 176 0.368 ± 0.002 ± 0.002 ± 0.004 ± 0.002 ± 0.002 ± 0.001 ± 0.00 1 ± 0.002 ± 0.003 ± 0.001

p-Mc. BHA 0.140 0.299 0.139 0.292 0.138 0.286 0.138 0.279 0.1 32 0.282 ± 0.003 ± 0.001 ±0.00 1 ± 0.001 ± 0.001 ± 0.001 ±0.001 ±0.001 ±0.00 1 ± 0.002

p-OMc. BHA 0.120 0.264 0.121 0.260 0.116 0.253 0.11 4 0.260 0.116 0.250 ± 0.001 ± 0.004 ± 0.002 ± 0.001 ± 0.00 1 ± 0.003 ± 0.002 ± 0.001 ± 0.00 1 ±0.001

p-CI. BHA 0.098 0.218 0.100 0.20 0.095 0.120 0.093 0.196 0.090 0.192 ± 0.002 ± 0.00 1 ± 0.002 ± 0.001 ± 0.003 ± 0.001 ±0.001 ± 0.002 ± 0.002 ± 0.002

Ph.Ac 1-!A 0.124 0.123 0.121 0. ! 18 0. 11 3 ± 0.002 ± 0.001 ± 0.001 ± 0.001 ± 0.002

BURUNGALE et al.: KINETICS OF BASE CATALYSED 0-ACYLATION OF HYDROXAMIC ACIDS !985

Table III -Rate constants for the reaction of benzohydroxamic acid and acetic anhydride using acetonitrile I dioxane in the absence and in the presence of catalyst, pyridine I triethyl amine at 303 K.

{ [HA] = 0.0025 mol dm-3, [AA] = 0.0025 mol dm"3 ], [Base] = 0.0025 mol dm-3

k, dm3 mol" 1 s· 1

Catalyst BHA p-Me. BHA p-OMe. BHA p-Cl. BHA Ph.Ac. HA Acetonitrile Dioxane Acetonitrile Dioxane Acetonitrile Dioxane Acetonitrile Dioxane Acetonitrile Dioxane

Without 0.090 0.066 0.514 0.039 0.054 catalyst ± 0.001 ± 0.001 ±0.001 ± 0.002 ±0.001 Pyridine 0.190 0.392 0.140 0.299 0.121 0.264 0.098 0.218 0.124

± 0.002 ± 0.002 ± 0.003 ± 0.001 ± 0.001 ± 0.004 ± 0.002 ± 0.001 ± 0.002 Triethyl 0.501 1.340 0.391 0.987 0.304 0.712 0.243 0.533 0.337 amine ± 0.005 ± 0.02 ± 0.006 ± 0.01 ± 0.007 ±0.01 ± 0.003 ± 0.004 ± 0.001

were found to be fairly constant. Kinetic measure-ments of acylation of benzohydroxamic acid have been carried out separately in acetonitrile and dioxane in the absence and in the presence of catalysts pyridine/triethylamine and results are recorded in Table III. Kinetic measurements were carried out at equal concentration of the reactants at five different temperatures in acetonitrile and at four different temperatures in dioxane using pyridine as a catalyst (Table IV) . The activation energy (Ea) was deter-mined from the slope of Arrhenius plots of log k vs Tt and other activation parameters were computed (Table IV) .

The entropies of activation (tS") for the reaction are all negative, suggesting rigid nature of transition state. Almost equal values of free energy of activation (t-.C"') of all hydroxamates indicate that probably a similar type of mechanism prevail s in all the cases. The rates of acylation of the hydroxamic acids in aceton itrile medium in the absence of tertiary amines were found to be hi gher than those found in dioxane medium. The rates of acylation of hydroxamic acids in aceton itrile medium in the presence of pyridine/ triethyl amine were lower than those observed in the dioxane medium. It was observed that acylation was faster in the presence of triethyl amine when compared to that in pyridine. The order of relati ve rates of the acylation of the hydroxamic acids in aceton itril e/dioxane in the presence of tertiary amines was found to be BHA > p-Me BHA > Ph.Ac.HA > p-OMe BI-IA > p-CI-BHA. The relative order of reactivity of the hydroxamic acids can be correlated to the substituents present in the benzene ring of the hyclroxamic ac ids with the help of linear free energy relationship plot. It was observed that the electron donating substituent in the benzeno icl ring of the hyclroxamic acids decreases the rate of the reaction. The slow rate of acylation in case of p-CI-B f-JA may

be clue to the effective mesomeric donation by chloro and negligible inductive electron withdrawal by chloro at reaction center.

Rates of acylation increased with the increase in temperature. The determined thermodynamic parameters indicate that the acylation of the hydroxamic acids are accompanied by overall negative value or entropy of activat ion , the low magnitude or entropy of activation , consistency of free energy of-activation values and lower val ues of frequency factors.

Discussion Acetonitrile is more polar aprotic solvent compared

to dioxane and there may be relatively easy dissociation of hydroxyl group of hydroxamic acids. Therefore, the acylat ion in the absence of catalyst is found to be faster in acetonitrile than in dioxane. In general tertiary amines are more basic in aprot ic so lvents. Tertiary amines like triethyl amine and pyridine are more basic in dioxane compared to more polar acetonitrile and hence the amines catalyse the dissociation of hydroxyl group of hydroxamic acids. That is why acylation in the presence of the amines is faster in dioxane as compared to that in acetonitrile. Of the two solvents triethyl am ine is more basic than pyridine. The rates of acylation were therefore found to be hi gher when triethyl amine was used as catalys t as compared to pyridine.

From the va lues of thermodynamic parameters , it is observed that t-.HN and L1S11 are the important parameters in con!rolling the rates of the reactions. The negative values of entropy of act ivation indicate that activated complex is less probable. The hi gh negative values of entropy of activat ion suggest that the reaction may occur between charge ions and neutral molecule and may generate rigid intermediate transition state resulting in slow rate of the reacti on. The values of frequency factor li es below 10 10 and

1986 INDIAN J. CHEM., SEC B, SEPTEMBER 2004

Table IV- Rate constants at different temperatures and activation parameters for the reaction of hydroxamic acids with acetic anhydride using acetonitrile I dioxane medium in presence of pyridine.

{[Hydroxamic acids]= 0.0025 M [Acetic anhydride]= 0.0025 mol dm-3 }

Acids 303 K 308K Aceto. Diox. Aceto. Diox.

BHA 0.190 0.392 0.254 0.624 ±0.002 ±0.002 ±0.004 ±0.005

p-Me.BHA 0.140 0.299 0. 192 0.421 ±0.003 ±0.001 ±0.001 ±0.003

p-OMe.BHA 0.120 0.264 0. 142 0.362 ±0.001 ±0.004 ±0.003 ±0.002

p-Cl. BHA 0.098 0.218 0.124 0.309 ±0.002 ±0.001 ±0.003 ±0.003

Ph Ac. HA 0.124 0. 152 ±0.002 ±0.004

K, dm3mol-1s- 1

Acids t. H" t. S" kJ mol' 1 J mol' 1 K' 1

Aceto. Diox. Aceto Diox.

BHA 50.56 71 .68 -87.46 -78.36

p-Me. BHA 39.40 55.01 -122.88 -65.23

p-OMe.BHA 27.98 47.47 -162.09 -91 .05

p-Cl . BHA 25 .29 33.29 -172.03 -139.10

Ph Ac. HA 30.82 -152.32

hence, present reaction may take place between the ions of like charges 17 . The low magnitude of D.ft and the large magnitude of D.S# indicate that the reaction is entropy controlled. The low value of D.ft also points out that in the rate determining activated complex the bond-breaking and bond formation are of almost equal magnitude 18. The consistency of D.G# values suggests that similar mechanism is operative in all the acylation reactions of the hydroxamic acids 19. The log k values were plotted against the substitution constants (cr.) in acetonitrile and 1,4-dioxane at 303 K and the plots were found to be linear with slopes 0.8242 and 0.6172, respectively. This indicates that there is not satisfactory Hammett correlation as the acylating center of the hydroxamic acids is not directly attached to benzene ring. All the electron donating substituents nearly conformed to the straight line. This linearity in the Hammett plot suggests that the rate determining step in the acylation of the hydroxamic acids is the same. The positive sign of

K, dm3mol- 1s- 1

313 K 318 K 323 K Aceto. Diox. Aceto. Diox. Aceto. Diox.

0.363 1.02 0.502 1.601 0.704 ±0.002 ±0.001 ±0.002 ±0.02 ±0.001

0.246 0.607 0.304 0.902 0.412 ±0.003 ±0.005 ±0.00 1 ±0.003 ±0.001

0.172 0.501 0.215 0.680 0.254 ±0.002 ±0.001 ±0.002 ±0.002 ±0.004

0.146 0.362 0.1 73 0.437 0.203 ±0.004 ±0.001 ±0.002 ±0.004 ±0.005

0. 184 0.223 0.293 ±0.003 ±0.004 ±0.004

t. G" kJ mol' 1

Aceto Diox.

76.79 74.12

77.86 75 .27

78.71 75.75

80.00 76.48

78.50

p value indicates the development of negative charge (the disappearance of positive charge) at reaction center during formation of transition state20 in the rate limiting step of the overall reaction. Consistent with the above facts the following possible mechanisms are proposed for the reactions (see Scheme 1).

Consistent with the above proposed mechanism the rate expression for the base catalysed 0-acylation of hydroxamic acids has been derived.

Abbreviations used in rate expression Hydroxamic acid (substrate) = S; Anion of

hydroxamic acid (Intermediate 1) = In 1; Anion of complex (Intermediate - 2) = In2; Acetic anhydride chloride (Reagent) = R; Tertiary amine (Base) = B; Product= P; k 1, k2, k3, k4, K', K" =Constants

Rate law expression for catalysed acylation of hydroxamic acids

The product is formed in step-3 . Hence the rate of chemical reaction is given by Eqn (4) .

BURUNGALE eta/.: KINETICS OF BASE CATALYSED 0-ACYLATION OF HYDROXAMIC ACIDS 1987

(i) Non-catalysed acylation in acetonitrile

0 Fast 0 II k1 II -

R -C-NH-OH.:::;;r====~ R -C-NH-0 +H+ k2

(Substrate)

0 ~0 II - "- II

R-C-NH-0 +CH3-C\

(Intermediate- 1)

0 CH3-C/

II 0

(Reagent)

(Intermediate - 1)

slow k •

3

-

0 0 II I

R -C-NH-O-\-CH3

0 I

CH3-C II 0

(Intermediate - 2)

~ ~ fast ,.. R -C-NH-0-C -CH3 k4

Product + CH3COOH

(ii) Catalysed acylation in acetonitrile I 1,4-dioxane

dx

dt

~ Fk~t ~ R -C-NH-OH + B .;:;;c=~~ R -C-NH-0- + B+H

k2 [In 1] [S] [B] ----- (l)

~ ~~ R -C-NH-0- + CH3-C\

0 CH3-~/

0 [In 1] [R] ----- (2)

~ 9~ R -C-NH-0-~-CH3 + B+H

~ ~ ---'•~R -C-NH-0-C -CH3

~0 I

CH3-n 0 [In2]

Scheme I

+ CH3COOH +B

[P] (3)

It should be expressed in terms of measurable · · · ( 4) quantities.

or dx = k4 [ In2] [B+H] dt

Hence applying steady state condition to In2 which is formed in step-2 and removed in step-3 i.e.

Rate of formation of In2 = Rate of removal of In2 It is difficult to determine the concentration of

intermediate In2.

1988 INDIAN J. CHEM., SEC B, SEPTEMBER 2004

Tn2 = k3 [InJ] [R]

k4 [B+H] .. . (5)

Substituting the va lues of In 2 in Eqn (4) we get,

~= k3 [InJ][R] dt

.. . (6)

It is difficult to determine the concentrati on of intermediate-! (In 1) ex perimentally.

Therefore app lyin g the steady state cond iti on to fn 1 which is formed in step- ! and removed in back ward directi on in step-1 and in forwa rd direction in step-2.

We find th at rate of fo rmation of In 1 = rate of removal of In 1 (use of steady state co ndit ion).

k 1 [S] [B] = k 2 [TnJ] [B+H] + k3 [TnJ] [R] ... (7) k

1 [SJ [)3] = [In1]k

2 [B+H] +k3 [R]

. k 1[SJ [B] · [In t] = -------k2 [B+H]+ k3 [R] ... (8)

Substituting the va lue of ln1 in Eqn (6) we get,

clx k I [S] (B] = k3 [B+H] ... (9) cit k 2 +k3 [R]

Dividing the numerator and denom inator by k2 [B+H] we get,

as

dx

cit

clx

cit

=

=

k3 [R] k I [S] [B]

k2 [B+H]

k 2 [B+H] k3 [R]

k2 [B+H] + k2

[B+H]

k3 [R] k I [S] [B] k 2 [B+H]

k1 [R]

+ k2-[B+J-I]

BURUNGALE e1 a/.: KINETICS OF BASE CATALYSED 0-ACYLATION OF HYDROXAMIC ACIDS !989

12 Blatt A H, Organic Syll/hesis Col/ Vol II , (Jones Wiley & Sons), 1943.

13 Artemenko A I, J Org Che111 USSR (Eng! Trans!), 7, 1971 ,724. 14 Yale H A, Che111 Rev, 33, 1943, 209. 15 Okawara T, Kanazawa Y, Yamasaki T & Furukawa M,

Syll/hesis, 2, 1987, 183 and references cited therein. 16 Ghosh K K & Panday A, Indian J Che111 , 39B, 2000, 509.

17 ManeR A, Zaware B H & Ingle DB, J Indian Che111 Soc, 77 , 2000,214.

18 Gangawani H, Sharma P K & Banerji K K, Indian J Chem, 39A, 2000, 436.

19 Veeraiah T & Sondu S, Indian J Chem, 37 A, 1998, 328. 20 Peter Sykes; A guidebook to mechanism in organic chemistry,

(Orient Longman), reprinted 1995, 368.