Indian Journal of Chemistry Vol. 43B, October 2004, pp. 22 12-22 16

Theoretical studies of the acid-catalyzed condensation of ninhydrin with aromatic compounds

Sandip Kumar Kundu, Suven Das & Animesh Pramanik *

Department of Chemi stry. Uni versity of Calcutta, 92, A . P. C. Road, Kolkata 700 009

E-mail: animesh_in200 1@yahoo.co.in

Received 18 February 2003; accepted (revised) 20 May 2004

Semiempiri ca l quantum chemical methodology (A M I ) has been employed to f ind out the potential energy (P.E.) surface for the ac id-catalyzed condensat ion of ninhydr in with phenol. The AM I/RHF computed activat ion entha lpies (~H#) of the multi -steps chemical process show that the ac id catalyzed ary lation of ninhydrin should take place smoothl y at room temperature, very much consistent with the experimental resu lt s. NMR and crys tall og raphic studies show lhat the monoary lated ninhydrin adducts from phenols preferably remain in int ramolecu lar hemiketal form. A M I/RH F computed heats of formati on in some representati ve cases also favour such intramolecu lar hemikewl formati on.

(Pc: Int.Ct.7 C 07 C 39/04, 39/08

The chemi stry of ninhydrin has been studied ex tensively . Much of the work has been directed toward the reaction of ami nes with ninhydrin. 1.2 Primary amines and a-amino ac ids react at the C-2 pos iti on of ninhyd rin and eventuall y lead t the fo rmati on of a highly coloured co ndensation product known as Ruhemann's purple. In add iti on to ni trogen­based nucleophiles, the C-2 position of ninh ydri n has been foundlo react with sulfur-, oxygen-, and carbon­based nucleophiles.2-fi Due to hi gh electrophilic character of the C-2 position of ninhydrin , extensive research work is going on to examine the electrophilic chemistry of ninhydrin toward aromatic substrates. It has been reported7

.8 that ninhydrin reacts with phenols

111 acetic ac id under stirring at room temperature for

I and 2

AcOH -r.t

a : R1 = R2 = R3 = R4 =H (Phenol) b : R1 = OH, R2 = R3 =R4 =H (Catechol) c : R1 = R2 =R4 = H, R3 =OH (Quinol) d : R1 = R3 =R4 = H, R2 =OH (Resorcinol) e: R1 = R3 = H, R2 = R4 = OH (Phloroglucinol) f : R1 = R2= OH, R3 = R4 = H (Pyrogallol)

1 hI' to produce the monoarylated ni nhydrin adducls 1 in hi gh yie lds (Scheme I). From IH and 13C NMR studies (as well as from X-ray studi es9

) it is known that the adducts 1 preferably remain in hemiketal form 2 which prevents further arylation of ninhydrin to produce the diaryl atecl nin hydri n acld ucts.5 Recently an acid-catalyzed reaction of ninhydr in with arenes was described in wh ich 2,2-di aryl- 1 ,3-i ndanedi ones 3 were prepared . 10.1 I The reac tion takes nea rl y 6 hr fo r completion on stirring a mi xture of ninh ydrin and an appropriate arene in concentrated H}S04 at room temperature (Scheme II). A growing interest has been observed among the chem ists to use ninhydrin as a starting material in organ ic sy nthesis. I } In all these cases the hi ghly eletrophilic character of the C-2

Scheme I

KUNDU el al.: ACID-CATALYZED CONDENSATION OF NINHYDRIN WITH AROMATIC COMPOUNDS 2213

x

OH 6 H

3 x

x = H, F, C~ Br, I, -CHJ , -OCH:

Scheme II

position of ninhydrin has been exploited to derive the appropriate ninhydrin adducts.

Despite the immense utilities of these type of reactions in organic chemistry , so fa r no theoretical and mechani stic studi es have been reported . Therefore, the acti vati on barriers and various thermodynam ic parameters re lated to this reaction are not know n. One of the fundamental goals of chemists is to affect the chemical transformations in a controlled and des ired fashi o n. This requires an intricate knowledge of the course of reactions and the facto r which influence them Therefore, it would be of considerable inte rest to c riti ca ll y evaluate the activation barri ers of the mul ti-steps chemical transformation and also to find out the thermo­dynam ic stability of reactants, products and van ous intermediates in volving the process.

Reaction path examined

In order to study the potentia l energy (P.E.) surface theoreti ca ll y for the ac id-ca ta lyzed condensation of ninhydrin with vario us a romatic substrates, pheno l was chosen as the representat i ve theoretical model compound. ]n general the ninhydrin adducts of pheno ls remain in mo noary lated fo rm as the second arylat ion of ninhydrin is prevented by the formation of stable hemiketals 2 (Scheme I ) of the mo noarylated adducts 1. However in theore tical in vest igation we have carri ed out the acid catalyzed second ary lati on of the mo noaryl ated adducts 2-hydroxy-2-aryl - l ,3-indanediones which is a reasonably sati sfactory mode l study of diarylation of ninhydrin with aromatic hydrocarbons (Scheme II) and methoxy aromatic sys tems. Qualitatively the whole reaction pathway can be rationalized in various steps as depicted in Scheme III. In Step 1, the acid catalyzed formation of carbocation A from the protonated ninhydrin and in Step 2 the production of

Wheland intermedi ate B by the nuc leophilic attack of phenol to the carbocat ion A have been described . Step 3 depicts the irrevers ible formation of monoarylared ninhydrin adduct C from the Wheland intermed iate B by aromatization . In the formation of diaryl ated ninhydrin adduct F , the initi a l step is the generation of carbocation D (Step 4), fro m the protonared mo noary lated adduct C. Next the Wheland inte rmedi ate E is formed by the nucleophilic attack of phenol on the carbocation D as shown in Step 5. Finally the inte rmediate E produces the diary lated ninhydrin adduct 2,2-di ary l- J ,3-indanedione F by the irreversible e limin ation of proton (Step 6) .

Computational details

Tn the present study AM 113 methodology (MOPAe 93.00) has been employed to obtain the optimum ground states , intermedi ates and transitio n states (TSs) on the potential energy (P.E.) surface for the acid cata lyzed condensati on of ninhydrin with phenol. The determination of P.E. surface at RHF level was carried out in the usual way by considering the new ly fo rmed bond di stance or breaking of o ld bO,1d di stance as the reacti on coordinate. The reactants, products, intermediates and transitio n states were characterized by their Hess ian indices at the AM lIRHF level. The present theoretical studies besides prov iding information o n the nature of the minimum energy reaction pathway (MERP) and the e lectronic structures of the stationary points on the P.E. surface, yield activation enthalpies (L'lH#) as well. A detailed examination of the key geometric and energetic changes a long the reaction pathway has been carried out fo r each step.

Results and Discussion

Energy profile for monoarylation of ninhydrin : In order to find out the AMI/RHF computed P. E.

2214 INDIAN 1. CHEM., SEC B, OCTOBER 2004

~IOOH ~ OH + 2 o

step 3

"" step 5

A

"" c

o HO

E

step 4

-H+

step 6

F

o HO

D

B

o

o HO

OH

Scheme III

surface for the formation of carbocation A from the protonated ninhydrin (Step 1, Scheme III) . the breaking of C-O bond was chosen as the reaction coordinate. The true transitio n state TS I (Hessian 1) was located at C-O distance 2.12"\ , with a com uted heat of formation as 73.9 Kcallmol. The AMlIRHF calculated enthalpy of activation is found to be 7.3 Kcal/mol indicating a facile process, consistent with the experimental result. The computed heat of reaction shows that the formation of carbocation A is endothermic by 5.2 Kcallmol.

In search of the P.E. surface for the formation of the Wheland intermediate B (Step 2, Scheme III), the newly formed C-C bond distance between the ortho­position of phenol and the carbocation centre of B was chosen as the reaction coordinate. The partial bond length at the transition state TS2 (Figur'e 1) was found to be 2.54A.. The AM I IRHF computed enthalpy of activation is very small , 5.2 Kcallmol. The calculation also predicts that the formation of B is an exothermic process w ith a heat of reaction -15.6 Kcallmol. A very low activation barrier as well as a high exothermicity ensure a very facile formation of the Wheland intermediate B at room temperature. The expulsion of proton from the Wheland intermediate B irreversibly produces the monoarylated ninhydrin adduct C (Step 3, Scheme III). In the process, the

~Hr

(kcal/mol)

TS2 11 5.8 :

5'l'i : 'I , I ,

110.6 I ,

A+llhcl1ol : : I , I , I , I , I ,

'--' 95. 1 B

TS3 120.7

TS4 I 10 J.7

\ ,,....,.! I I , I

I ' I I ' 9 <)I I ' I I' I ~-.J

91.8 C '90.2

D+HP

Reaction coordinate

Figure 1-AM IfRHF Computed energy profile

breaking of C-H bond is the reaction coordinate . The theoretical investigation reveals that the lone pair of oxygen of the neighbouring -OH group at C-2 position of B acts as a base in abstracting the proton for aromatization. The transition state TS3 (Figure 1) is found to have a partial C-H bond length of 1.46"\ with a AMlIRHF computed heat of formarion 120.7 Kcallmol. The enthalpy of activation for the aromatization process has been theoretically estimated

KUNDU el al. : ACID-CATALYZED CONDENSATION OF NINHYDRIN WITH AROMATIC COMPOUNDS 2215

ninhydrin step 1

A ... .. step 2 step 3

8 .. C ... (protonated) LlH# = 7.3 kcal/mol

(TS1 ) LlH# = 5.2 kcal/mol

(TS2) LlH# = 25.6 kcal/mol

(TS3)

Scheme IV - AM1/RHF Computed activation enthalpies for first arylation

as 25 .6 Kcallmol , slightly over estimated at AM lIRHF level. However, the calculation predicts that in the process of monoarylation of ninhydrin the aromatization is the rate determining step (Step 3, Scheme III). Overall the theoretical investigation predicts that the acid-catalyzed condensation of ninhydrin with phenols to form the monoarylated adducts C should take place smoothly at room temperature, very much consistent with the experimental results (Scheme IV).

Energy profile for diarylation of ninhydrin: As we have seen in the formation of carbocation A (Step 1, Scheme III) , the formation of carbocation D (Step 4, Scheme III) is also a very facile process with a computed (AM lIRHF) activation barrier of about 9.9 Kcallmol (Figure 1). The process is slightly exothermic by 1.6 Kcallmol. The nucleophilic attack of phenol to the carbocation centre of D produces the Wheland intermediate E (Step 5, Scheme III) . The cOITesponding transition state TSS (Figure 2) was located at C-C bond distance 2.16A with a computed heat of formation 143 .6 Kcallmol. The calculated activation of enthalphy at AM lIRHF level is found to be 15.6 Kcallmol , which is higher than the activation barrier for the formation of intermediate B (Step 2, Scheme III) by 10.5 Kcallmol. This result is quite reasonable from steric paint of view. The second arylation of the monoarylated carbocation D is sterically hindered causing an increase in activation barrier. It has been experimentally observed that if the arene is sterically bulky such as 1,2,3-trimethoxy­benzene, the acid catalyzed condensation only generates the monoarylated adduct even after prolong reaction time. 14 The second arylation is prevented due to steric hindrance. The AMlIRHF computed activation barrier correctly reproduces the experimental results. Finally , the second arylated adduct of ninhydrin, 2,2-diaryl-I ,3-indanediones F will be formed from the Wheland intermediate E by the irreversible elimination of proton (Step 6, Scheme III). The calculated activation enthalpy is found to be 14.4 Kcallmol (Figure 2) at AM 1/RHF level. The computed results show that both Step 5 and 6 (Scheme III) have comparable activation barrier, 15 .6 and 14.4 Kcallmol respectively. Importantly, the

~Hf

(kcal/mol)

TSS 143.6 /'----. / I / I / I / I / I / I

/ \ :15.6 I

/ I / I / I / I

---J \ 128.0 I

D+phenol \ I I I I I /

I---J

12 1.6

E

TS6 136. 1 ;--,

/ I / I

/ ' / ' , ' , \

,\4.5 \ I \--125.4

F

Reaction coord inate

Figure 2-AM IIRHF Computed energy profi le

theoretical results demonstrate that like monoarylation, the diarylation of ninhydrin should take place smoothly at room temperature in acidic medium (Scheme V), provided the arene is sterically small such as various aromatic hydrocarbons described in Scheme II.

Thermodynamic stability of 1,3-dioxoindanes 1 and hemiketals 2. NMR studies in solution phase5

and crytallographic studies9 in solid state show that the monoarylated ninhydrin adducts 1 from phenol s (Scheme I) preferably remain in intramolecular hemiketal form 2. In order to get an idea about relative thermodynamic stability of 1,3-dioxoindanes 1 and the corresponding intramolecular hemiketals 2 and consequent equilibrium position between the two we have carried out AMI calculations on some representative systems (Table I). The results show that the hemiketals 2 are generally more stable than the corresponding 1,3-dioxoindanes 1. The observed lowest energy difference between 2 and 1 is 2.5 Kcal/mol for the ninhydrin adduct of catechol and the highest one is 6.0 Kcallmol for that of phloroglucinol. Similarly it was found out that energy difference are 3.0,3.2 and 2.7 Kcallmol for the ninhydrin adducts of quinol, resorcinol and pyrogallol respecti vely. Comparable energy difference (3.1 Kcallmol) is also found for analogous product from phenol itself. According to Boltzman law, all these energy differences are more than enough to drive the

2216 INDIAN J . CHEM., SEC B, OCTOBER 2004

step 4 o ... c ...

step 5 step 6 .... E DH# = 9.9 kcal/mol

(T84) DH# = 15.6 kcal/mol

(T85)

-----i .. ~ F DH# = 14.4 kcal/mol

(T86)

Scheme V - AM1 /RHF Computed activation enthalpies for second arylation

Table I-AM I Calculated heats of formation, t.Hr(Kcal/mol)

Substrates

Phenol

Catechol

Quinol

Resorcinol

Phloroglucinol

Pyrogallol

t.Hr of ninhydrin adducts 1

( 1,3-dione)

-82.0 -85. 1

- 125.8 - 128.3

- 125.2 -128.2

- 126.6 - 129.8

-167.5 - 173.5

-170.2 - 172.9

t.(t.Hr) 2

(helll i-ketal)

3.1

2.5

3.0

3.2

6.0

2.7

equi librium in favour of the hemiketals 2 over 1,3-dioxoindanes 1 (Scheme I) . The refore, the AMIIRHF computed heats of formation correctly reproduces the observed experimental result s.

Conclusion

The theoret ical investigation shows that the acid cata lyzed formation of carbocations A and 0 (Scheme III) for both first and second ary lation of ninhydrin , are very fac ile processes. The format ion of Wheland in termediates Band E are also very fac ile, the requ ired activation barriers are just 5.2 and 15.6 Kcal/mol respectively . However, the in'eversible aromatization in the formation of monoary lated ninhydrin adducts C (Step 3, Scheme III) has rel at ively higher acti vation barrier of 25.6 Kcal/mol at AM lIRHF level. The model theoretical studies with phenol predict that for a sterically small arene, the acid catalyzed condensation with ninhydrin is a very facile process at room temperature. The calculation also correct ly reproduces that the intramolecular hemiketals of monoarylated ninhydrin adducts from

phenols are thermodynamically more stabl e than the corresponding I ,3-diketo fo rm .

Acknowledgement

Author (SKK and AP) are thankful to UGC , New Delhi and Un ivers ity of Calcutta for providing financial support. One of the authors (SO) is grateful to CS IR, New Delhi for a JRF.

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