Synthesis of Benzimidazo [1, 2-c] quinazolines via Metal-Free

Mar 7, 2016 - (PIDA)-mediated intramolecular C−H bond cycloamination reaction. This method results in a direct oxidative C−N bond formation in a c...
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Synthesis of Benzimidazo[1,2‑c]quinazolines via Metal-Free Intramolecular C−H Amination Reaction Chao Shen,† Lingfang Wang,‡ Ming Wen,‡ Hongyun Shen,§ Jianzhong Jin,*,†,‡ and Pengfei Zhang*,§ †

College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310015, China College of Petroleum Chemical Industry, Changzhou University, Changzhou 213164, China § College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China ‡

S Supporting Information *

ABSTRACT: A series of benzimidazo[1,2-c]quinazolines have been synthesized via phenyliodine(III) diacetate (PIDA)-mediated intramolecular C−H bond cycloamination reaction. This method results in a direct oxidative C−N bond formation in a complex molecule by using a metal-free protocol. A plausible reaction mechanism was described on the basis of the experiments. Some new compounds were evaluated for their antitumor activity against HUH 7 and SK-HEP-1 hepatocarcinoma cell line. Among the compounds screened, 4m was found to be the most active compound against HUH 7.

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INTRODUCTION The synthesis of derivatives of quinazolines has been the focus of great interest recently.1−3 This is in part due to the broad spectrum of biological properties such as anti-inflammatory,4 antimalarial,5 anticonvulsant,6 antidiabetic,7 and antitumor activities.8 Among the quinazoline derivatives, benzimidazo[1,2-c]quinazolines have acquired increased relevance in medicinal chemistry in the past few years.9,10 A variety of methodologies for construction of the compounds containing this core structure were reported. Khajavi and co-workers reported an efficient and facile synthesis of 6-substituted benzimidazo[1,2-c]quinazolines via cyclocondensation of ortho esters with 2-(2-aminophenyl)benzimidazole using microwave irradiation and conventional heating methods (Figure 1a).11 Fu and co-workers developed a general copper-catalyzed reactions of substituted 2-(2-halophenyl)-1H-benzo[d]imidazoles with αamino acids to give the benzoimidazo[1,2-c] quinazolines in moderate to good yields (Figure 1b).12 Very recently, Koutentis et al. introduced a Cu(OTf)2-catalyzed PIFA-mediated oxidative cyclization of 4-anilinoquinazoline-2-carbonitriles affording substituted products and a Pd(OAc)2- and CuIcatalyzed nonoxidative coupling of 4-(2-bromoanilino)benzoimidazo[1,2-c]quinazolines uinazoline-2-carbonitrile to yield the corresponding products in high yields (Figure 1c). Furthermore, an efficient Pd(0)-catalyzed nonoxidative C−N coupling was also developed for the construction of benzoimidazo[1,2-c]quinazolines by direct cyclization of 3-(2bromophenyl)-4-imino-3,4-dihydroquinazoline-2-carbonitriles in satisfactory yields (Figure 1d).13 However, the application of these methods is usually limited by disadvantages associated with the use of uncommon ligands, toxic metal catalysts, special starting material, and harsh reaction conditions. Because of these disadvantages of the existing methods, there has been increasing demand for more efficient and environ© XXXX American Chemical Society

mentally benign methodologies for the preparation of the title heterocyclic compounds. In the past few years, metal-free C−N coupling via C−H activation has emerged as a promising tool to construct nitrogen-containing heterocycles.14−19 We herein report a new metal-free method for a series of biologically meaningful benzimidazo[1,2-c]quinazolines via a direct oxidative C−N bond formation using mild reaction conditions, simple workup, and the ready availability of the starting substrates. Our design of the new methodology hinged on an suitable reaction substrate which would not only have the 4anilinoquinazoline skeleton as the precursors for the C−N coupling, but also can give the resulting products which have the potential biological activities (Figure 2). The discovery of the anticancer drugs erlotinib in the early 2000s prompted intensive research on 4-anilinoquinazoline compounds since then, 20 leading to the development of new attractive compounds such as gefitinib, lapatinib, icotinib and afatinib. Nevertheless, it is still necessary to develop novel epidermal growth factor receptor targeting therapeutic agents with enhanced potency that can overcome drug resistance. Recently, our group has developed a novel route for the synthesis of erlotinib derivatives which showed good cytotoxicity against human hepatocellular carcinoma BEL-7402cells.21 Prompted by these results and continuing our longstanding interest in developing novel C−X(X = N, S) bond-forming reactions for efficient construction of heterocyclic frameworks,22−25 it was decided to synthesize a diverse range of erlotinib-related benzoimidazo[1,2-c]quinazolines derivatives. Received: November 23, 2015 Revised: March 4, 2016 Accepted: March 6, 2016

A

DOI: 10.1021/acs.iecr.5b04452 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

Research Note

Industrial & Engineering Chemistry Research

Scheme 1. Synthesis of 4-Anilinoquinazoline 3a−o

Table 1. Optimization of Reaction Conditionsa

Figure 1. Recent development for construction of benzoimidazo[1,2c]quinazolines.

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RESULTS AND DISCUSSION The starting 4-anilinoquinazoline 3 (Scheme 1) was prepared by the following two-step process:3 (a) chlorination of the appropriate quinazolinone 1 with thionyl chloride in DMF to give the chloroquinazoline 2 in almost quantitative yields, and then (b) 2 was condensed with the appropriate arylamines in acetonitrile at room temperature to give the 4-anilinoquinazoline 3 in 75−95% yields (see Supporting Information for details). Then 3a was chosen as the model substrate to probe the feasibility of the proposed conversion. Inspired by a report from Fossey and co-workers,26 on the synthesis of benzo[4,5]imidazo[2,1-i]purines, we hoped to employ the similar C−H activation/intramolecular amination approach for the benzoimidazo[1,2-c]quinazolines derivatives. Unfortunately, application of the Fossey methodology to 3a only afforded the desired product 4a in low yield (Table 1, entry 1). We were pleased to observe moderate conversion when no metal catalyst was used (Table 1, entry 2). After much experimentation on optimizing the solvent, it was found that the use of highly polar solvents like 1,1,1,3,3,3-hexafluoroiso-

entry

oxidant (equiv)

solvent

temp (°C)

time (h)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

PhI(OAc)2(2) PhI(OAc)2(2) PhI(OAc)2(2) PhI(OAc)2(2) PhI(OAc)2(2) PhI(OAc)2(2) PhI(OAc)2(2) PhI(OAc)2(1) BQ(2) K2S2O8(2) CH3COOOH(2) PhI(OAc)2(2) PhI(OAc)2(2) PhI(OAc)2(2) PhI(OAc)2(2)

AcOH/Ac2O toluene CH3CN DCE EtOAc HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP

80 80 80 80 80 80 40 40 40 40 40 40 40 40 rt

6 6 6 6 6 6 6 6 6 6 6 1 0.5 0.25 0.5

32c 50 23 45 trace 55 85 46 0 0 0 85 87 50 45

a Reaction was carried out with 3a (1 mmol), oxidant (2 mmol) in solvent (3 mL) under air. bIsolated yields. cFor the reaction, 10 mol % of Cu(OTf)2 was used as catalyst.

propyl alcohol (HFIP) afforded product 4a in high yield (Table 1, entries 3−6). This polyfluorinated alcohol has high polarity, high ionizing power, and weak nucleophilicity, as well as better ability to solubilize reaction substrates. It is noted that the HFIP has been used as an optimal solvent for recent C−N coupling reactions.14d,e In addition, it is found that satisfactory yield was achieved when lowering the reaction temperature to 40 °C (Table 1, entry 7). While checking the minimum requirement of oxidant loading for the best performance of the reaction, it was found that decreasing the catalyst loading will affect the yield of the product. For example, when 1 equiv of oxidant was used, only 46% yield was achieved (Table 1, entry 8). Next, various oxidants such as BQ, K2 S 2O 8, and CH3COOOH were tested, which revealed that PhI(OAc)2 generally gives better results than these oxidants (Table 1,

Figure 2. Structure of erlotinib and bioactive benzoimidazo[1,2-c]quinazolines. B

DOI: 10.1021/acs.iecr.5b04452 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

Research Note

Industrial & Engineering Chemistry Research Table 2. Synthesis of benzoimidazo[1,2-c]quinazolines via metal-free C−N couplingsa

a

Reaction was carried out with 3 (1 mmol), PhI(OAc)2 (2 mmol) in HFIP (3 mL) under air. bIsolated yields.

and m-ethynyl substituted substrates (3k and 3m) were employed. If steric bulk was increased even further to a 2,5dimethoxyphenyl group, albeit the product 4n was obtained with a moderate yield. In addition, in reactions in which two regioisomeric products could be formed (Table 2, entries 11− 13), only the less sterically hindered products were generated. Furthermore, we investigated the scope of substitutions at the quinazolines fragment. When the substrate without substitutions at the quinazolines fragment undergo the reaction efficiently (Table 2, entry 15). To test the feasibility of a large-scale reaction, the reaction of 4-iodoanisole (3a) (20 mmol) was investigated. The reaction could afford 3.23 g of 4a in 88% yield after recrystallization (Scheme 2). Therefore, this protocol could be used as a practical method to synthesize the precursors of some important bioactive molecules. On the basis of these findings and previous literature reports,15 a plausible mechanism was outlined in Figure 3. We suggest that the operating mechanism for this reaction starts from an interaction between PhI(OAc)2 and 4-anilinoquinazoline 3a, to result in the electrophilic N-iodo species A after losing one molecule of acetic acid. In the subsequent steps the

entries 9−11). Gratifyingly, the cyclization reaction was completed in a much shorter reaction time (Table 1, entries 12−14). While when the reaction was allowed to take place at room temperature, the reaction was very sluggish (Table 1, entry 15). The best result was obtained after 0.5 h at 40 °C using 2 equiv of PhI(OAc)2 as oxidant. With the optimized conditions in hand, we next investigated the scope of the cyclization of a series of benzoimidazo[1,2c]quinazolines. Substitutions at different positions of the aniline ring were tolerated, as well as a variety of functional groups (Table 2). Both electron-donating, such as Me, OMe, OEt, and electron-withdrawing groups, such as CF3 and F in the para positions relative to the aniline nitrogen, were well tolerated, and good to excellent yields of the corresponding substituted benzoimidazo[1,2-c]quinazolines were obtained (66−91%). It is noteworthy that a halogen-substituent including F, Cl, Br and I remained intact under these reaction conditions (Table 2, entries 5−8), an observation that suggests further diversification of the process is possible. To our delight, the cyclization also occurred with an carbonyl group as substituent, thus expanding the functional group tolerability (Table 2, entry 10). The reactions processed well when electron-deficient m-chloro C

DOI: 10.1021/acs.iecr.5b04452 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

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Industrial & Engineering Chemistry Research

ethynyl group was found to be the most active compound. However, all of the selected compounds show much lower activity than reference drug erlotinib. Subsequently the further structure−activity relationships will be studied to determine how the substituent affected the antitumor activity and to design the best chemical structure in the future.

Scheme 2. Large-Scale Reaction: 3a (10 mmol), PhI(OAc)2 (20 mmol), HFIP (30 mL), 40 °C, 0.5 h, under Air. Isolated Yield after Recrystallization

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CONCLUSIONS In summary, we have developed a highly efficient and diversified method for the construction of benzimidazo[1,2c]quinazolines scaffolds from readily available 4-anilinoquinazoline via a phenyliodine(III) diacetate (PIDA)-mediated intramolecular C−H bond cycloamination reaction. A plausible reaction mechanism was described on the basis of the experiments. In addition, some of the synthesized compounds were evaluated for their antitumor activity against HUH 7 and SK-HEP-1 hepatocarcinoma cell line. Among the compounds screened, 4m was found to be the most active compound against HUH 7. Other applications of this methodology are currently underway and will be disclosed in due course.

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EXPERIMENTAL SECTION General. The starting materials were commercially available and were used without further purification except solvents. The products were isolated by column chromatography on silica gel (200−300 mesh) using petroleum ether (60−90 °C) and ethyl acetate. Melting points were determined on an X-5 Data microscopic melting point apparatus. 1H NMR and 13C NMR spectra were recorded on a Bruker Advance 400 spectrometer at ambient temperature with CDCl3 or DMSO-d6 as solvent unless otherwise noted and tetramethylsilane (TMS) as the internal standard. 1H NMR data were reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = double−doublet, m = multiplet, and br = broad), coupling constant (J values, Hz). Mass spectra (EIMS) were acquired on an Agilent 5975 spectrometer. Analytical thin layer chromatography (TLC) was performed on Merk precoated TLC (silica gel 60 F254) plates. General Procedure for C−N Cross-Coupling Reactions. To a stirred solution of 4-anilinoquinazoline 3 (1.0 mmol) in HFIP (3 mL) was added PIFA (2.0 mmol) at 40 °C. The resulting mixture was stirred at the same temperature until TLC indicated the total consumption of the substrate (within 30 min). The reaction was quenched by the addition of 5% aqueous NaHCO3 (20 mL), and the mixture was extracted with CH2Cl2 (30 mL). The extract was washed with brine and dried over MgSO4. The solvent was then evaporated, and the residue was purified by column chromatography using a mixture of petroleum and EtOAc as the eluent to afford the desired benzoimidazo[1,2-c]quinazolines 4.

Figure 3. Plausible mechanism.

electrophilic annulation on the pyridine nitrogen through cleavage of the N−I bond at the release of a molecule of PhI and acetic acid generates intermediate B which upon deprotonation forms final product 4. Finally, some of the newly synthesized compounds were evaluated for their antitumor activities against HUH 7 and SKHEP-1 hepatocarcinoma cell line (Table 3). Most of the Table 3. Cytotoxicity of the Selected Compounds against Various Human Carcinomas IC50 (μM)a compound 3a 3b 3e 3i 3m (erlotinib) 3n 4a 4b 4e 4i 4m 4n

HUH 7 87.66 86.51 62.73 41.20 21.20 60.38 36.50 46.51 50.73 41.20 30.32 56.21

± ± ± ± ± ± ± ± ± ± ± ±

1.27 1.38 2.86 1.45 1.41 3.66 1.93 2.48 3.67 1.05 2.16 1.98

SK-HEP-1 69.01 96.34 82.94 54.55 14.55 65.05 39.02 48.14 42.93 34.25 29.15 40.35

± ± ± ± ± ± ± ± ± ± ± ±

1.87 2.53 0.88 1.76 1.72 0.80 2.87 1.54 1.08 2.46 0.80 2.17

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a

Data were obtained in at least two independent experiments. A standard deviation of 0 means that the same value was obtained in all experiments.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.iecr.5b04452. Detailed experimental procedure; characterization of the products; 1H and 13C NMR spectra. (PDF)

compounds were effective against HUH 7 and SK-HEP-1. These results suggest that benzoimidazo[1,2-c]quinazolines 4 showed stronger antitumor activities against HUH 7 and SKHEP-1 than compounds 3 as shown in Table 3. With the IC50 study of compounds 4a,4b and 4i,4m, it indicated that electronwithdrawing groups in the aromatic rings tend to increase the inhibition ratio. Among the selected compounds, 4m with a

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AUTHOR INFORMATION

Corresponding Authors

*Tel.: +86 571 28862867. Fax: +86 571 28862867. E-mail: [email protected]. D

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(15) Rao, D. N.; Rasheed, S.; Vishwakarma, R. A.; Das, P. Hypervalent iodine(III) catalyzed oxidative C-N bond formation in water: synthesis of benzimidazole-fused heterocycles. RSC Adv. 2014, 4, 25600−25604. (16) Kantak, A. A.; Potavathri, S.; Barham, R. A.; Romano, K. M.; DeBoef, B. Metal-free intermolecular oxidative C-N bond and formation via tandem C-H and N-H bond functionalization. J. Am. Chem. Soc. 2011, 133, 19960−19965. (17) Manna, S.; Matcha, K.; Antonchick, A. P. Metal-free annulation of arenes with 2-aminopyridine derivatives: the methyl group as a traceless non-chelating directing group. Angew. Chem., Int. Ed. 2014, 53, 8163−8166. (18) Liang, D.; He, Y.; Liu, L.; Zhu, Q. Metal-free annulation of arenes with 2-aminopyridine derivatives: the methyl group as a traceless non-chelating directing group. Org. Lett. 2013, 15, 3476− 3479. (19) He, Y.; Huang, J.; Liang, D.; Liu, L.; Zhu, Q. C-H cycloamination of N-aryl-2-aminopyridines and N-arylamidines catalyzed by an in situ generated hypervalent iodine(III) reagent. Chem. Commun. 2013, 49, 7352−7354. (20) Dowell, J.; Minna, J. D.; Kirkpatrick, P. Erlotinib hydrochloride. Nat. Rev. Drug Discovery 2005, 4, 13−14. (21) Shen, C.; Yuan, M. L.; Wu, Q. J.; Zhang, P. F. Synthesis and application of erlotinib derivatives. ZL 2015072800710910, 2015. (22) Shen, C.; Xia, H. J.; Yan, H.; Chen, X. Z.; Ranjit, S.; Xie, X. J.; Tan, D.; Lee, R.; Yang, Y. M.; Xing, B.; Huang, K.-W.; Zhang, P. F.; Liu, X. A concise, efficient synthesis of sugar-based benzothiazoles through chemoselective intramolecular C-S coupling. Chem. Sci. 2012, 3, 2388−2393. (23) Shen, C.; Xu, J.; Yu, W.; Zhang, P. F. A highly active and easily recoverable chitosan@copper catalyst for the C-S coupling and its application in the synthesis of zolimidine. Green Chem. 2014, 16, 3007−3012. (24) Shen, C.; Zhang, P. F.; Sun, Q.; Bai, S.; Hor, T. S. A.; Liu, X. Recent advances in C-S bond formation via C-H bond functionalization and decarboxylation. Chem. Soc. Rev. 2015, 44, 291−314. (25) Wen, M.; Shen, C.; Wang, L.; Zhang, P. F.; Jin, J. Z. An efficient D-glucosamine-based copper catalyst for C-X couplings and its application in the synthesis of nilotinib intermediate. RSC Adv. 2015, 5, 1522−1528. (26) Qu, G. R.; Liang, L.; Niu, H. Y.; Rao, W. H.; Guo, H. M.; Fossey, J. S. Copper-catalyzed synthesis of purine-fused polycyclics. Org. Lett. 2012, 14, 4494−4497.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (No. 21302171, 21376058), Zhejiang Provincial Natural Science Foundation of China (No. LZ13B020001), and Science and Technology Plan of Zhejiang Province (No. 2014C31153).

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REFERENCES

(1) Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A. Recent advances in the structural library of functionalized quinazoline and quinazolinone scaffolds: synthetic approaches and multifarious applications. Eur. J. Med. Chem. 2014, 76, 193−244. (2) Witt, A.; Bergman, J. Recent developments in the field of quinazoline chemistry. Curr. Org. Chem. 2003, 7, 659−677. (3) Marzaro, G.; Coluccia, A.; Ferrarese, A.; Brun, P.; Castagliuolo, I.; Conconi, M. T.; Regina, G. L.; Bai, R.; Silvestri, R.; Hamel, E.; Chilin, A. Discovery of biaryl aminoquinazolines as novel tubulin polymerization inhibitors. J. Med. Chem. 2014, 57, 4598−4605. (4) Smits, R. A.; Adami, M.; Istyastono, E. P.; Zuiderveld, O. P.; van Dam, C. M. E.; de Kanter, F. J. J.; Jongejan, A.; Coruzzi, G.; Leurs, R.; de Esch, I. J. P. Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4 receptor inverse agonists. J. Med. Chem. 2010, 53, 2390−2400. (5) Verhaeghe, P.; Azas, N.; Gasquet, M.; Hutter, S.; Ducros, C.; Laget, M.; Rault, S.; Rathelot, P.; Vanelle, P. Synthesis and antiplasmodial activity of new 4-aryl-2- trichloromethylquinazolines. Bioorg. Med. Chem. Lett. 2008, 18, 396−401. (6) Kashaw, S. K.; Kashaw, V.; Mishra, P.; Jain, N. K.; Stables, J. P. Synthesis, anticonvulsant and CNS depressant activity of some new bioactive 1-(4-substituted- phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea. Eur. J. Med. Chem. 2009, 44, 4335−4343. (7) Malamas, M. S.; Millen, J. Quinazolineacetic acids and related analogs as aldose reductase inhibitors. J. Med. Chem. 1991, 34, 1492− 1503. (8) Chilin, A.; Conconi, M. T.; Marzaro, G.; Guiotto, A.; Urbani, L.; Tonus, F.; Parnigotto, P. Exploring epidermal growth factor receptor (EGFR) inhibitor features: the role of fused dioxygenated rings on the quinazoline scaffold. J. Med. Chem. 2010, 53, 1862−1866. (9) Habib, O. M. O.; Hassan, H. M.; El-Mekabaty, A. Novel quinazolinone derivatives: synthesis and antimicrobial activity. Med. Chem. Res. 2013, 22, 507−519. (10) Lamazzi, C.; Leonce, S.; Pfeiffer, B.; Renard, P.; Guillaumet, G.; Rees, C. W.; Besson, T. Expeditious synthesis and cytotoxic activity of new cyanoindolo[3,2-c] quinolines and benzimidazo[1,2-c]quinazolines. Bioorg. Med. Chem. Lett. 2000, 10, 2183−2185. (11) Khajavi, M. S.; Rad-moghadam, K.; Hazarkhani, H. A facile synthesis of 6-substituted benzimidazo[1,2-c]-quinazolines under microwave irradiation. Synth. Commun. 1999, 29, 2617−2624. (12) Liu, Q.; Yang, H.; Jiang, Y.; Zhao, Y.; Fu, H. General and efficient copper-catalyzed aerobic oxidative synthesis of N-fused heterocycles using amino acids as the nitrogen source. RSC Adv. 2013, 3, 15636−15644. (13) Mirallai, S. I.; Koutentis, P. A. The conversion of 4anilinoquinazoline- and 3-aryl-4-imino-3,4-dihydro-quinazoline-2-carbonitriles into benzo[4,5]imidazo[1,2-c]quinazoline-6-carbonitriles via oxidative and nonoxidative C-N couplings. J. Org. Chem. 2015, 80, 8329−8340. (14) Chu, J. H.; Hsu, W. T.; Wu, Y. H.; Chiang, M. F.; Hsu, N. H.; Huang, H. P.; Wu, M. J. Substituent electronic effects govern direct intramolecular C-N cyclization of N-(biphenyl)pyridin-2-amines induced by hypervalent iodine(III) reagents. J. Org. Chem. 2014, 79, 11395−11408. E

DOI: 10.1021/acs.iecr.5b04452 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX