Mechanistic Investigation of the Reactions between Cyclohexane

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Cite This: Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

Mechanistic Investigation of the Reactions between Cyclohexane Carboxaldehyde and Ureido Groups Yiyong He,*,† Paul Foley,‡ Stephanie Hughes,‡ John Argyropoulos,§ and Arne Ulbrich† †

Corporate R&D, The Dow Chemical Company, 1897 Building, Midland, Michigan 48667, United States Corporate R&D, The Dow Chemical Company, Midland, Michigan 48667, United States § Dow Coating Materials, The Dow Chemical Company, Midland, Michigan 48667, United States ‡

S Supporting Information *

ABSTRACT: Model reactions have been performed to explore the reactivity of a variety of ureido groups with cyclohexane carboxaldehyde. The reaction mechanism between ureido and aldehyde functionalities is more complicated than expected. A new heterocyclic product was identified, which is very stable and solvent resistant. The final product profile is reactant and solvent dependent. In the cases of urea, alkyl urea, and benzyl urea, the reaction pathway goes from hemiaminal to aminal, to enamine, and finally to the heterocyclic product with nearly 100% yield. For other investigated ureido groups, the reaction stopped at the enamine product, and products are a mixture of hemiaminal, aminal, and enamine. All reaction steps are reversible except for the last step. The structure of the unique cyclic product was determined combining NMR and LC−MS analysis, and the reaction pathway was verified by kinetics studies.

1. INTRODUCTION Polyurethanes are used in many applications such as coatings, foams, adhesives, and elastomers because urethane linkages offer good mechanical strength, excellent chemical resistance, and stability to light. To date, isocyanates are used to make urethane linkages by reaction with polyols,1,2 but there is a growing concern about exposure to the isocyanates.3 An alternative route to urethane linkages has been developed by the Dow Chemical Company and is based on the reaction of polycarbamates with polyaldehydes.4−7 An extension of this technique is the cross-linking of polyurea with polyaldehyde.8 Probably the best known is urea-formaldehyde resins. The purpose of this study was to explore the reactivity of ureido groups (groups containing NH2CONH−) with an aldehyde group to determine the types of possible reactions. Model compounds were used to identify the products that could be formed. In particular, the chemicals shown in Figure 1 were studied. The aldehyde used for the model reactions was cyclohexane carboxaldehyde. This is because cyclohexane dicarboxaldehyde is the commercial cross-linker which the Dow Chemical Company used in its isocyanate-free polyurethane technology.6,7 The selection of cyclohexane carboxaldehyde eliminated the complexity of cross-linking and enabled us to understand the fundamental reaction mechanism for product development. The reactions between aldehydes and urea have been explored quite extensively in the literature, and their reaction products (Figure 2) are different depending on the types of aldehyde and urea used. The first category of reaction is between aromatic aldehyde and urea. Ju et al. developed a simple and efficient synthesis of isoquinoline derivatives by the © XXXX American Chemical Society

condensation of ortho-alkynyl aromatic aldehydes/ketones with urea in the presence of copper salts.9 Wang et al. reported a simple and efficient method for the synthesis of cis-2,4,5triarylimidazolines 10 based on a one-step procedure of aromatic aldehydes and urea in the presence of cesium carbonate.10 The second category of reaction is between alkyl aldehyde and urea. Li et al. synthesized urea−isobutyraldehyde− formaldehyde (UIF) resins from urea, isobutyraldehyde, and formaldehyde using sulfuric acid as the catalyst by a two-step method. In the first step reaction, ureidoalkylation occurred between urea and isobutyraldehyde, and 4-hydroxy-6-isopropyl5,5-dimethyl-tetrahydro-pyrimidin-2-one 11 was obtained.11 In a very early paper, Ogata investigated the rate and equilibrium constants of the condensation of some aliphatic aldehydes with urea to form alkylidenediureas, measured by spectrophotometry in aqueous solutions at 24.2 °C.12 It was found that electron-releasing groups in aldehydes tend to decrease the rate of forward reaction. The reaction is reversible and is subject to both acid and base catalysis. These results agree with the expectation from the suggested reaction mechanism involving the rate-determining attack of urea on free aldehyde molecules. The third category of reaction is between aryl aldehyde and urea. Butler et al. reported the cyclization of aryl aldehydes with Received: Revised: Accepted: Published: A

January 1, 2018 February 7, 2018 February 9, 2018 February 9, 2018 DOI: 10.1021/acs.iecr.8b00005 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

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Industrial & Engineering Chemistry Research

reaction product obtained by this process is targeted as a crosslinker for coating compositions. One common feature of the above literature is that they fixed urea and varied the structure of aldehydes. In this work we fixed the aldehyde to be cyclohexane carboxaldehyde and varied the structure of urea derivatives. Our focus was to understand the fundamental reaction mechanism and kinetics of a complicated multistep reaction and identify a new product structure, which turned out to be a universal product resulting from many ureido groups.

2. EXPERIMENTAL SECTION 2.1. Materials. Chemicals 1−9 and trifluoroacetic acid (TFAA) were purchased from the Sigma-Aldrich Corporation. The cyclohexanecarboxaldehyde 1 contains several percent of cyclohexane carboxylic acid, most likely due to the oxidation of cyclohexane carboxaldehyde. Deuterated dimethyl sulfoxide (DMSO-d6) and chloroform (CDCl3) was purchased from the Cambridge Isotope Laboratories, Inc. Dimethyl sulfoxide (DMSO) and toluene were purchased from the Fisher Scientific, Inc. All chemicals were used as received. 2.2. Synthesis. Unless specified in the text, the reactions between the chemical 1 and other chemicals containing ureido groups were carried out in DMSO-d6 solutions. The typical concentrations are 1.34 mmol of chemical 1 and 2.68 mmol of an ureido chemical in 3.0 g of DMSO-d6. Two drops of TFAA was added as the catalyst. The mixture was loaded in a capped glass vial and shaken for complete dissolution. Then it was heated to 60 °C and reacted for 2 days without stirring. The resulting solution was transferred to 10 mm NMR tubes for NMR analysis. In a few cases, the product precipitated or crystallized. Then the solid was separated and dissolved in an appropriate solvent for NMR study. 2.3. NMR Spectroscopy. Most NMR experiments were done at room temperature. A few samples were heated to 80 °C for the solubility reason. 13C NMR experiments were performed on a Bruker Avance 400 MHz (1H frequency) NMR spectrometer equipped with a 10 mm DUAL C/H cryoprobe. All experiments were carried out without sample spinning. Spectra were processed with either NUTS or MNOVA program using a 1 Hz exponential filter for apodization. For inverse-gated quantitative 13C NMR experiments, the following acquisition parameters were used: 60 s relaxation delay, 90° pulse of 13.1 μs, 512 scans. Each spectrum was centered at 100 ppm with a spectral width of 300 ppm. The 13C NMR spectra were referenced to 39.5 ppm for the DMSO-d6 solvent. The 2D heteronuclear single-quantum coherence spectroscopy (HSQC) experiment was acquired with 128 increments (t1) and 2048 data points (t2), a relaxation delay of 1.5 s, acquisition time of 0.37 s, 90° pulse of 17.0 μs, and 16 scans. The sweep widths of 2800 Hz for 1H and 16668 Hz for 13 C were employed. The 2D heteronuclear multiple-bond coherence spectroscopy (HMBC) experiment was acquired with 128 increments (t1) and 2048 data points (t2), a relaxation delay of 1.5 s, acquisition time of 0.39 s, 90° pulse of 17.0 μs, and 32 scans. The sweep widths of 5208 Hz for 1H and 22349 Hz for 13C were employed. 2.4. Mass Spectroscopy. Of a solution of approximately 0.5 wt % of the analyte in 1:1 chloroform/methanol, 25 nL was injected onto a Thermo Scientific Q Exactive LC/MS system equipped with a Dionex UltiMate 3000 HPLC system. The product was analyzed by gradient elution reversed phase HPLC

Figure 1. Chemical structures of cyclohexane carboxaldehyde and selected chemicals with ureido groups.

Figure 2. Chemical structures of aldehyde/urea reaction products reported in literatures.

urea or thiourea to give cyclic triazinanes 12 (R = H, Me, Ph; R1 = substituted phenyl).13 The fourth category is multicomponent reactions involving aldehyde and urea. Probably the most renowned one is the Biginelli reaction. The Biginelli reaction is a multiplecomponent chemical reaction that creates 3,4-dihydropyrimidin-2(1H)-ones 13 from ethyl acetoacetate, an aryl aldehyde (such as benzaldehyde), and urea.14−16 The reaction can be catalyzed by Brønsted acids and/or by Lewis acids such as copper(II) trifluoroacetate hydrate17 and boron trifluoride.18 This reaction was most recently reviewed by Moorthy et al.19 One patent disclosed a process to make a reaction product by mixing at least one multifunctional aldehyde with at least one cyclic urea in the presence of at least one alcohol.20 The B

DOI: 10.1021/acs.iecr.8b00005 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

Article


Figure 3. 13C NMR spectrum and peak assignments of the product mixture from the reaction of 1 and 3 (molar ratio = 1:1) in toluene at 60 °C for 2 days.

Scheme 1. Generalized Reaction Pathways and Proposed Mechanism for Ureido and Aldehyde Functionalities

at 35 °C using 0.1% formic acid in water as solvent A, 0.1% formic acid in acetonitrile as solvent B, and 1 g/L ammonium formate as postcolumn makeup before electrospray ionization and after UV detection. The gradient flow rate was 0.8 mL/min and the makeup flow rate was 0.1 mL/min. An Agilent Infinitylab EC-C18 (50 mm × 3 mm × 2.7 μm dp) column was

used as the stationary phase. The gradient program was 40% B for 1 min followed by a linear ramp to 98.5% B at 12 min and then holding at 98.5% B to 16 min. The system was returned to starting conditions over 0.25 min and the column was reequilibrated for 2.75 min before beginning the next injection sequence. C


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Figure 4. 13C NMR spectrum and peak assignments of the purified product from the reaction of 1 and 3 (molar ratio = 1:2) in DMSO at 60 °C.

of reaction and its chemical structure was confirmed based on ACD Laboratories prediction of 13C NMR spectrum and validated by DEPT-135 NMR spectrum and peak intensity ratio. Products D and E were dominant. Product D has the unique feature of the CCH double bond,22 evidenced by the peaks at 116 and 115 ppm in Figure 3. DEPT-135 experiment (not shown) confirmed that the 116 ppm peak is a quaternary carbon and the 115 ppm peak is a methine carbon. In the case of the reaction between ureido and aldehyde, D is an intermediate product and not easily separated from other components. In the case of a reaction between carbamate and aldehyde,23 a similar enamine structure to D is the final product. A more detailed structure assignment will be reported in a separate paper. Product E was totally unexpected, which is the final product demonstrated by a later kinetics experiment. The big challenge here is the assignment of chemical structure for it. In the following sections, more results are provided to support the identity of this cyclic product as well as the reaction pathway and kinetics for its formation. The formation of product E was proposed by the mechanism illustrated in Scheme 1. A crucial intermediate, N-acyliminium ion X (or its neutral counterpart N-acylimine),24 was formed by water elimination from intermediate B or urea elimination from intermediate C. In other words, intermediates B and C are connected through the N-acyliminium ion X which is in equilibrium with its enamide tautomer D. This situation closely resembles that of the keto−enol equilibrium involving the presence of two intermediates with opposite electronic character. The reaction of D and X enables formation of intermediate Y by intramolecular ring closure and generates the final product E. Unfortunately, the presence of the Nacyliminium ion X is hardly detectable due to its unfavorable equilibrium with D. 3.2. Structure Determination of the Final Product. The same reaction as in Figure 3 was carried out in a different solvent, DMSO, for the reason of easier separation. The predominant product is a solid which phase-separated from the solution. The solid was washed twice by DMSO, and eventually dissolved in CDCl3 for NMR characterization. 13C NMR

Detection of the column effluent proceeded by UV absorption from 190 to 800 nm, negative mode electrospray ionization mass spectrometry, and positive mode electrospray ionization (not shown). The electrospray source was operated at 4000 V and 300 °C with 60 units of sheath gas and 20 units of auxiliary gas. The inlet capillary was held at 320 °C and the S-Lens at 50 units. Scan and tandem mass spectra of the most abundant ions were obtained through a data-dependent algorithm. Scan mass spectra were acquired over a mass range from 120 to 1800 amu with an automatic gain control (AGC) target of 1 000 000 charges and a maximum injection time of 125 ms. Resolution for both scan and tandem mass spectra was set to 17 500 fwhm at 200 m/z. For tandem mass spectra, the first mass was set to 50 m/z, the AGC target to 200 000 charges injected over a maximum of 50 ms, and the collision energy was set to 40 units ± 75%. All data were recorded in centroided mode.

3. RESULTS AND DISCUSSION 3.1. Reaction Mechanism of Ureido and Aldehyde. To understand the reaction mechanism between ureido and aldehyde functional groups, chemicals 1 and 3 were selected as the model system. Figure 3 is the 13C NMR spectrum of their product mixture carried out in toluene at 60 °C at a stoichiometric ratio of 1:1 with TFAA as the catalyst. To reduce the complexity of NMR spectrum, the product mixture was dried with N2 purge and redissolved in DMSO-d6 for NMR characterization. The unreacted cyclohexane carboxaldehyde 1 was completely evaporated as well as the majority of the toluene solvent. Other than the unreacted n-butyl urea 3, three products (aminal C, enamine D, and a cyclic structure E) were observed, and the proposed reaction pathway and mechanism are presented in Scheme 1. With the addition of a −NH2 nucleophile to a carbonyl carbon followed by proton transfer, hemiaminal B would be the first intermediate to expect.21 However, B was not observed experimentally, indicating that it was consumed very fast. The reaction kinetics study in a later section confirms this speculation. The next intermediate product C was observed but in a very small amount. Product C is expected for this type D


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Figure 5. HSQC (left) and HMBC (right) NMR spectra of the same sample as presented in Figure 4.

Figure 6. Mass spectrum at 5.85 min that is consistent with the structure of E3. The dimer is formed during ionization and is not a separate compound.

identification. DEPT-135 experiment (spectrum not shown) verified that 7 is a quaternary carbon and 3 is a methine carbon. As an independent check, LC−MS experiment was done to obtain the molecular weight of the cyclic product. The sample analyzed is the purified product shown in Figure 4. From NMR spectrum, there is only one predominant product. The acquired LC−UV and LC−MS chromatograms (Figures S12−S17) indicate that the main component in the sample is at a purity of greater than 90%. Its UV spectrum is consistent with the absence of a conjugated UV chromophore. The scan and tandem mass spectra of the peak at 5.85 min are consistent with the structure of E3 as shown in Figure 6. As a reference information, DSC and FTIR data were also obtained for the product E3 (Figures S18 and S19). E3 has a melting point of 252 °C (onset temperature). It can be dissolved in chloroform for recrystallization. 3.3. Reaction Kinetics. In this section we will illustrate how Scheme 1 was proposed based on a reaction kinetics study. For cleaner product separation to facilitate quantification, t-butyl urea 4 was chosen instead of n-butyl urea 3. A 1:1 molar ratio of chemicals 1 and 4 was mixed in DMSO-d6 in a 10 mm NMR tube at room temperature. After adding two drops of TFAA, the tube was immediately put in a NMR magnet preset at room

spectrum of the purified product is shown in Figure 4. The purified solid contains one single product E3,25 with the proposed structure in the inset of Figure 4. The key feature of it is a heteronuclear six-membered ring (carbons 2, 3, 7, 4 and two nitrogens). The reaction to prepare E3 has some similarity to the Biginelli reaction, but is not the same. 2D NMR experiments were performed to verify the proposed structure. The HSQC and HMBC spectra of the sample are shown in Figure 5, which explains the proposed structure very well. In the right figure, the proton at position 3 was resolved as a doublet, resulting from the 3-bond coupling to the amide proton next to it. This proton is remotely correlated to the carbons at position 1, 2, 4, 5, and 7. This provides direct support to the proposed cyclic structure. High resolution 1H NMR provides more coupling information among the protons in E3, as shown in Figure S1. For example, the peak splitting for one of the amide protons and protons 5 and 6 were resolved. All the peak splitting patterns are consistent with the proposed cyclic structure E3. It is interesting that the peaks of protons on carbons 4 and 8 did not show splitting due to peak broadening in Figure S1, but their correlation peak was clear in the COSY spectrum (Figure S2). In Figure 4, carbons 7 and 3 are critical for the structure E


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Industrial & Engineering Chemistry Research temperature and pretuned. Multiple 13C NMR spectra were taken to follow the reaction. The reaction generated the same types of products as the reaction of 1 with 3 (Figures S3 and S4). By integrating the corresponding NMR resonance peaks, the relative molar ratios of detected species were obtained and then plotted against reaction time as shown in Figure 7. Because the cyclic product E4 is insoluble in the reaction solution, its fraction was obtained from the amount of crystalline product produced.

catalyst. In a few minutes, the solution appeared gelled. No good solvent was found for the gel. It has very limited solubility in CDCl3. The dilute CDCl3 solution was studied by 13C NMR, and its spectrum is presented in Figure 8. The product contains

Figure 8. 13C NMR spectrum of the reaction product between 1 and 2 carried out in DMSO-d6 at room temperature. Then the solid product was dissolved in CDCl3 without purification.

one predominant specie, and its structure F is proposed in the inset of Figure 8. The peak intensity ratio and the DEPT-135 experimental result (not shown) perfectly match the proposed structure. ACD Laboratories predicted chemical shifts agree reasonably well with the spectrum. The product F makes sense because 2 is a bifunctional molecule under the reaction mechanism of Scheme 1. If cyclohexane dicarboxaldehyde is used in the reaction instead of 1, the product F is expected to become a tetra-functional molecule with another aldehyde group attached on each of the cyclohexane rings, and the reaction system will most likely get highly cross-linked. 3.5. Reaction of Other Ureido Chemicals and Aldehyde. So far we have demonstrated that the reactions of urea 2, n-butyl urea 3, t-butyl urea 4 with cyclohexane carboxaldehyde 1 all follow the same mechanism outline in Scheme 1. The next studied reaction is 1 and benzyl urea 5 (1:2 molar ratio) in DMSO-d6 at 60 °C with TFAA as the catalyst. The observation (Figure S6) is very similar to the reactions of 1 and 3 as well as 1 and 4. In all the three cases, a single product E was eventually formed. This indicates that the cyclic product E is intrinsic to the general reaction between urea and aldehyde functionalities. A variety of other ureido functional groups (chemicals 6−9) were investigated to obtain their reactivity with cyclohexane carboxaldehyde (1). In all cases, the molar ratio of 1 to ureido chemicals were fixed at 1:2, and the reactions were carried out in DMSO-d6 with TFAA as the catalyst at 60 °C for 2 days. The quantitative results are summarized in Table 1 along with the previous four reactions. The 13C NMR spectra of these reaction mixtures are appended in Figures S7−S10. Interestingly, the last four reactions in Table 1 did not proceed to product E. Even though these ureido chemicals were in excess amount, the reactions were still not 100% completed because a significant amount of 1 remained unreacted. Solubility is not the root cause that prevented these four reactions from proceeding to product E. The intermediates B, C, and D were all soluble in DMSO-d6 at 60 °C, and the NMR characterizations were carried out directly on the reaction mixtures without dilution or

Figure 7. Kinetics data for the reaction of chemicals 1 and 4 (molar ratio = 1:1) in DMSO-d6 at 25 °C.

Figure 7 shows that, within 3 min of mixing (the first data point), approximately half of the reactants were reacted to generate aminal C4 and enamine D4. On the basis of the early stage trends of the curves for the two intermediate products, it appears that C4 was quickly converted to D4. This is rationalized by Scheme 1 in that the short-lived X is in unfavorable equilibrium with D. Once C4 was converted back to X, it predominantly moved forward to D4. The hemiaminal intermediate B4 was not observed, probably due to extremely short lifetime. Within a few hours of the reaction, D4 reached a maximum while C4 kept decreasing. The final cyclic product E4 started to be produced at about the maximized concentration of D4. In Scheme 1, the intermediate reactions before D4 are reversible. The evidence is shown in Figure S5. In Figure S5, a similar kinetics study to that shown in Figure 7 was conducted. The difference is that, after 60 min of reaction at room temperature, the reaction mixture was heated to 70 °C. It was noticed that the intermediate products C4 and D4 decreased immediately after the heating. In the meantime, the two reactants 1 and 4 were regenerated. The final step reaction in Scheme 1 is irreversible because 100% conversion was eventually achieved. In this specific situation, it could be because the final product E4 was insoluble in the reaction solution, thus driving the reaction to the end. The final product E4 is resistant to many common solvents. There is more evidence in section 3.6 supporting the last step as truly thermodynamically irreversible. 3.4. Reaction of Urea and Aldehyde. In the ureido family, urea 2 is a special compound with bifunctionality. Thus, its reaction with cyclohexane carboxaldehyde 1 was explored closely. 1 and 2 at 1:1 molar ratio was mixed in DMSO-d6 at room temperature and a few percent of TFAA was added as a F


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the intermediate products (hemiaminal B, aminal C, enamine D) were soluble and the reaction proceeded all the way to the end giving the cyclic product E as the sole final product (Figure 7). In contrast, when toluene was used as the solvent for the same reaction, the enamine intermediate D was insoluble. As a result, the reaction stopped at D and could not proceed to the last step. Eventually D was the predominant product observed (Figure S3).

Table 1. Quantitative Conversion of Aldehyde to Different Products in Scheme 1a reaction mixture 1:2 molar ratio 1 1 1 1 1 1 1 1

+ + + + + + + +

conversion of cyclohexane carboxaldehyde 1 hemiaminal B aminal C enamine D cyclic E

2 3 4 5 6 7 8 9

0 0 0 0 5.9% 7.5% 6.6% 28.9%b

0 0 0 0 20.2% 16.7% 15.0% 66.7%

0 0 0 0 59.9% 52.6% 56.4% 1.8%

100% 100% 100% 100% 0 0 0 0

unreacted 0 0 0 0 14.0% 23.1% 21.9% 2.5%

4. CONCLUSIONS To expand knowledge of the cross-linking chemistry based on polyaldehyde, model reactions have been studied to explore the reactivity of a variety of different ureido groups with cyclohexane carboxaldehyde. The reactions between ureido and aldehyde functionalities are more complicated than expected. In the cases of urea, alkyl urea, and benzyl urea, the reaction pathway goes from hemiaminal to aminal, to enamine, and finally to a heteronuclear six-membered ring structure (cyclic product). To our knowledge the cyclic product has not been reported before. All reaction steps are reversible except for the last step. Because of this, the whole reaction can be driven completely to the cyclic product when the intermediates are soluble. For other investigated ureido groups, the reaction stopped at the enamine product. The reactions were not complete and the products are a mixture of hemiaminal, aminal, and enamine. The structure of the unique cyclic product was determined by combining 2D NMR and LC−MS−UV analysis. The reaction mechanism was proposed and the reaction pathway was verified by a kinetics study. The solvent for the reaction has a strong impact on the distribution of products. When toluene was used as the solvent for the reaction of t-butyl urea and cyclohexane carboxaldehyde, the predominant final product is enamine instead of the cyclic product. This observation is attributed to the lack of solubility of the enamine intermediate in toluene.

All reactions were carried out in DMSO-d6 at 60 °C except for the reaction 1 + 2, which occurred at room temperature. The relative uncertainty of reported conversions is approximately ±5%. b16.4% is the aminal-acetal product (see Figure S11), 12.5% is the hemiaminal product B. a

separation. A more plausible explanation is the reduced nucleophilicity of the nitrogen atom bearing an acyl or a phenyl group (ureas 6−8) and the absence of a hydrogen atom in the tertiary nitrogen in urea 9 which inhibits the ring closure of the intermediate Y. The reaction of 1 and 4 was run at 60 and 25 °C in two separate experiments. Both proceeded to 100% cyclic product E, though the reaction at 25 °C is much slower. 3.6. Solubility Effect on the Reactions. It is an amazing feature that the first four reactions in Table 1 proceed to 100% completion. Initially it was postulated that the last step reaction to form product E is solubility driven, because the product is insoluble or has very limited solubility in most of our reactions. However, that hypothesis did not hold in the case of benzyl urea 5. The cyclic product E5 from the reaction of 1 and 5 has decent solubility in several tested solvents such as DMSO-d6, toluene, and methanol. The reactions in these three solvents all proceeded to near completion. Thus, the cyclic product E must be thermodynamically very stable and in extreme favor of the reaction, considering the last step reaction in Scheme 1 has a relatively slow rate. The solubility of product E in the reaction solvent DMSO-d6 and NMR analysis solvent CDCl3 was qualitatively summarized in Table 2. At elevated temperatures, the solubility increases somewhat. A logical observation is that the solubility of the products in the reaction mixture affects the observed product distribution. Using the thoroughly explored reaction of 1 and 4 as an example, when DMSO-d6 was used as the reaction solvent, all

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.iecr.8b00005. Additional 1H NMR, COSY, LC−UV, and LC−MS chromatograms, DSC, and FTIR data for the product E3; 13 C NMR spectra and reaction kinetics data for other ureido−aldehyde reactions studied in the paper (PDF)

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*E-mail: [email protected]. Tel.: 989-636-9106. Fax: 989-6386443. ORCID

Yiyong He: 0000-0003-4402-4875

cyclic product E from n-butyl urea 3

t-butyl urea 4

in DMSO-d6 at RT

insoluble

insoluble

in DMSO-d6 at 80 °C in CDCl3 at RT

limited solubility soluble

insoluble

a

limited solubility

AUTHOR INFORMATION

Corresponding Author

Table 2. Rough Solubility Test on the Cyclic Product E under Different Conditions conditiona

ASSOCIATED CONTENT

Notes

benzyl urea 5

The authors declare no competing financial interest.

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limited solubility soluble

ACKNOWLEDGMENTS We thank Dr. Chengli Zu who helped us on a preliminary MS test on one of the reactions, and thank Dr. Xiaoyun Chen for a FTIR raw data. The work was supported by The Dow Chemical Company.

N/A

RT = room temperature. G


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N-Acylimines as Reactive Substrates. Adv. Synth. Catal. 2016, 358, 3657−3682. (25) The letter in the structure code denotes the category of product as shown in Scheme 1, and the number denotes its starting reactant listed in Figure 1. For example, E3 means it is the cyclic product E made from the reactant 3.

REFERENCES

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Mechanistic Investigation of the Reactions between Cyclohexane

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