computational study of maleamic acid cyclodehydration with acetic anhydride

Computational Study of Maleamic AcidCyclodehydration With Acetic Anhydride

MIRCEA CONSTANTINESCU,1 DANIELA IVANOV2

1Department of Physical and Theoretical Chemistry, Al. I. Cuza University, Faculty of Chemistry,11 Carol Blvd, 700 506 Iasi, Romania2P. Poni Institute of Macromolecular Chemistry, 41A Gr. Ghica Voda Alley, 700 487 Iasi, Romania

Received 28 October 2004; accepted 10 January 2005Published online 28 November 2005 in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/qua.20889

ABSTRACT: The reaction mechanisms of N-substituted maleamic acids (MA)cyclodehydration (CDH) to the corresponding maleimides (M) and isomaleimides (IM) andIM rearrangement to M were studied by the PM3 Hamiltonian with charge model 1(CM1P) of the AMSOL computational method with solvation effect in order to establish themost probable pathways. CDH was considered in the presence of acetic anhydride in thepresence of an acetate anion or triethylamine as the dehydrating agent in CH2Cl2 as thesolvent. In the first step, our computational results supported carboxylic proton losses,provided by a nucleophilic center on the dehydrating agent. In the next step, maleamic acidanion could either add a molecule of a dehydrating agent (path A) or cyclicize (path B).Our results indicate the path B to require more energy than path A, so path B is consideredless likely to occur. The formation (path A) of an anion complex I2 between the anion ofMA and the dehydration agent was supported as well as acetate anion loss to form theneutral mixed anhydride I3. The ring closure to M or IM occurs only after I3 amide protonloss, meaning that the dehydrating agent necessitate another nucleophilic center. Thecyclization of I4 anion over amide nitrogen or oxygen to the reaction outcome depends onthe electronic effect of amide nitrogen substituent. The same results were obtained studyingCDH of N-substituted ophthalmic acids with acetic anhydride and for MA with N,N�-dicyclohexylcarbodiimide as dehydrating agent, in the same solvent. In such circumstances,one can consider them the common features of a general CDH reaction mechanism of MA.Our computational results found the IM to M rearrangement to correspond to the reversiblefinal path of synthesis mechanism although the other investigators considered it to takeplace under a different reaction. They also supported the importance of the acetate anion inboth cyclization and rearrangement mechanisms; the presence of tertiary amine blocks theacetic acid formed during reaction, determines I3 amide proton loss and preventsrearrangement. The theoretical conclusions are consistent with the experimental results.© 2005 Wiley Periodicals, Inc. Int J Quantum Chem 106: 1330–1337, 2006

Key words: reaction mechanism; PM3/AMSOL/CM1P; cyclodehydration;rearrangement; acetic anhydride; isomaleimide; maleimide

Correspondence to: D. Ivanov; e-mail: [email protected]

International Journal of Quantum Chemistry, Vol 106, 1330–1337 (2006)© 2005 Wiley Periodicals, Inc.

Introduction

S tandard synthesis of N-substituted maleim-ides (M) and their N-substituted isomers iso-

maleimides (IM) is based on the cyclodehydration(CDH) of the corresponding N-substituted mal-eamic acids (MA) prepared by known processes [1].MA cyclic dehydration usually leads to a mixture ofM and IM in different ratio (Scheme 1), althoughmany investigators investigating the synthesis of Mdid not give a proper account of possible side prod-uct.

Theoretical backgrounds of the reaction mecha-nism have not been completely elucidated, despitethe large interest in practical applications of theproducts. M have been known for some time andhave been widely used in organic synthesis [2], inpolymer chemistry [3], and in biochemistry [4].During the past few years, M with functionalgroups have received increasing attention due totheir ion-exchange properties, optical and catalyticactivities, fire-resistance characteristics, high sensi-tivity and versatility in lithographic applications, ordue to their ability to function as a photoinitiator[5–8]. IM are also compounds of wide interest.They are used in organic synthesis [9], as mono-mers in oligomers [10, 11], homopolymers [12], orcopolymer synthesis [13], or as fungicides and de-foliants [14]. IM as derivatives of chromophoresmay be readily coupled to compounds of clinical or

biological interest for the detection and measure-ment of biological compounds [15, 16].

Direct pyrrolytic CDH requires high activationenergy that practically is ensured by high temper-atures and makes the method disadvantageous[17]. The use of dehydrating agents facilitates CDH,making it possible even in mild conditions. Theliterature mentioned as possible dehydrationagents for MA cyclic dehydration acetic anhydridein the presence of sodium acetate [18–20].or trieth-ylamine [21–23] trifluoroacetic anhydride withoutan acid acceptor [24] or in the presence of tertiaryamine [25–27], N,N�-dicyclohexylcarbodiimide [22],etc. The literature reports mainly synthetic aspectsbut just few papers refer to the possible mechanismof MA cyclic dehydration.

IM are considered the kinetically favored prod-ucts of MA cyclic dehydration; it is known thattheir tendency to rearrange to the thermodynami-cally favors M [28]. IM (or N,N�-bisisomaleimide)rearrangement in the presence of specific catalystsrepresents a convenient procedure for preparationof high purity M (or N,N�-bismaleimide) in mildconditions and good yields [29–31]. Different rear-rangement mechanisms in respect to synthesespathways were reported.

The present study reconsiders the cyclic dehy-dration of the MA with the goal of elucidating thefeasible reaction paths for both CDH reaction andIM rearrangement to M. Two different substituentswere taken into account, an electron-releasing ofalkyl type (Bu-) and an electron withdrawing ofaryl type (Ph-). Acetic anhydride in the presence ofeither acetate anion or tertiary base was consideredas dehydrating agent, in CH2Cl2 as the solvent.

Method and Theoretical Background

The geometry optimizations of reactants, reac-tion intermediates, products, and transition stateswere performed using the PM3 Hamiltonian withcharge model 1 (CM1P) of the AMSOL computa-tional method with solvation effect [32] on an IN-TEL P4 1.7 GHz PC Computer. Because of the com-plexity of the reactive system in the study, andbecause the main goal of our study is the identifi-cation of feasible reaction paths, we considered theselected level of theory a good compromise. More-over, the activation barriers calculated usingsemiempirical methods appear to be slightly higherthan the full B3LYP [33].

SCHEME 1. General cyclodehydration (CDH) of N-substituted maleamic acids (MA) to the correspondingmaleimide (M) and isomaleimide (IM).

MALEAMIC ACID CYCLODEHYDRATION WITH ACETIC ANHYDRIDE

VOL. 106, NO. 6 DOI 10.1002/qua INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY 1331

The energy (E0) corresponding to one geometryminimization is considered the sum of the corre-sponding total energy (ET), Gibbs energy of solva-tion (�Gsolv) and zero-point energy (ZPE). In con-trast, we admitted that the energy evolution duringa chemical reaction can be estimated only for con-stant reactive systems (consisting of the same typeand number of atoms) so the energy of the reactivesystem represents the sum of the energies of allcomponents in the system.

Transition states (TS) were calculated from theevolution of reaction energy and proved by theimaginary values of the corresponding frequencies.The length of the new modifying bond was selectedas the reaction coordinate, and the other reactionparameters were minimized. The maximum of en-ergetically profile represented the nearest TS andwas used as input for the eigenvector following(EF) algorithm to calculate TS. IRC analyze con-firmed that the resulted TS leads either to the reac-tants or to the supposed products. There were an-alyzed several reaction paths being selected theones corresponding to the lowest TS energy. Amonotone increase of energy indicated that TScould not be located; therefore, the reaction could

not take place, and another mechanism was to beconsidered.

We admitted that reactions take place in distinctsteps, each involving the formation and/or break-ing of one bond on the basis of the Dewar statementof normally prohibited synchronous multibondprocesses [34]. As calculations found the differ-ences between the energies of the frontier orbitals tobe �6 eV [35, 36], we considered CDH a charge-controlled reaction. In such circumstances, chemicalreactivity is ruled by the values of the highest op-posite charges.

Results and Discussion

CYCLODEHYDRATION MECHANISM IN THEPRESENCE OF ACETATE ANION

The first step was considered the formation ofmaleamic acid anion by nucleophilic acetate anionattack over MA (0 state). The geometry optimiza-tion indicated the O atom of the acetate anion andamidic C or carboxylic H from MA (with similarvalues so that both reactions could theoretical oc-cur) as the most probable interacting centers. Tak-

TABLE I ______________________________________________________________________________________________Energies, frequencies (in square brackets), and components of reaction system for Bu-maleamic acid CDH(path A).

Reaction states

Others components in the system(mol)

ET � �Gsolv (eV) ZPE (eV) E0 (eV)Acetic

anhydrideAcetateanion

Aceticacid

0 1 1 — �4517.33219 9.57185 �4507.76034TS0 [�884.1 cm�1] 1 — — �4516.81305 9.34252 �4507.47053I1 1 — 1 �4517.41818 9.60988 �4507.80830TS1 [�197.2 cm�1] — — 1 �4516.64263 9.57441 �4507.06822I2 — — 1 �4516.80065 9.57177 �4507.22888TS2 [�218.5 cm�1] — — 1 �4516.42463 9.56361 �4506.86101I3 — 1 1 �4516.89454 9.54389 �4507.35065TS3 [�2397.5 cm�1] — — 1 �4516.50651 9.23819 �4507.26831I4 — — 2 �4517.07108 9.58655 �4507.48453TS4O [�255.3 cm�1] — — 2 �4516.38278 9.48986 �4506.89292I5O — — 2 �4516.54006 9.53478 �4507.00528TS5O [�269.7 cm�1] — — 2 �4516.20175 9.48687 �4506.71489IM — 1 2 �4517.05995 9.49203 �4507.56792TS4N [�214.2 cm�1] — — 2 �4516.55801 9.54319 �4507.01482I5N — — 2 �4516.88136 9.53456 �4507.34680TS5N [�424.3 cm�1] — — 2 �4516.59700 9.45998 �4507.13702M — 1 2 �4517.62565 9.51097 �4508.11468

CONSTANTINESCU AND IVANOV

1332 INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY DOI 10.1002/qua VOL. 106, NO. 6

ing into account the reaction over C, the relatedactivation energies were found �32 kcal/mol forBu-maleamic acid and 30 kcal/mol for Ph-mal-eamic acid (1 kcal � 4.184 kJ). However, the attackover H requires lower activation energy (Table 1, 2)recommending this path. Therefore this reactionleads the most probable to TS0 and finally to I1.

The reactions between carboxylic O from I1 an-ion and either carbonylic C from acetic anhydrideor amidic C from I1 could take place in the next stepwith the same probability. The former attack could

lead to the addition of the dehydration agent to I1(path A) and the latter to the cyclization of the MAanion (path B) as previously suggested by Cotter etal. [22] (see Scheme 2).

Path A

The addition reaction leads by TS1 to I2 anion.This stage was not considered by the previous pro-posed mechanisms. Into the next step I2 readilystabilize by ejection of the acetate anion by TS2 tothe mixed anhydride I3 (Scheme 3).

The mixed anhydride I3 could theoretically fur-ther cyclicize either over carboxyl C by amide O (a)or N (b) attack or over amide carbonyl C by theanhydride O (c) or carboxyl O (d) attack. Compu-tational results did not indicate any possible TS

SCHEME 2. I1 maleamate anion formation and theo-retical reactivity: addition (path A) and cyclization (pathB).

TABLE II _____________________________________________________________________________________________Energies, frequencies (in square brackets), and components of reaction system for Ph-maleamic acid CDH(path A).

Reaction states

Others components in thesystem (mol)

ET � �Gsolv (eV) ZPE (eV) E0 (eV)Acetic

anhydrideAcetateanion

Aceticacid

0 1 1 — �4691.351911 8.898283772 �4682.45362TS0 [�935.11 cm�1] 1 — — �4690.805722 8.504695996 �4682.30102I1 1 — 1 �4691.417669 8.732471317 �4682.68519TS1 [�294.2 cm�1] — — 1 �4690.50777 8.697999324 �4681.80977I2 — — 1 �4690.698987 8.669814675 �4682.02917TS2 [�184.6 cm�1] — — 1 �4690.596472 8.717121524 �4681.87935I3 — 1 1 �4691.069854 8.665521936 �4682.40433TS3 [�2429.7 cm�1] — — 1 �4690.471874 8.409215079 �4682.06265I4 — — 2 �4691.111678 8.783593933 �4682.32808TS4O [�256.8 cm�1] — — 2 �4690.488685 8.640719446 �4681.84796I5O — — 2 �4690.591282 8.695310942 �4681.89597TS5O [�266.0 cm�1] — — 2 �4690.200139 8.643754716 �4681.55638IM — 1 2 �4691.056653 8.711224428 �4682.34542TS4N [�225.5 cm�1] — — 2 �4690.561527 8.636947039 �4681.92458I5N — — 2 �4690.74394 8.666736044 �4682.07720TS5N [�227.9 cm�1] — — 2 �4690.508274 8.607548282 �4681.90072M — 1 2 �4691.551751 8.685641439 �4682.86611

SCHEME 3. Formation of mixed anhydride I3 and in-ternal proton donation to I4.



corresponding to the strained cyclic structures thatcould result in a–d structures meaning that otherroute is more probable to occur. Positive charges oncarboxylic C or amidic C from I3 are higher than theone on amide H, meaning that the attack of acetateanion O over these centers could be favored (e andf, respectively). Although these reactions are ener-getically favored, the resulted compounds do notpresent any interest.

The amide proton donation with the acetate an-ion I4 formation (Scheme 3) appears to be morefeasible path. According to our computational re-sults, this way is also energetically favored (TablesI and II) probably because it supposes the minimummolecular rearrangements.

For the last steps, the highest opposite charges appearover amide O or N and carboxylic C in I4 or carbonylicC from acetic anhydride. From both a collision statisticand atomic charge point of view, the internal cyclizationis the most probable path (Scheme 4).

Internal cyclization could occur either by O at-tack with I5O formation leading to IM or by Nattack when I5N results, and finally M is obtained.It is to be mention that cyclization is also a chargecontrolled reaction and can occur only after amideproton loss. Our calculations confirmed I5O andI5N intermediates as possible to be formed as pre-vious predicted by Cotter and colleagues, not insynthesis, but in their rearrangement mechanism.

Tables I and II present the most important pa-rameters of the system during reaction, reactionstates energies (ET��Gsolv, ZPE, E0) and imaginaryvalues of the frequencies � corresponding to the TS.

Relative energies with respect to initial states ascalculated for the most probable paths for CDH

with acetic anhydride along path A are presented inFigure 1 for Bu-maleamic acid and in Figure 2 forPh-maleamic acid, respectively.

Comparison of the two profiles shows that themixed anhydride I3 has a lower energy for Ph-maleamic acid, suggesting an increased stability.This intermediate structure was proved experimen-tally by infrared (IR) spectra [37]. Furthermore, theactivation barrier necessary for MA to react alongpath A require as much energy (20.7 kcal/mol) toform only M (TS2) from Bu-maleamic acid as forIM (TS5O) from Ph-maleamic acid. This conclusioncould explain the tendency of the symmetricalproduct (M), exclusive formation from Bu-mal-eamic acid, and the mixture of the two productsfrom Ph-maleamic acid, as observed experimen-tally.

SCHEME 4. Internal cyclization of mixed anhydrideanion I4 to the main products.

FIGURE 1. Schematic representation of the relativeenergy profile related to the initial state for CDH of Bu-maleamic acid to M and IM products, using acetic an-hydride in CH2Cl2 (path A).

FIGURE 2. Schematic representation of the relativeenergy profile related to the initial state for CDH of Ph-maleamic acid to M and IM products, using acetic an-hydride in CH2Cl2 (path A).



Our calculations support that the rearrangementreaction occurs by the final paths of synthesis mech-anism, but following the reversible way (Scheme 4),although the previous papers proposed differentmechanisms for rearrangement and synthesis reac-tions. Thus, acetate anion attacks IM at the carbox-ylic C center, giving an intermediate that dissociateto I4 anion. It could further proceed to cyclizationover amide O, leading to I5N intermediate andfinally to M. The activation energy necessary for thefirst reaction is quite high (Figs. 1 and 2) as ob-served experimentally [29]. This presumption ex-plains the acetate anion importance (M is obtainedby IM rearrangement only in the presence of ace-tate anion) as well as why heat alone did not causerearrangement [20, 22].

Path B

The cyclization of I1 anion (Scheme 2) by TSJ1lead to J2 intermediate that into the next step couldadd the dehydrating agent to give by TSJ2 to J3(Scheme 5). J3 intermediate could eject an acetateanion and J4 neutral intermediate is formed. IMwould results as solely reaction product only afteramide proton donation to the acetate anion.

Our computational results indicate that only J3intermediate formation (TSJ2)would require �38kcal/mol, a value greater than the energy asked bypath A. In such circumstances path B is less probableto take place so path A appears to be more predict-able. In contrast, path A is the single that can explainthe formation of both IM and M as main products.

CYCLODEHYDRATION MECHANISM IN THEPRESENCE OF TERTIARY AMINE

In some other experiments, CDH consists of thetreatment of MA solution with triethylamine(NEt3), followed by the addition of acetic anhy-dride. Our calculus indicates as the first step theformation with the highest stability of a molecularcomplex between MA and NEt3. Carboxylic proton

donation to NEt3 requires supplementary energy(Table III) when the corresponding ion pair results.

When acetic anhydride is added the mechanismtake place along the same steps previous described(path A). The resulting acetic acid reacts with ter-tiary amine [22] to give a molecular complex similarto MA. In this way, the rearrangement reactionbecomes less possible. Moreover, I3 could theoret-ically interact with either acetate anion or NEt3

(Scheme 6) to give I4 intermediate.The first reaction would require the sum of acti-

vation energy corresponding to acetate anion ex-traction from molecular complex with NEt3 (23.53kcal/mol) and the activation energy correspondingto TS3 (1.90 kcal/mol for the Bu- and 7.88 kcal/molfor the Ph-substituent). The latter reaction necessi-tates the sum of energy corresponding to NEt3 de-livery from molecular complex with acetic acid(1.45 kcal/mol) and the activation energy corre-sponding to TS3NEt3 (15.76 kcal/mol for the Bu-and 14.90 kcal/mol for the Ph-substituent). If com-pare the energies necessary for the two reactions, itis obvious that the reaction with NEt3 is energeti-cally favored. Hence, the role of NEt3 is to soak upthe amide proton, as previous supposed [23].

To test our theoretical assumptions, we studiedCDH of Bu- and Ph-maleamic acids in conditionpresented elsewhere [38]. The reactions were con-ducted at room temperature (25°C), at reflux inCH2Cl2 (40°C) and at reflux in C6H6 (80°C). Reac-tion evolution was easily detected by thin-layerchromatography [30], using TLC aluminum sheetsSilica gel 60 F254 (Merck) and a mixture of C6H6/acetone of 3:1 as the solvent. Visualization wasrealized under short wave UV at 254 nm. WhenNEt3 was added over MA suspension the rapidsolubilization occurred. We noted that Bu-mal-eamic acid leads to M and that IM appears only astraces; Ph-maleamic acid cyclicizes to a mixture of�40% IM an 60% M; the excess of acetic anhydrideaffects the reaction by favoring the side reactions[39] that appear as a new spot. These conclusionsare consistent with the theoretical results.

SCHEME 5. Possible reactions along path B.



Conclusions

Calculations at the AMSOL/PM3/CM1/(SM5.4P)level of method showed the following evidence formaleamic acids CDH with acetic anhydride:

1. The first step consists of carboxylic protondelivery, meaning that the dehydration agenthas a nucleophilic center in need.

2. The formation of a neutral complex interme-diate between MA and the dehydration agentsupposes that the dehydration agent mustalso possess an electrophilic center.

3. Cyclization occurs in the final steps, and onlyafter amide proton loss, when electrostatic at-traction exceeds the strain in the cycle; it is

obvious that the dehydrating system has asecond nucleophilic center in need.

4. The negative intermediate cyclicize overamide nitrogen or oxygen, mainly dependingon the electronic effect of amide nitrogen sub-stituent [19, 40]; our results confirm that aro-matic substituent increases chemical stabilityof the reaction states by conjugation effect.

5. The resulting heterocycle is energeticallymore stable than the neutral intermediate.

6. IM rearrangement to M proceeds under thefinal synthesis mechanism paths but follow-ing reversible way I5O3 I43 I5N (Scheme 4,Figs. 1 and 2); it is obvious that heat and thepresence of acetate anion facilitate the reac-tion and the presence of a tertiary amine pre-vent it.

7. The role of the tertiary amine is to interceptthe acetic acid produced during the reactionand to soak up the amide proton of neutralintermediate.

Furthermore, the results of our previous studyon the same reaction system, using N,N�-dicyclo-hexylcarbodiimide as dehydrating agent, in thesame solvent [17] led us to the same 1–5 conclusionspresented. In contrast, our calculus confirms thesame queries as necessary for N-substituted oph-thalmic acids CDH with acetic anhydride. These

TABLE III ____________________________________________________________________________________________Energies for MA (Bu- and Ph-substituted) and acetic acid reaction with triethylamine (NEt3) to thecorresponding ion pairs.*

Reaction states ET � �Gsolv (eV) ZPE (eV) E0 (eV)

RBuCOOH � NEt3 �3298.8 11.0190 �3287.8RBuCOOH . . . NEt3 �3298.9 11.1038 �3287.8TSBu [�2336.3 cm�1] �3297.9 10.7341 �3287.2RBuCOO� . . . H�NEt3 �3298.3 11.0499 �3287.2RBuCOO� � H�NEt3 �3297.8 11.0050 �3286.8RPhCOOH � NEt3 �3472.6 10.2008 �3462.4RPhCOOH . . . NEt3 �3472.8 10.2565 �3462.6TSPh [�2351.6 cm�1] �3471.9 9.91484 �3462RPhCOO� . . . H�NEt3 �3472.2 10.2684 �3462RPhCOO� � H�NEt3 �3471.7 10.1980 �3461.5CH3COOH � NEt3 �1992.9 7.1488 �1985.8CH3COOH . . . NEt3 �1992.9 7.1219 �1985.8TSCH3 [�2301.6 cm�1] �1991.9 6.7828 �1985.1CH3COO� . . . H�NEt3 �1992.2 7.1559 �1985CH3COO� � H�NEt3 �1991.7 7.1354 �1984.6

* Frequencies of the corresponding TS are given in square brackets.

SCHEME 6. Internal proton donation of mixed anhy-dride I3 in the presence of NEt3.



general conclusions lead us to consider them as thecommon features of a general CDH reaction mech-anism of MA.

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computational study of maleamic acid cyclodehydration with acetic anhydride

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