Reaction Scale and Green Chemistry: Microscale or Macroscale

Article pubs.acs.org/jchemeduc

Reaction Scale and Green Chemistry: Microscale or Macroscale, Which Is Greener? Rita C. C. Duarte LAQV/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre 687, Porto 4169-007, Portugal

M. Gabriela T. C. Ribeiro* LAQV/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre 687, Porto 4169-007, Portugal

Adélio A. S. C. Machado Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua do Campo Alegre 687, Porto 4169-007, Portugal S Supporting Information *

ABSTRACT: The different ways microscale and green chemistry allow reducing the deleterious impacts of chemistry on human health and the environment are discussed in terms of their different basic paradigms: green chemistry follows the ecologic paradigm and microscale the risk paradigm. A study of the synthesis of 1-bromobutane at macro- → microscale (109.3 → 10.9 g of the limiting reagent, butan-1-ol) showed that green chemistry mass metrics (AE, atom economy; RME, reaction mass efficiency; MI, mass intensity; E-factor, environmental factor; CEE, carbon efficiency) are unsuitable for evaluating the advantages of micro- versus macroscale. Poorer values of mass metrics at the microscale and the same green star at both scales showed that green metrics do not recognize that microscale improves safety. As so far no metrics have been proposed for evaluating this purpose, a new risk index (scale risk index, SRI) was developed for assessing the improvement of safety on downsizing the scale of synthesis experiments in chemistry teaching laboratories. The performance of SRI to show the benefits of microscale was assessed for syntheses of 1-bromobutane, tetramminecopper(II) sulfate monohydrate, and dibenzalacetone. KEYWORDS: Microscale Lab, Green Chemistry, Safety/Hazards, Upper-Division Undergraduate, Synthesis, Problem Solving/Decision Making

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INTRODUCTION

ment); (ii) reaction times (the exposure of students to hazardous substances is minimized); and (iii) quantity of waste (the impact on the environment is minimized). Advantages of microscale outside the scope of this paper result from the reduction of costs of reagents, which means direct economic benefits and allows the inclusion in laboratory courses of experiments involving reagents that are more expensive. As far as the authors could ascertain, no reports of metrics of the efficacy of microscale have been published. Green chemistry emerged later, during the 1990s, from an initiative of US EPA,6−8 with a more extensive scope than microscale. It includes teaching and research laboratories as

Microscale and green chemistry are two different approaches to reduce the negative impacts of performing chemistry (in this study, the scope considered is limited to educational laboratories in both cases). Apparently, microscale started to emerge in the 1960s (a search in this Journal showed that the first paper including the world microscale in the title was published in 19631), but only in the 1980s did its development acquire full speed (the second oldest article2 in this Journal and four more appeared in 1985, and in the following years papers on the subject kept increasing). The first of many books on microscale laboratory experiments was published in 1986.3 Microscale has been advocated for experiments in chemistry teaching laboratories because it shows several advantages with decreases of4,5 (i) the amounts of substances (there are improvements in safety for human health and the environ© XXXX American Chemical Society and Division of Chemical Education, Inc.

Received: January 22, 2017 Revised: July 24, 2017

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DOI: 10.1021/acs.jchemed.7b00056 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Article

well as industrial chemistry, and a broader and deeper aim, as expressed by Anastas and Warner8 (p 8): “...green chemistry is an approach that provides a fundamental methodology for changing the intrinsic nature of a chemical product or process so that it is inherently of less risk to human health and the environment”. In summary, microscale and green chemistry share the purpose of reducing the deleterious impacts of chemistry on human health and the environment, and therefore, it is expected that these approaches can be used together to reach this purpose. Indeed, this was pointed out at the beginning of this century by Zafran et al.,4,5 the first of these papers being entitled “Microscale and Green Chemistry: Complementary Pedagogies”. In both papers, the authors presented a large number of experiments on green chemistry implemented at the microscale, showing marked mutual benefits in several of them, and demonstrating the synergic connection between the two approaches to improve the benignity (meaning, for instance, less hazardous chemistry, less impact on the environment) of chemistry. Since then, several papers describing microscale synthesis experiments as green in the title9 or in the abstract/ keywords10 have been published in this Journal. However, none of these papers includes a detailed analysis of the different fundamentals of microscale and green chemistry and their mutual connections, as well as metrics for evaluation of the microscale outcomes. Nevertheless, Goodwin,11 upon remarking on the “synergy of microscale, green organic lab experiments,” discussed in ref 4, states that “small-scale reactions per se are not necessarily green”, but that “it cannot be denied that green experiments that are conducted on a small scale are inherently lower in risk (...) than the same experiments conducted on a larger scale”. This statement suggested that the two approaches to benignity involve distinct basic concepts and stimulated our research on the differences and connections between them. Risk refers to the probability of occurrence of accidents when a cause (actually, more often, a set of several causes acting in parallel) triggers a hazard (potential source of harm) to a danger (and real harm may occur), when the accident or a “near miss” happens. Chemical greenness is a very complex multidimensional concept, which is very difficult to evaluate because it involves many components, requiring several metrics to assess its different dimensions. During the work of our group for development of the graphic metric green star, 12−15 one of the syntheses studied (tetramminecopper(II) sulfate monohydrate14) included experiments at both macro- and microscales. Green star is a semiquantitative graphic metric that assesses the greenness by the degree of accomplishment of each of the 12 principles of green chemistry8 that apply to the case under evaluation (details in Supporting Information Section 2.2).12,13 The results of the metric are presented graphically in an Excel radial plot as a star: the greener the area of this star is, the more principles are accomplished and higher the greenness is. The green star does not consider the amounts of substances used and the yield obtained, as these are the same for syntheses where only the scale changes, provided temperature and pressure are maintained. The results for the above-mentioned syntheses showed a decrease of the yield on the microscale (95.4% at macroscale to 91.9%, for stoichiometric ratio of reactants), with only a slight worsening of mass metrics (RME, MI, E-factor, and XEE, see Figure 1 for definitions), and the decrease of the yield was attributed to losses in the procedures at microscale. In later work, a similar study involving the synthesis of

Figure 1. Green chemistry mass metrics definitions.

dibenzalacetone, but providing data on procedures at three scales, confirmed the deterioration of yield and mass metrics at increasingly lower scales.16 This is not unexpected because at the microscale the relative losses of a solid product during the workup for its isolation may be relatively higher than at the macroscale, due to increased difficulties of manipulation. In this case, the yield and the mass green metrics that depend on it will have degraded values, indicating a loss of greenness. These results suggested that green metrics are not suitable to evaluate the achievements of microscale toward obtaining benignity, and that this evaluation requires another type of metric, confirming that the fundamentals of the benignity of microscale are different from those of green chemistry. The present paper reports further work to elucidate this situation, based on the synthesis of 1-bromobutane that shows a large decrease of yield at microscale with strong worsening of mass metrics. In the first part, a theoretical discussion of the different ways microscale and green chemistry promote benignity, which matured along all this work, is presented. Upon the conclusion that green metrics are not suitable to assess quantitatively the benefits of microscale, work on the design of an alternative metric for this purpose was developed. This is described in a second part of the article where such a metric, the scale risk index (SRI), is presented and evaluated. A review of some common industrial safety indices17−30 showed that, due to their complexity, they were not suitable to be used in the chemical educational context, but were useful for inspiring the design of SRI. Finally, to test its behavior, the SRI was applied to the synthesis of 1-bromobutane and to the other two syntheses, with different characteristics, performed previously at different scales (tetraamminecopper(II) sulfate monohydrate14 and dibenzalacetone16). This methodology is presented in Figure 2 (see discussion on details below). The intention of this report is to call the attention of chemical educators to the complexity of both the connections between green chemistry and microscale and the hazards of chemical substances and reactions. Indeed, it is a challenge for the development of further experiments to exemplify this multidimensional complexity and allow further understanding of these connections. This knowledge is important to support the elimination of the risks in the practice of laboratory chemistry.

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GREEN CHEMISTRY VERSUS MICROSCALE In the search for chemical benignity, two factors have to be considered to assess the risks of a substance (Figure 3): (i) the B



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impacts of high acute toxicity, but ignores almost completely other hazards, for instance, the noxiousness to sustainability. Moreover, there are difficulties in applying the paradigm, such as the lack of complete data about the toxicity of many compounds, even for some prepared by industrial chemistry long ago.33,34 On the other hand, this paradigm is not reliable, and the consequences for human health and the environment may be disastrous, as when the exposure controls fail. On the contrary, the ecologic paradigm32 gives more importance to the toxicity and to the noxiousness to the environment, prescribing the proactive use of nontoxic substances, the elimination of waste, etc. Green chemistry aims to eliminate hazards to protect the health of humans and the biosphere, as well as the deterioration of the environment, with strong intention, thus following the ecologic paradigm. Indeed, green chemistry means an important contribution for the desirable transition from the risk paradigm to the ecologic paradigm. In laboratory work, microscale allows decreasing of risks4,5 by reducing exposure, thus working within the risk paradigm, without involvement of the ecological paradigm used in green chemistry. This may suggest that microscale is out of the scope of green chemistry. However, as chemical greenness is relative and full benignity is rarely achieved with green chemistry, it is advantageous to use the microscale in laboratory experiments addressed to teaching green chemistry to reduce risks. Indeed, there is no conflict of this use with the different paradigmatic fundamentals of microscale and green chemistry, because in the expression risk = f(exposure, hazards) in Figure 3 there is no complete separation of the variables exposure and hazards. Such a separation is assumed when often this expression is simplified to risk = exposure × hazards,31,35 but this simpler expression ignores second and higher order interactions between the variables, being an approximation. On the other hand, as the basic paradigms of green chemistry and microscale are different, it is expected that the evaluation of their outcomes requires different procedures and metrics. For microscale, metrics have to capture exposure, in contrast with metrics for green chemistry, where ideally exposure is irrelevant, because it intends to eliminate hazards proactively. However, even in green chemistry, as in practice full elimination of hazards is never achieved, it is advisible to pay attention to exposures, depending on the type of hazards that may remain.

Figure 2. Roadmap for development of the work.

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Figure 3. Risk components and green chemistry: the transition from the risk paradigm to the ecological paradigm is supported by green chemistry.

EXPERIMENTAL WORK

Synthesis of 1-Bromobutane

A number of experiments at macro- and microscale were performed in which the 1-bromobutane was prepared from butan-1-ol, sodium bromide, and concentrated sulfuric acid. A 19% excess of sodium bromide and 98% excess of sulfuric acid were used. The experiments followed published protocols36 (details about experimental procedures in Supporting Information Section 1 and ref 37); p-xylene was prescribed only by the microscale protocol,36 but for better comparison of scales it was also used at the macroscale in the present work. The scale factor of the amounts of the three reactants for downscaling was 1/10: butan-1-ol (limiting reactant), 109.3 → 10.9 mmol; sodium bromide, 129.4 → 12.9 mmol; and concentrated sulfuric acid, 215.7 → 21.6 mmol. The same decrease of scale was applied to all auxiliary reagents (p-xylene, water, sodium hydroxide, and anhydrous calcium chloride). The workup of

exposure to the substance, and (ii) the intrinsic hazards of the substance, which may be of various types, such as toxicity, explosivity, inflammability, and noxiousness to the sustainability.31 The consideration and assessment of these factors involve two different paradigms: the risk paradigm and the ecologic paradigm. The risk paradigm32 seeks to reduce risk by limiting the exposure to quantities or concentration intervals of the substance for which the hazards have no deleterious consequences. For this purpose, control barriers may be required. In practice, this paradigm gives more importance to hazards that may cause disasters with high economic costs or C



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Table 1. Green Chemistry Mass Metricsa Metrics

Abbreviation

Expression

Ideal value 100%

38

= AEb

39

1

39

0

40, 41

100%

39

Atom economy

AE

⎞ ⎛ p MWP AE = 100⎜ ⎟ a b c + + ( MW ) ( MW ) ( MW ) ⎝ A B C ⎠

Reaction mass efficiency

RME

⎞ ⎛ mP RME = 100⎜ ⎟ ⎝ mA + mB + mC ⎠

Mass intensity

MI

MI =

Environmental factor

E-factor

E‐factor =

Carbon efficiency

CEE

⎛ ⎞ nPnCP CEE = 100⎜ ⎟ ⎝ (nA nCA ) + (nBnCB) + (nCnCC) ⎠

mA + mB + mC + mS + maux mP m waste mP

Reference

a

a, b, c, p, stoichiometric coefficients; mA, mB, and mC, actual masses of the reactants; mP, mass of the product; mD, mass of byproducts; mS, mass of solvents; maux, mass of other auxiliary materials (in the present case, desiccants); mwaste, mass of waste; MWA, MWB, MWC, and MWP, molecular weights of the reactants and of the product; nA, nB, nC, nP, actual quantities (mol) of the reactants and of the product; nCP, nCA, nCB, nCC, number of atoms of carbon in the molecular formula of the product and of the reactants. bThe maximum value of RME = AE is reached if stoichiometric amounts of reactants are used and the yield is 100%.

the procedures is complex, involving two distillations and three washes with different solvents, followed by decantation. Three experiments were performed for each case. The yield obtained was about 77% (76.9 ± 1.6%) at macroscale and 33% (32.8 ± 0.5%) at microscale, showing a large decrease with scale. To assess qualitatively the presence or absence of 1bromobutane, 1H NMR spectra were obtained (Supporting Information Section 1.3).

and A corresponds to C4H9OH, B to NaBr, C to H2SO4, P to C4H9Br, and D to both NaHSO4 and H2O (a = b = c = p = d = 1). Using numerical data from the experiments at macro- and microscale (in Supporting Information Section 2.1.1), yields and the values of the mass metrics, calculated by expressions in Table 1, are presented in Table 2 for both scales. The value of

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Table 2. Comparison of Mass Metrics for the Synthesis of 1Bromobutane at Macroscale and Microscalea

HAZARDS 1-Bromobutane is a highly flammable liquid and vapor, causes skin irritation and serious eye irritation, may cause respiratory irritation, and is toxic to aquatic life with long lasting effects. Butan-1-ol is a flammable liquid and vapor, causes skin irritation and serious eye damage, and may cause respiratory irritation and drowsiness or dizziness. Sulfuric acid causes severe skin burns and eye damage. p-Xylene is a flammable liquid and vapor, is harmful in contact with skin or if inhaled, and causes skin irritation. Sodium hydroxide (solution) causes severe skin burns and eye damage. Anhydrous calcium chloride causes serious eye irritation. Details on hazards are provided in Supporting Information Section 1.4.

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Mass Metric Yield (%) AE (%) atom economy RME (%) reaction mass efficiency MI mass intensity CEE (%) carbon efficiency

Macroscale

Microscale

76.9 ± 49.81 27.0 ± 10.0 ± 76.9 ±

32.8 ± 49.81 11.5 ± 23.6 ± 32.8 ±

1.6 0.6 0.2 1.6

0.5 0.2 0.4 0.5

Number of replications for each procedure = 3, average ± standard deviation provided (excess: sodium bromide, 19%; sulfuric acid, 98%).

a

the E-factor was not calculated because it is difficult to determine the mass of waste produced, but it can be obtained by difference (E-factor = MI − 1). Water, used as solvent, was considered in the calculations. The water may deliver very high values for E-factor and MI if a large amount is used. Therefore, its mass is not generally incorporated in the calculation of these metrics because it deteriorates their sensitivity, hiding for instance the role of other solvents.42 However, in teaching, its inclusion helps the students to understand the metrics, because its exclusion subverts their definitions in Figure 1. The value of AE, ca. 50%, shows that the intrinsic mass greenness of the synthesis is limited. The yield is well below 100% and deteriorates the real greenness obtained experimentally when the synthesis is implemented in the laboratory, as shown by the low values of RME, much lower than AE. The comparison of the values of all the metrics at the two scales shows that the material greenness decreases at the microscale, where mass losses of the product along the complex workup had a strong effect on the value of yield: it decreased from about 77% to 33%, 2.3 times lower. RME and CEE also decreased while MI increased, all in the same proportion. This constant proportion can be explained by calculation of the

ASSESSMENT OF GREENNESS

Mass Metrics

In Table 1 the formulas for calculation of mass green metrics are presented for reactions involving three stoichiometric reagents (reactants), like in the present case. The symbols in the formulas refer to the equation a A + b B + c C → pP + d D

where A, B, and C represent the reactants (A being the limiting reactant, butan-1-ol in this case); P the product; D the byproducts; and a, b, c, p, d the stoichiometric coefficients. In the present synthesis the chemical equation is C4 H 9OH + NaBr + H 2SO4 → C4 H 9Br + NaHSO4 + H 2O D



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influence of yield on the mass metrics43 (Supporting Information Section 2.1.2). Moreover, these calculations provide an alternative procedure to obtain values of the metrics that show a good agreement with the experimental values, supporting the quality of the work (discussion in Supporting Information Section 2.1.2.3). In summary, these results show decreased greenness at the microscale, due to losses in the product along the workup, and therefore, the assessment of material greenness by mass metrics does not support the use of microscale. However, as mass metrics do not account for hazards or safety, only for the level of materialization of the synthesis, further analysis is required.

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DESIGN OF THE SCALE RISK INDEX A preliminary review of the common industrial safety indices available in the chemical engineering literature (in Supporting Information Section 3.1) was used as inspiration for the conception of the SRI. The review suggested that three basic variables should be taken into account: the hazards of the substances involved in the synthesis,17−21,23−26,28,30 the time of exposure to substances,22,28,29 and the amounts of substances used.17,19,27 For capturing these variables, all with strong implications on safety, SRI is expressed by

Green Star

SRI = t(∑ (s Hi + sEi + sPhi)mi)

For the construction of the green star (Figure 4), data on properties and hazards for all substances involved were

SRI = t ∑ s Himi + t ∑ sEimi + t ∑ sPhimi

(1)

(2)

= SRIH + SRIE + SRIPh

where • t is the time for performing the synthesis (total time = time for the reaction + time for the workup); • mi is the mass of each substance involved; • sHi, sEi, and sPhi are scores respectively for the human health, environmental, and physical hazards of each substance involved (feedstock, products, byproducts and auxiliary substances−catalytic reagents, solvents, separation agents, etc.), see below; • SRIH, SRIE, and SRIPh are, respectively, the SRI components for human health, environmental, and physical hazards

Figure 4. Green star for the synthesis of 1-bromobutane.

SRIH = t ∑ s Himi

(3)

SRIE = t ∑ sEimi

(4)

SRIPh = t ∑ sPhimi

(5)

The product and byproducts may be individualized for easier calculation of SRI

collected, from which the scores to construct the star13,15 were obtained (data and details in Supporting Information Section 2.2). The green star does not consider the amounts of substances used and the yield obtained. On the other hand, safety hazards are considered when principles 1, 3, 5, 9, and 12 are qualitatively assessed. However, if the physical conditions are the same at different scales, the hazards are the same and have no influence on the green star. Therefore, this graphic metric is the same for syntheses where only the scale changes, with the same conditions of temperature and pressure being kept at different scales. The present case fulfills this condition, and the green star is the same for both scales. The GSAI (the green star area index, defined as the ratio (%) between the green area of the green star and the area of the star of maximum greenness)13,44 shows that the greenness of the experiment is poor (GSAI = 15.00), in agreement with the information provided above by mass metrics. In summary, the assessment of greenness by mass metrics indicates that there is a loss of material greenness when the syntheses are performed at microscale, but the green star suggests that both processes are equally poor in terms of greenness. In conclusion, the two types of green metrics give contradictory results, and provide no evidence of the advantages of microscale.

SRI = t[(∑ (s Hi + sEi + sPhi)mi)reagents

∑ (sHP + sEP + sPhP)mP + ∑ (s HD + sED + sPhD)mD] +

(6)

where • sHP, sEP, and sPhP are the scores of the human health, environmental, and physical hazards of the product. • sHD, sED, and sPhD are the corresponding scores of the byproducts. • mP is the mass of the product and mD the mass of the byproducts. The hazards of all the substances used in the synthesis are obtained from Safety Data Sheets (SDS), from where the GHS Classification Hazard codes45 are collected. These are used to score the hazards in a scale from 0 (no risk) to 2 (high risk); details are in Table 17S (Supporting Information Section 3.3). The criteria used for scoring are similar to those used in the green star13 (details in Supporting Information Section 3.3). The waste is not included in the calculations, as it is difficult to measure the masses of the individual components of waste, and most of these are already accounted in SRI as feedstocks, etc. E



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Table 3. SRI, Time and Hazard Factors at Microscale and Macroscalea Synthesis 1-Bromobutane Tetraamminecopper(II) sulfate monohydrate13 Dibenzalacetone15

Scale Micro Macro Micro Macro Micro Macro Micro Macro Micro Macro

Scale Factor (n) (g/g) 1:10

0.10

1:20

0.05

1:4

0.25

1:5

0.20

1:20

0.05

Time (h)

HFR (g)

HFP (g)

HFD (g)

HF (g)

SRI (g h)

3.5 5.0 1.3 1.5 0.95 1.22 0.90 0.95 0.90 1.22

14.12 141.27 1.71 32.60 91.06 364.24 18.26 91.06 18.26 364.24

2.45 57.50 0.09 1.88 0 0 0 0 0 0

0.86 20.18 0 0 0 0 0 0 0 0

17.43 218.95 1.80 34.48 91.06 364.24 18.26 91.06 18.26 364.24

61.0 1094.8 2.4 51.7 86.7 444.7 16.5 86.7 16.5 445

a HFR, hazard factor of reagents; HFP, hazard factor of the product; HFD, hazard factor of the byproducts; HF, hazard factor global, SRI ideal value = 0.

SRI, SRIH, SRIE, and SRIPh are expressed in gram hour (g h). In the calculation of SRI, only the masses of substances that present hazards are considered. SRI increases with the increase of (i) the scores of the hazards, (ii) the masses of hazardous substances, and (iii) the total time of the experiment. SRI is a direct metric of risk (the higher its value, the higher the risk) and is therefore an inverse metric of safety and benignity. A preprepared Excel for calculation of SRI is included in the Supporting Information. To make the analysis of results easier to interpret regarding how SRI captures the hazards of the substances and varies upon changing the scale and time (see below), it is convenient to have simpler formulas for SRI and to obtain expressions that relate the values of SRI at different scales. Expression 6 may be simplified to SRI = t(HFR + HFP + HFD) = t HF

When the product and byproducts are not hazardous, HF′P, HF″P, HF′D, and HF″D are zero, and as HF′R = nHF″′R, expression 12 is simplified to (SRI′/SRI″) = nt ′/t ″

where n is the scale factor n=

∑ (sHi + sEi + sPhi)mireagents

HFP = (s HP + sEP + sPhP)mP HFD =

∑ (sHDi + sEDi + sPhDi)mDi

HF = HFR + HFP + HFD

(17)

and SRI ratio/(time ratio × scale factor) = 1

(18)

This relationship (expression 18) characterizes the case where the compounds produced by the reaction involve no hazards (see below). These expressions allow previewing changes in SRI at different scales from the value of SRI at one scale and a better understanding of the behavior of SRI. In the present work, SRI was calculated from experimental data for macro- and microscale experiments by expressions 1 and 12, and expressions 14, 17, and 18 were used for the discussion.

(7)

(8)

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(9)

ASSESSMENT OF THE PERFORMANCE OF SRI The values of SRI for the synthesis of 1-bromobutane and the other two syntheses reported in the literature with data for different scales were calculated for evaluating its performance under different situations. The synthesis of tetraamminecopper(II) sulfate monohydrate was performed at the macro- and microscale, with the scale 20 times smaller at the microscale (scale factor 1:20).14 In the case of the synthesis of dibenzalacetone, data on three procedures at different scales, two at macroscale (100 and 25 mmol of the limiting reactant, acetone) and one at microscale (5 mmol), were provided (scale factors 1:4, 1:5 and 1:20, respectively).16 Details about the data on conditions and metrics (values of mass metrics and green star)14,16 are provided in Table 25S, Supporting Information Section 4.3). The detailed calculations and results of SRI for the three syntheses are presented in Tables 22S−24S (Supporting Information Section 4.2). The following discussion is addressed to assess how the SRI captures and handles the data on the different variables included in its calculation, in an attempt to elucidate how the index deals with the diverse and complex information at play. The discussion aims at analyzing how SRI distinguishes

(10) (11)

SRI′ = SRI″t ′/t ″ × [HF′R + HF′P + HF′D /(HF″R + HF″P + HF″D )] (12)

or, using expression 11 (13)

Therefore SRI ratio = time ratio × HF ratio

(16)

SRI ratio = time ratio × scale factor

For a given synthesis, when the proportionality of the masses of the reagents is maintained on a changing scale, a value of SRI at one scale (SRI′) may also be calculated from SRI at another scale (SRI″) by expressions 12 and 13 below, where t′ and m′, and t″ and m″, are the values of time and masses for SRI′ and SRI″, respectively

SRI′/SRI″ = (t ′/t ″)(HF′/HF″)

∑ m′ireagents /∑ m″ireagents

From expression 15

where HFR, HFP, HFD, and HF are, respectively, the hazard factors of reagents, product, and byproducts, and the global hazard factor HFR =

(15)

(14) F



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Information Section 5). This information can be used to attempt a decrease of the amounts of the more dangerous substances on downscaling. For instance, it may be possible to reduce SRI by decreasing the mass of a hazardous solvent at larger ratios than the downscale ratio, provided this extra reduction has no negative impacts on the outcome of the synthesis. This and similar possibilities have to be tested in additional experimental work on a case-by-case basis to confirm the success of the attempts. It is worth noting that these favorable cases exemplify the use of green chemistry to support microscale, in contrast with the proposal of Zafran et al.4,5 to use microscale for improving green chemistry, confirming they are “complementary pedagogies”.

between macroscale and microscale, and evaluates the safety of different syntheses, and how hazards of the substances involved in the syntheses and the yields influence the SRI values. The last part of the discussion constitutes a first attempt to pursue an effort to elucidate how microscale and green chemistry are related in practice. The SRI values obtained for each of the three syntheses at different scales are presented in Table 3 (details in Table 26S, Supporting Information Section 4.3). Although the values of SRI at both scales show large differences between the syntheses (last column of Table 3), the SRI value is always lower for the procedure at the microscale, confirming that the index captures the increase in safety of microscale. The values of all HFs (HFR, HFP, HFD, and HF) for each synthesis, which depend on the masses and hazards at stake (expressions 8−11), are also always lower for microscale (columns 6−9), as expected. The highest value of SRI (1094.8) was obtained for 1-bromobutane at the macroscale (109 mmol of butano-1-ol), although the corresponding HF (218.95) was not the highest, the result being a consequence of this synthesis involving a long time for the work (5.0 h). The lowest SRI (2.4) and HF (1.80) were obtained for tetramminecopper(II) sulfate monohydrate at the microscale (0.4 mmol of copper sulfate), with the time also being low. The set of values for SRI for the synthesis of dibenzalacetone shows a decrease from 445 to 87 upon a scale decrease by a 1:4 factor from macroscale (100 mmol of acetone) to intermediate scale (25 mmol of acetone), and then to 16.5 in response to a further 1:20 scale decrease to microscale (5 mmol of acetone). The decrease of SRI on scaling down is mainly due to the decrease of masses and, by implication, of the hazard factors, HFs (364.24 → 91.06 → 18.26), the decrease of time for the synthesis being relatively low (1.22 → 0.95 → 0.90). The values of SRI collected for the three syntheses upon scaling down confirm that the index shows enough sensitivity to the variables that SRI is meant to capture to be useful for assessing the safety gains of microscale. The comparison of the behavior of SRI for the three syntheses, at different scales, shows differences in the details of the behavior of SRI. The study of SRI ratios and its relations with HF, time and yield ratios, and scale factors (expressions 14 and 17) show that SRI consistently discriminates different situations of hazards of the substances involved in the syntheses (detailed discussion in Supporting Information Section 5). The comparisons may be summarized as follows: 1. When the product and byproducts are not hazardous, the SRI ratio depends on the time ratio and the scale factor; expression 14 is simplified to expression 17, suitable to deal with the situation. 2. When the product and/or the byproducts are hazardous and the yields at macro- and microscale are similar, the situation is similar to 1, and expression 17 is still valid. 3. When the product and/or the byproducts are hazardous but the yields at macro- and microscale are different, the SRI ratio depends on the time ratio and HF ratio, and expression 14 is required. 4. In conclusion, the results show that SRI is suitable to deal with the complexity of hazards of chemicals present in the synthesis. On the other hand, the inspection of the parcels of SRI is useful to provide information on the types of risks involved in handling the substances in the synthesis (Supporting

Limitations of SRI

Like other metrics, SRI has limitations. For instance, the lack of information about the safety of some of substances may limit the knowledge of the hazards involved in the synthesis. Moreover, SRI captures only the information on the hazards of the substances involved, not on the hazards of the synthesis reaction and how they change on scaling; for instance, the risk of thermal runaway of strong exothermic reactions decreases on downscaling, but this reduction is not detected. Another difficulty of using the index may be the correct determination of the time of the experiment, let alone its use as time of exposure, especially if it involves “dead times” in which the performer is not required to be present. On the other hand, the use of SRI for comparison of the safety of different synthesis is not licit because there is no standard to benchmark such assessments, let alone two standards to establish a common scale of measurement. Moreover, due to the uncertainties in assessing some of the hazards of the substances and the way these are scored to be integrated in the index, it is practically impossible to attribute uncertainties to SRI values. Therefore, even when used for comparison of different scales of the same synthesis, the index provides only semiquantitative assessment; i.e., the difference or the ratio of its values at two scales should not be used as a rigorous measure of the variation of the benignity when the scale is changed. However, as benign processes are expected to have lower SRI, with the ideal value being zero, low values of SRI should be a goal in educational laboratories. In practice, it can be used for assessing the safety of a synthesis at different scales and choosing a scale suitable to keep the risks at a low enough level. SRI may also be useful for synthesis scale-up from grams to hundreds of grams (10−100:1 scale ratios) normally developed in the research laboratory, as the first stage of the industrial process research and development. Safety considerations in this activity deserve increasing attention, as a safe final process is more easily reached if safety is embedded along the development, starting at its beginning in the laboratory.46 On the other hand, the importance of the acquisition of a safety culture along university under- and postgraduate degrees felt nowadays47 presses for more training on hazard evaluations, integration of safety precautions in research work, etc. In this context, graduate students (and supervisors) may use SRI to explore how the hazards of reagents affect the risks of their use on increasing the scale. Finally, SRI captures only the influence of scale on the safety of the synthesis, leaving out any assessment of other advantages of microscale that result from a significant reduction of the amounts of reagents used, like the reduction of pollution and G



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waste, as well as costs. Therefore, other metrics are required to provide a complete assessment of the full advantages of using microscale.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

The Complex Relation between Microscale and Green Chemistry

ORCID

M. Gabriela T. C. Ribeiro: 0000-0002-1233-9971

The results for the synthesis of 1-bromobutane at the microscale show that when microscale experiments with complex workup are performed, the yields obtained may be lower than at the macroscale, with negative impacts on mass metrics (material greenness). In the other two syntheses, only slight deteriorations of material greenness were observed. As discussed, the hazards of the substances involved in a synthesis influence the SRI ratio on scaling down to microscale, but the way this influence occurs depends on the hazards of the specific substances and their role in the synthesis. Given the diversity of the hazards of chemicals and the variety of chemical reactions used in synthesis, it seems impossible, at the present stage, to present a sound treatment of the influence of downscaling on the greenness. Evaluation of the behavior of other syntheses on scaling down will be required to shed more light on the complexity of this field. In conclusion, as results of this work suggest that it is impossible to find a manageable general interrelation between green chemistry and microscale, they have to be considered concurrently on case-by-case studies to improve the benignity of chemistry. In the educational context, the parallel calculation of greenness metrics and SRI may give an opportunity to discuss different aspects of both green chemistry and safety to favor insights on the complexity of both fields and their conflicts. This situation means that balanced decisions are required to reach the best solution in each context, something that the students should also be made aware of.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The work of M.G.T.C.R. and R.C.C.D. received financial support from the European Union (FEDER funds through COMPETE) and National Funds (FCT, Fundaçaõ para a Ciência e Tecnologia) through Project Pest-C/EQB/LA0006/ 2013.

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CONCLUSIONS Although both microscale and green chemistry contribute to increasing the safety of the practice of chemical synthesis, the practice of green chemistry at the microscale may affect the greenness negatively. This occurs when the yield is lower at the microscale and worsens the mass metrics. The index presented in this article, SRI, proves to be effective for showing the difference between macro- and microscale impacts on the safety of both organic and inorganic syntheses, because it captures the hazards of and the exposure to the substances involved in the synthesis process. Finally, the present study suggests that the parallel use of greenness metrics and SRI will be useful to assess the overlapping of the benefits of green chemistry and microscale for reaching increased benignity in chemistry. Moreover, the simultaneous use of green metrics and SRI shows the difficulties of pursuing benignity in the chemical endeavor toward global sustainability.

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Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.7b00056. Experimental details, green mass metrics and green star, brief revision on industrial safety indices and details to calculate SRI, and discussion on further aspects of the response of SRI to hazards (PDF) Excel file to calculate SRI automatically from data (including the three examples in the text) (XLSX) H



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Reaction Scale and Green Chemistry: Microscale or Macroscale

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