TETL-D-13-01043R1 (1) Copy

Elsevier Editorial System(tm) for Tetrahedron Letters Manuscript Draft Manuscript Number: TETL-D-13-01043R1 Title: Experimental design of the microwave assisted synthesis of the poly(vinyl phenylthionecarbamate) Article Type: Short Communication Keywords: PVA derivative; Functionalization; Microwave-assisted synthesis; Experimental design. Corresponding Author: Prof. Elena María Otazo-Sanchez, PhD Corresponding Author's Institution: Universidad Autonoma del Estado de Hidalgo First Author: Irais Gómez Order of Authors: Irais Gómez; Elena María Otazo-Sanchez, PhD; Francisco Prieto; Alfredo Guevara; José Villagómez

Cover Letter

UNIVERSIDAD AUTÓNOMA DEL ESTADO DE HIDALGO INSTITUTO DE CIENCIAS BÁSICAS E INGENIERÍA

Pachuca, Hidalgo. May 30th, 2013 In attention to: Professor J. Wood Tetrahedron letters Regional Editor for the Americas. Dear Sir: We are grateful to you and the reviewer for the constructive comments and suggestions. We have taken into account the proposals in this new version of the manuscript. Enclosed herewith the revised manuscript, submitted to be considered for publication in Tetrahedron letters: Experimental design of the microwave assisted synthesis of the poly(vinyl phenylthionecarbamate)

AUTHORS: Irais Gómez, Elena M. Otazo, Francisco Prieto, Alfredo Guevara, José R. Villagómez

The aim of this work is the microwave assisted synthesis of a sulfur PVA derivative, the poly(vinyl phenylthionecarbamate), by a solvent-free functionalization. We have performed a 22 experimental design to determinate the influence of the reaction conditions on the workup. I resume the main important subjects and contributions of the present manuscript:

1. A report of the safe and solvent-free procedure for the preparation of the named PVA derivative under microwave radiated heterogeneous conditions. 2. A quantitative study of the influence of time and temperature reaction on the % yield, % functionalization and the undesired by-product formation, through a 22 Instituto de Ciencias Básicas e Ingeniería, Carretera Pachuca - Tulancingo Km. 4.5, Ciudad Universitaria, Colonia Carboneras, Mineral de la Reforma, Hidalgo, México, C.P. 42184 FAX: 52 (771)72000 ext 6502 Tel.: 52 (771) 72000 ext 2208 Tel: 52-1(771)1300238

E-Mail: [email protected]

UNIVERSIDAD AUTÓNOMA DEL ESTADO DE HIDALGO INSTITUTO DE CIENCIAS BÁSICAS E INGENIERÍA

experimental design for the microwave assisted workout. The resulted predictive models based on the variable dependencies are analyzed. 3. The apparent activation energy for the microwave-assisted heterogeneous functionalization reaction, calculated by the Arrhenius equation. This quantity could be considered as a preliminary basis to further kinetic studies.

We believe this letter will catch the attention of most readers. This work would be interesting to polymer and synthetic chemists, engineers and materials science researchers by providing a reproducible one step preparation for new PVA derivative by in a smallscale process.

We would be very grateful if you consider this manuscript to be published in Tetrahedron Letters. Sincerely,

Dra. Elena M. Otazo-Sánchez Centro de Investigaciones Químicas Universidad Autónoma del Estado de Hidalgo

Instituto de Ciencias Básicas e Ingeniería, Carretera Pachuca - Tulancingo Km. 4.5, Ciudad Universitaria, Colonia Carboneras, Mineral de la Reforma, Hidalgo, México, C.P. 42184 FAX: 52 (771)72000 ext 6502 Tel.: 52 (771) 72000 ext 2208 Tel: 52-1(771)1300238

E-Mail: [email protected]

*Graphical Abstract (for review)

*Response to Reviewers

TETL-D-13-01043 Professor J. Wood Tetrahedron letters Regional Editor for the Americas Dear Sir: We received your corrections of the manuscript TETL-D-13-01043. We want to acknowledge and be grateful to you and the referee. The suggestions from the reviewer have been very helpful and constructive. We have taken into account all these proposals and almost all have been introduced in this new version of the manuscript. Query 1: The author should cite the article: International Journal of Polymer Analysis and Characterization (2005), 10(1-2), 27-39. It reported the traditional synthesis of PVA-PT. Answer 1: Yes, we have already included and discussed. It corresponds now to reference 19. Thank you very much for this information, as we didn´t found this reference before. We finally downloaded the article. Indeed, it was an unexpected problem and we spent much time asking friends to do this for us (we have no access to the Journal in our university). We insert the following texts: Page 1, left column, paragraph 4: “There is a brief description of this reaction between PVA and phenyl isothiocyanate (PITC)19 producing the polymeric thionecarbamate ester. The workup was performed during 3 hours, using piperidine as catalyst, and the product was further purified with ethanol. Probably, the derivative was impure, as the experimental %N is higher than the theoretical one (7.82%). 1H-NMR in DMSO-6d were recorded and few IR bands were assigned”.

Query 2: There are some grammatical or careless errors in the manuscript need to be revised. Answer 2: Yes, please excuse us. We sent the manuscript to a native English speaking lady who is English Professor at our University. There were also some chemistry names in capital letters (sorry!!). We hope that now it is acceptable.

Query 3. Did the author try the relative large scale for the microwave assisted functionalization which is described in this manuscript? Answer 3: This investigation was carried out in just one microwave vessel, the main one which has connected both sensors (temperature and pressure). It was performed in a small scale (0.5 g), which is the highest quantity recommended for General Safety in the oven MARS 5.

And yes, we are intended to scale up by using the 12 vessels of the microwave equipment. When? After the reaction optimization has finished. We plan to include these optimization results in the next manuscript and send it to Tetrahedron, together with the detailed work about the conventional synthesis. This suggestion was included as another advantage in: Page 3, right column, paragraph 3: “Even though the conventional heating and the microwave assisted synthesis are similar concerning % F and % PT, the main advantages of the later are: a) Accurate control of the KVIP, b) Reduction of the temperature reaction, c) Reproducibility of the experiments, d) Safety and e) Simplicity to scale-up in the microwave conditions“.

Query 4: Although the microwave-assisted synthesis of isothiocyanate-functionalized PVA-based polymer is first reported by this manuscript, it will attract much attention if the properties or application of the PVA-PT is disclosed further. Answer 4: Thank you. The assignment of IR and Raman absorptions is discussed in another manuscript, which was written by another doctor thesis student (Richards, RM). Also, she presented the characterization of the PVA derivative as a new material for Mn(II) absorption in a UNESCO/IUPAC Conference (South Africa, 2008). She is waiting for the approval of her manuscript in another journal. We discussed with her, what should we do about your suggestion and decided to rewrite the paragraph: Page 2, right column, paragraph 1: “Moreover, PVA-PT was characterized by comparing reported25 and recorded IR (Figure 1) and Raman (Figure 2) spectra”.

We review the whole manuscript and I hope it will fit the guidelines and polices of the editors. Thank you again. Sincerely, Elena Otazo

*Revised Manuscript Click here to view linked References

Graphical Abstract

Experimental design of the microwave assisted synthesis of the poly(vinyl phenylthionecarbamate)

Leave this area blank for abstract info.

Irais Gómez, Elena M. Otazo*, Francisco Prieto, Alfredo Guevara, José R. Villagómez Área Académica de Química (AAQ), Universidad Autónoma del Estado de Hidalgo

(6 min, 125°C)

% Functionalization

1

Tetrahedron journal homepage: www.elsevier.com

Experimental design of the microwave assisted synthesis of the poly(vinyl phenylthionecarbamate) Irais Gómez, Elena M. Otazo, Francisco Prieto, Alfredo Guevara, José R. Villagómez Área Académica de Química (AAQ), Universidad Autónoma del Estado de Hidalgo, Carretera Pachuca-Tulancingo km 4.5, Ciudad Universitaria, Mineral de la Reforma, Hidalgo, 42184, México.

ARTICLE INFO

ABSTRACT

Article history: Received Received in revised form Accepted Available online

The microwave assisted solvent-free functionalization of poly(vinyl alcohol) with phenyl isothiocyanate was performed and studied by a 22 experimental design. The estimated activation energy was 40.43 kJ/mol. 2013 Elsevier Ltd. All rights reserved.

Keywords: PVA derivative Functionalization Microwave-assisted synthesis Experimental design

Chemical functionalization is a useful tool for the introduction of desired side-groups attached to the polymeric backbones, which present an easy-to-transform particular function. The most popular polymers used as starting substrates are natural macromolecules, ie, chitosane,1 starch,2 lignin,3 cellulose,4 and other synthetic ones, such as polystyrene,5 poly(acrylic acid)6 and polyurethane,7 among others.8

derivative was impure, as the experimental %N is higher than the theoretical one (7.82%). 1H-NMR in DMSO-6d and IR spectra were recorded and few IR bands were assigned. PVA was also functionalized with 1,6-hexamethylene diisocyanate, producing a polymeric lubricant additive.20 In addition, the PVA derivative with 4-maleimidophenyl isocyanate has been studied in order to improve the PVA mechanical and thermal properties.21

Generally, those transformations are difficult to perform, due to the heterogeneous workup. Microwave energy is an attractive and suitable choice for new polymeric materials preparation, allowing different kinds of anchorages, such as: covalent,9 surface,10 localized-activation11 and selective.12 Green and scaleup process are also attractive advantages.13

On the other hand, the C=S group has suitable binding properties towards metal ions.22 For example, substituted thioureas have been reported as good ionophores for Pb (II), Cd (II) and Hg (II) ion selective electrodes.23 A polymer with anchored CS function would also be a good option for new absorption materials toward metal-polluted water.

The experimental design is an efficient strategy to identify factors influencing a synthesis procedure. Grafting percentage,14 yield,15 water vapour permeability and moisture content,16 have been reported as representative response parameters in polymer materials preparation.

In this work, we report the microwave-assisted synthesis of poly(vinyl phenylthionecarbamate) (PVA-PT), based on the reaction of PVA with PITC. Moreover, a 22 experimental design is performed, in order to evaluate the effects of the reaction time and temperature –declared as known variables input parameters (KVIP)- on the % functionalization (% F, model 1), % yield of PVA-PT (% PT, model 2) and % yield of 1,3-diphenylthiourea (% DPT, model 3) –stated as Unknown Variable Output parameters (UVOP)-. Linear predictive models (1-3) are achieved. Finally, the activation energy for the microwave assisted PhNH(CS)- functionalization heterogeneous reaction of PVA is estimated by using model 1. No microwave synthesis

Poly(vinyl alcohol) (PVA) exhibits pending -OH groups which are easy to access and transform.17 It is well known that thionecarbamates are obtained by the addition reaction of alcohols to isothiocyanates.18 There is a brief description of this reaction between PVA and phenyl isothiocyanate (PITC)19 producing the polymeric thionecarbamate ester. The workup was performed during 3 hours, using piperidine as catalyst, and the product ——— was further purified with ethanol. Probably, the

 Corresponding author. Tel.: + 52-7717172000 Ext. 2208; fax: +52-7717172000 Ext. 6502; e-mail: [email protected]

2

Tetrahedron

procedure for PVA derivatives with C=S containing-functions has yet been reported.

PVA and 1.5 mL (0.013 mol) PITC were introduced into the sample vessel and sealed.

Preliminary unsuccessful attempts were carried out in boiling solvents, such as dry pyridine without catalyst. Then, the transformation was achieved in heterogeneous conditions: 1.0 g (0.023 mol) PVA and 3 mL (0.025 mol) PITC were magnetic stirred and heated in an oil bath at 170 ºC. Scheme 1 shows the reaction procedure for PVA-PT preparation. In those conditions, the undesirable hydrolysis24 Wohler-like reaction takes place and the by-product DPT is formed (scheme 2). It is easily separated from crude PVA-PT with acetone extraction. The PVA-PT was insoluble in must conventional organic solvents, such as CHCl3, CH2Cl2, (CH3)2CO and slightly soluble in DMSO.

Then, a 22 factorial design was performed, by adjusting the stated KVIP in the microwave oven, following the 2-levelsmatrix design: time (X1: 4 and 6 min) and temperature (X2: 125 and 135°C). The functionalization extent of PVA was measured by the %N experimental-theoretical ratio (Model 1) Moreover, PVA-PT was characterized by comparing reported25 and recorded IR (Figure 1) and Raman (Figure 2) spectra. Both demonstrate that the conventional heating synthesis product (b) and microwave assisted one (c) are the same. PVA-PT spectroscopic data: IR (KBr, cm-1) : 3340 (O–H), 3060(C-Har), 2910 and 2940 (C–Hal), 1710 (C=O), 1599 (C=C), 1526 (thioureide I), 1314 (thioureide II), 1219 (thioureide III), 1050-1026 (C-O-C); : 1429 (CH2), 1330 (C-H and OH); ω: 756 (C-Har). Raman (cm-1) : 3045(C-Har), 2920 (C-Hal), 1750 (C=C), 1430 (thioureide II), 1250 (thioureide III), 1000 (phenyl), 614 (thioureide IV); : 1445 (CH2). Maximum obtained yield: 0.9209 g (45.26%). Experimental Elem. Anal: maximum % N achieved 4.67. (Theoretical values for a 100% functionalization: % N 7.82). The byproduct DPT was identified by melting point (Exp. 154ºC. Lit.26 154°C) and IR spectrum.27

Scheme 1. Preparation of PVA-PT.

The UVOP were calculated for all experiments (Table 1) and the data were evaluated by the MINITAB (version 14) software for Windows28 to calculate the coefficients for each KVIP and their interactions. No significant coefficient was obtained for the KVIP interaction in the model 3.

Scheme 2. 1,3-diphenylthiourea formation.

R2 values were calculated using ANOVA. The significance was higher than 95%, considering the correlation coefficients R2 99.65%, 97.36% and 99.90% for models 1, 2 and 3, respectively.

The described procedure was unsafe and the temperature was difficult to be controlled. So, we outlined a microwave approach to this workup. The reaction was performed in an oven MARS 5, at 600 W and 2.45 GHz, preheated for 5 min. 0.5 g (0.011mol)

Table 1. Unknown Variables Output Parameters for the 22 factorial design. % functionalization (% F) Experiments*

% yield of DPT (% DPT)

% yield of PVA-PT (% PT)

Replicates

Replicates

Replicates

I

II

III

I

II

III

I

II

III

1 (- -)

4.61

3.71

3.33

29.60

27.06

29.20

3.36

3.46

3.94

2 (+ -)

59.76

56.43

58.10

37.81

38.70

37.10

13.86

14.32

13.70

3 (- +)

50.42

47.73

48.50

44.35

45.26

42.45

18.36

19.27

18.69

4 (+ +)

34.81

33.91

37.62

39.30

38.20

39.43

29.35

29.68

29.04

*: (+) and (-): High and low levels of KVIP (time and temperature, respectively)

Figure 1. IR Spectra. (a) PVA, (b) PVA-PT conventional synthesis and (c) PVA-PT microwave assisted synthesis.

Figure 2. Raman Spectra. (a) PVA, (b) PVA-PT conventional synthesis and (c) PVA-PT microwave assisted synthesis.

3 The predictive models are found experimental range. The adjusted satisfactory. Statistics indicates a experimental data and the results precision.

to be adequate within the R2 and SD were also good reliability of the show a high degree of

The interaction factor (X1X2) has a minor negative effect on the % F and % PT. It has no effect at all on the DPT formation. The response surface plots of the models 1, 2 and 3 are shown in Figure 3 for all UVOP. They show the best values of the KVIP to reach the maximum or minimum responses. The best microwave assisted synthesis conditions were: time = 6 min and temperature = 125 ºC (see black dots in Figure 3). The calculated maximum for % F was 60% in the studied procedure. In these conditions, the calculated % PT and % DPT were 42% and 14% respectively.

The models were described by the following polynomials: %F

=

-2358.29+449.92X1+18.03X2-3.38X1∙X2

(1)

% PT

=

-539.71+93.96X1+ 4.40X2-0.71 X1∙X2

(2)

% DPT

=

-208.57+ 5.24X1+ 1.53 X2

(3)

Even though the conventional heating and the microwave assisted synthesis are similar concerning % F and % PT, the main advantages of the later are: a) Accurate control of the KVIP, b) Reduction of the temperature reaction, c) Reproducibility of the experiments, d) Safety and e) Simplicity to scale-up in the microwave conditions.

The time reaction variable (X1) shows the highest and the most significant coefficients in all polynomials, principally for the model 1. This study shows that the longer time, the higher % functionalization and % yield. On the other hand, the undesired formation of DPT (model 3) is also favored with time, but the coefficient is two orders of magnitude lower than the model 1 and 18 times lower than model 2. This situation suggests that the reaction rate for % the functionalization is 18 times higher than the DPT formation.

The temperature dependence of the rate constant (assuming it proportional to the % F) was evaluated by the Arrhenius graphical method, shown in Figure 4. Data (7 points) were calculated from model 1 within the temperature range 396 - 410 °K, at a fixed reaction time (5 min). A 40.43 kJ/mol apparent activation energy (Ea) was estimated by the linear regression analysis. This value suggests a moderate reactivity, in agreement with the fact that no reaction is achieved below 125ºC, possible due to the lack of diffusion of PITC into the solid PVA.

The temperature factor (X2) has also a positive effect for all UVOP, and coefficients are lower than in X1 variable. The higher temperature, the better % F and % PT are achieved. This is not surprising, as the temperature rises the reaction rates. On the other side, time and temperature increase the desired reaction due to the favored PITC diffusion into the bulk PVA.

% Functionalization

% Yield of PVA-PT -1

X2

0 1

1

-1

-1

-1

0

0

0

X1

1

X2

1

X1

% Yield of DPT

-1

-1

X2

0

0 1

1

X1

Figure 3. Surface plots of UVOP vs KVIP for the microwave assisted reaction of PVA with PITC. The black dots mark the best desired response values.

4

Tetrahedron

6.

7.

8.

Figure 4. Temperature-dependence of PVA % Functionalization in the microwave assisted heterogeneous reaction. In conclusion, poly(vinyl thionecarbamate) is successfully synthesized by the heterogeneous addition reaction of PVA to phenyl isothiocyanate. IR and Raman spectra confirm the PhNH(CS)- functionalization. The microwave-assisted synthesis approach offers better control on the reaction time and temperature than the traditional heating; and provides a safer, easier, reproducible and scale-up workup. The 22 experimental design demonstrates that the reaction temperature and time effects are highly significant on the UVOP. The reaction time effect is the most important. The experimental best set of independent variables achieved for the highest % functionalization (60%), moderate % yield of PVA-PT (42%) and low % yield of undesired DPT (14%) are: 6 min and 125°C. The estimated activation energy for the microwave-assisted heterogeneous functionalization reaction is 40.43 kJ/mol.

Acknowledgments Funding for this research was provided by the Mexican Government`s Secretariat of Public Education (project PROMEP/UAEH-CA-59/2011) and the Autonomous Hidalgo State University. IGL thanks Mexican National Council for Science and Technology (CONACYT) for the doctoral scholarship received during this research. References and notes 1.

2.

3.

4.

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5 22.

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Maleimidophenyl Isocyanate. Polym.-Plast. Technol. Eng. 2012, 51 (1), 65-70. (a) Rodríguez-Fernández, E.; Manzano, J. L.; Benito, J. J.; Hermosa, R.; Monte, E.; Criado, J. J., Thiourea, triazole and thiadiazine compounds and their metal complexes as antifungal agents. J. Inorg. Biochem. 2005, 99 (8), 15581572; (b) Watts, A. S.; Gavalas, V. G.; Cammers, A.; Andrada, P. S.; Alajarín, M.; Bachas, L. G., Nitrateselective electrode based on a cyclic bis-thiourea ionophore. Sens. Actuator B-Chem. 2007, 121 (1), 200207; (c) Akrivos, P. D., Recent studies in the coordination chemistry of heterocyclic thiones and thionates. Coord. Chem. Rev. 2001, 213 (1), 181-210; (d) Raper, E. S., Copper complexes of heterocyclic thioamides and related ligands. Coord. Chem. Rev. 1994, 129 (1–2), 91-156. Otazo-Sanchez, E.; Perez-Marin, L.; Estevez-Hernandez, O.; Rojas-Lima, S.; Alonso-Chamarro, J., Aroylthioureas: new organic ionophores for heavy-metal ion selective electrodes. Journal of the Chemical Society, Perkin Transactions 2 2001, 0 (11), 2211-2218. Castro, E. A.; Moodie, R. B.; Sansom, J. P., Chem. Soc. 1985, 2, 737. Richards, R.; Otazo, E.; Prieto, F.; Gordillo, A.; Gonzalez, C. In Synthesis, thermal and spectroscopic characterization of new PVA derivative for metal ion water contaminants absorption: poly(vinyl phenylthionecarbamate), 10th Annual UNESCO/IUPAC Conference on Macromolecules & Materials, Mpumalanga, South Africa, 7-11 September 2008; p 32. Vogel, A. I., A Text Book of Practical Organic Chemistry. London, 1956. Panicker, C. Y.; Varghese, H. T.; George, A.; Thomas, P., FT-IR, FT-Raman and ab-initio studies of 1,3-diphenyl thiourea European Journal of Chemistry 2010, 1 (3), 173178. Minitab, Meet MINITAB Version 14 for Windows®. USA, 2003.

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Table(s)

Table 1. Unknown Variables Output Parameters for the 22 factorial design. % functionalization (% F) Experiments*

% yield of DPT (% DPT)

% yield of PVA-PT (% PT)

Replicates

Replicates

Replicates

I

II

III

I

II

III

I

II

III

1 (- -)

4.61

3.71

3.33

29.60

27.06

29.20

3.36

3.46

3.94

2 (+ -)

59.76

56.43

58.10

37.81

38.70

37.10

13.86

14.32

13.70

3 (- +)

50.42

47.73

48.50

44.35

45.26

42.45

18.36

19.27

18.69

4 (+ +)

34.81

33.91

37.62

39.30

38.20

39.43

29.35

29.68

29.04

*: (+) and (-): High and low levels of KVIP (time and temperature, respectively)