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Copper-Catalyzed Hydrogen/Iodine Exchange in Terminal and 1-Iodoalkynes Ryan Chung, Anh Vo, and Jason E Hein ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03515 • Publication Date (Web): 28 Feb 2017 Downloaded from http://pubs.acs.org on February 28, 2017

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Copper-Catalyzed Hydrogen/Iodine Exchange in Terminal and 1-Iodoalkynes Ryan Chung,† Anh Vo,‡ and Jason E. Hein†* †

Department of Chemistry, The University of British Columbia, Vancouver, BC, V6T 1Z1, Canada

‡

Department of Chemistry and Chemical Biology, University of California, Merced, Merced, CA 95343, United States of America

Detailed kinetic profiles of the copper-catalyzed exchange between the acetylenic proton and iodide of terminal and 1-iodophenylacetylenes are reported. The electronic nature of the alkynes does not influence the equilibrium of the exchange (Keq = 1), only the rate of equilibration. Notably, the profiles are the same for electron-rich, methyl-substituted phenylacetylenes but is divergent for electron-deficient, trifluoromethyl-substituted variants. The heretofore unreported exchange process yields practical considerations regarding reactions involving iodo- and terminal alkynes. copper catalysis, 1-iodoalkynes, exchange equilibrium, copper acetylide, hydrogen/iodine exchange, automated reaction sampling

1 ACS Paragon Plus Environment

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Introduction 1-Haloalkynes are useful synthetic intermediates that offer access to diverse halogenated products primed for further elaboration.1 Recent work has taken advantage of these versatile building blocks through hydration,2 nucleophilic addition,3 cycloaddition,4 and even tandem or multicomponent transformations,5 proceeding without initial scission of the Csp-halogen bond. During our study of the cycloaddition between 1-iodoalkynes and organic azides,4a we observed an exchange of the acetylenic proton/iodide between phenylacetylene 1 and 1iodoalkyne 2 (Scheme 1D) under triazole-forming conditions.

To reveal the mechanistic

implications of these observations we sought to measure the native exchange equilibria. Previously, Abe and Suzuki observed Finkelstein-like nucleophilic displacement of bromide at the terminal sp-carbon in 1-bromoalkynes by superstoichiometric CuI (Scheme 1A).6 Conversely, the deliberate hydrodehalogenation of 1-haloalkynes to the parent terminal alkyne has been reported (Scheme 1B).7 In a recent report, Díez-González and co-workers briefly mentioned an observed exchange between (iodoethynyl)benzene and 1-hexyne (Scheme 1C);8 however, no experimental data was provided. To our knowledge, a detailed examination of the thermodynamic and kinetic features of the dynamic exchange between hydrogen and iodine at acetylenic centers has yet to be provided (Scheme 1D). Herein, we report our most recent study profiling this process.


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Scheme 1. Selected examples of halogen substitution in 1-haloalkynes.

Results and Discussion The exchange was monitored using HPLC by removing timed aliquots of the reaction mixture, facilitated greatly by an automated sampling apparatus like that we have previously described.9 (A schematic of the sampling apparatus is shown in Figure 1.) However, unlike our previous studies, simple dilution of the aliquots with methanol for HPLC analysis was insufficient to arrest further reaction due to the catalytic efficiency of copper. An insufficient quench was evident when the same sample, analyzed at different time points, showed variable concentration. Therefore, a new quench procedure was developed to ensure that each sample provided representative data of the reaction at the point of sampling regardless of the time elapsed before analysis.


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The bicinchoninic acid (BCA) protocol developed by Smith and co-workers is a wellestablished protein concentration assay that relies on the reduction of copper(II) salts by peptidic bonds.

The standard procedure involves preparing an aqueous solution of the disodium

bicinchoninic acid salt in the presence of copper(II) sulfate and other additives. Upon exposure to the BCA assay, peptidic bonds will oxidize and reduce copper(II) to copper(I); the concentration of protein then becomes linearly proportional to the absorbance of the purple copper(I)-BCA complex.10 The BCA dianion itself is what our quench procedure relies on since it has been found to be very selective for copper(I).10-11 By adapting the biochemical Smith assay, the aliquots were dispensed into a methanol solution of the bis(triethylammonium) bicinchoninic acid salt, which immediately stopped the reaction through tight complexation with CuI (Scheme 2).12 Control experiments ensured that the quench did not perturb the equilibrium quantities and that the chemical speciation and concentrations remained stable over time. BCA was chosen in lieu of an oxidative quench13 since it was found to disrupt the equilibrium concentrations.

All attempts to arrest the exchange chemistry by oxidizing the copper or

providing a thiolate agent to induce precipitation interfered with the alkyne or iodoalkyne concentration, either via promoting alkyne dimerization or decomposition of the sensitive iodoalkyne component.


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Figure 1. Schematic of automated reaction aliquot removal and quenching.

Scheme 2. Complexation of CuI by 2 equivalents of bicinchoninic acid. The BCA-copper complex is characterized by its distinctive purple color.a

O 2C O 2C

CO 2 N

CuI

2

CO2

N

N

N

O 2C

a

N Cu N

CO2

Counter-ions not shown for clarity.


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Table 1. Hydrogen/Iodine Exchange Experiments

X

H

X conditions

1a-c Y

I

I 1a'-c'

Y

2a-c

H 2a'-c'

1a,a': X = CH3; b,b': X = H; c,c': X = CF3 2a,a': Y = H; b,b': Y = CH 3; c,c': Y = CF 3

entry

X

Y

conditionsa

Keqb

kobsc

1

CH3

H

A

0.97d

9.17

2

H

CH3

A

0.93

8.85

3

CH3

H

B

1.04

63.3

4

H

CH3

B

0.97

60.5

5

CF3

H

A

0.99

16.5

6

H

CF3

A

1.00

8.84

7

CF3

H

B

1.02

—e

8

H

CF3

B

0.97

—e

a

Conditions “A”: 1 (0.1 M), 2 (0.1 M), 5 mol % CuI, 5 mol % TCPTA, MeCN, 25 ºC; Conditions “B”: 1 (0.1 M), 2 (0.1 M), Et3N (0.2 M), 1 mol % CuI, 1 mol % TCPTA, MeCN, 25 ºC (TCPTA = tris((1-cyclopentyl-1H-1,2,3-triazol-4-yl)methyl)amine). bKeq = ([1’][2’])/([1][2]). c x 103 min–1; see SI for calculations. dValue determined by extrapolation of concentration data. e Exhibits complex kinetics. Entries 1, 2, 5, and 6 (Table 1) were performed under standard conditions,14 “A” (5 mol % CuI, 5 mol % TCPTA ligand, MeCN, 25 ºC; TCPTA = tris((1-cyclopentyl-1H-1,2,3-triazol-4yl)methyl)amine)). For entries 3, 4, 7 and 8, exogenous base (2 equiv. Et3N; TEA) was added to see if there was any noticeable effect on the exchange from base-assisted deprotonation. In these cases, the reaction proceeded too quickly for adequate aliquot removal and the catalyst and ligand loading were reduced to 1 mol % (Conditions “B”).

We exclude complete ligand

substitution of TCPTA by TEA due to the absence a bright canary-yellow, inactive copper-


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acetylide precipitate that has been previously characterized.15 Indeed, performing the reaction without TCPTA ligand leads immediately to an insoluble aggregate. To fully capture any electronic factors influencing the exchange, the experiments for each set of conditions were performed in pairs, alternating the substitution of the starting materials. In one trial, the para-substituent was located on terminal alkyne 1 (X = CH3 or CF3), leaving iodoalkyne 2 unsubstituted (Y = H).

Reciprocally, the reaction was then performed with

substituted iodoalkyne 2 (Y = CH3 or CF3) with unsubstituted 1 (X = H). Figure 2 represents a selection of data for entries 1–4.16 The appearance of the exchange products, 1’ and 2’, can be fitted to a first-order exponential and the observed rate constant, kobs, extracted.17 Comparing Figure 2(a) against 2(b) (entry 1 vs. 3), the approach to equilibrium with added base still follows exponential behavior but at a much faster rate (kobs(B)/kobs(A) ≈ 7), despite the five-fold reduction in catalyst. However, under these conditions there was a noticeable amount of by-product formation, contributing to a slight mass imbalance (Figure 2(c)). Isolation and independent synthesis revealed these species to be dimeric species 5a, 6a, and 6b (Figure 3); their formation is presumed to occur through a Cadiot-Chodkiewicz-type coupling process.18,19 With no base added, these species form only in trace amounts on the exchange time scale.


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H

I

I

+ X 1a (X = CH3) or 1b (x = H)

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H +

Y

X 2a (Y = H) or 2b (Y = CH3)

1a' or 1b'

Y 2a' or 2b'

Figure 2. Exchange equilibrium reaction progress graphs for (a) entry 1 (X = CH3, Y = H), (b) entry 3 (X = CH3, Y = H), (c) entry 3, dimeric by-products, (d) entries 3 and 4, overlay. Notably, while the terminal concentrations of the by-products represent a statistical mixture of the homo- and heterodimeric species, the behaviors of their formation presents an interesting mechanistic aspect. For example, the concentration of heterodimer 5a in entry 3 is consistently the largest but experiences a rapid initial increase (0–20 min) followed by linear growth (Figure 2(c)). For both entries 3 and 4, the homodimer derived from the starting terminal alkyne 1 (i.e., 6a for entry 3) is always secondary in concentration and exhibits a similar profile to that of 5a.


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In contrast, the homodimer of the starting iodoalkyne, (6b for entry 3), does not form until after the initial burst and there is no incipient rapid increase in concentration. Alternatively stated, despite dynamic exchange there is a propensity to form heterodimer 5a and homodimer 6a over 6b, which is unexpected based on predictions from the terminal Keq. These nuances certainly would have been overlooked had a single end-point analysis been employed and reinforce the benefits of highly time-resolved reaction progress analysis. H

CH3 5a

H

CF3 5b

R

R 6a-c a: R = CH3; b: R = H; c: R = CF3

Figure 3. Homo- and heterodimeric diynes byproducts formed upon addition of exogenous base. Although the equilibrium position is identical for all alkyne/iodoalkyne pairs (Keq = 1), interesting information can be gathered by comparing kobs values against electronic effects. When the exchange was carried out under Conditions “A” (no base) and with unsubstituted or electron rich terminal alkynes (X = H or CH3, respectively), kobs is approximately the same20 irrespective of the iodoalkyne partner (Table 1, entry 1 cf. 2 and 6). Despite alkyne dimerization for entries 3 and 4, equilibration is still well behaved and displays a much larger kobs when compared to the same systems without added TEA (Table 1, entries 1, 2 cf. 3, 4). For the electron-rich alkyne pairs, the rates of equilibration within each set of conditions was identical, regardless of substitution of the starting materials (kobs(1) ≈ kobs(2) and kobs(3) ≈ kobs(4)).


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As such, it appears that the electronic characteristics of the terminal alkyne has the largest effect on rate. Comparing entries 1 and 5 (Conditions “A,” no base), it is clear that the rate is larger when an electron-deficient alkyne is employed in comparison to an electron-rich alkyne (kobs(5)/kobs(1) ≈ 2). Intriguingly, exchange of electron poor alkynes or iodoalkynes (X or Y = CF3; entries 7 and 8) under base exhibited complex profiles, no longer fitting an exponential function (Figure 3(a)). Even so, beginning the reaction with unsubstituted phenylacetylene 1b still produces an overall slower exchange process. Overlay of the data depicts stark differences between these two reactions and while the positions of the equilibria are identical, the profile for entry 7 exhibits sigmoidal behavior whereas for entry 8 the exchange is only slightly deviant from exponential. The rate and chemoselectivity of the dimeric by-products for entries 7 and 8 are also very instructive (Figures 4(b) and 4(c)). Once again, heterodimer 5b is the major byproduct and homodimer 6c, created from the electron poor components (X or Y = CF3), is the next major product. When starting with terminal alkyne 1c (X = CF3), the reaction profile for both heterodimer 5b and homodimer 6c mirror each other, displaying an initial faster rate followed by a slower pseudo-zero-order regime. Like the electron-rich alkynes, homodimer 6b does not appear until this initial rapid phase is complete. When the reciprocal experiment is conducted, homodimer 6b, arising from coupling of the terminal alkyne, is initially the second most abundant species; however, after 10 min the formation of 6c overtakes 6b.


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X

H

X

1c (X = CF3) or 1b (X = H) Y

I

2a (Y = H) or 2c (Y = CF3)

I 1c’ or 1b'

Y

H 2a’ or 2c'

Figure 4. (a) Overlay of exchange equilibrium for entries 7 and 8, (b) entry 7, dimeric byproducts, and (c) entry 8, dimeric by-products.


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The reaction progress analysis for the dialkyne byproducts indicates that dimerization likely arises solely from a Cadiot-Chodkiewicz-type coupling process involving a Cu-acetylide and an iodoalkyne and not Glaser oxidative dimerization of two terminal alkynes.19a-c, 21 While we did not rigorously exclude oxygen in these experiments, the observed rate and selectivity of the diyne products supports this conclusion.

This argument is based on the dominance of

heterodimerization, especially early in the catalytic process when the requisite iodoalkyne and terminal alkyne are both present in high concentration. The next most abundant byproduct is the homodimer resulting from the original terminal alkyne component. Again, this reflects the critical role of the σ-acetylide in this cross-coupling pathway. It is also noteworthy that the reaction profile for the homodimer corresponding to the initial terminal alkyne component is very similar to that of the heterodimer, suggesting both are formed via similar chemical pathways. The delay in the formation of the homodimer derived from the starting iodoalkyne further confirms our hypothesis, as H/I exchange must first occur to create sufficient terminal alkyne (2’ in Scheme 2) in order to engage in Cadiot-Chodkiewicz courpling.

Scheme 2. Proposed catalytic cycle depicting simultaneous exchange and dimerization.

BH

[CuI ]

R R'

B + H

step 1

R 1

B + R'

I 2

step 2

I

[CuI ]

[CuI ] R'

H step 4

2' BH

R'

R

step 3'

I

R

step 4'

dimers

step 3

[CuI ]

[CuIII ]

R' R'

I 1'


[CuI ]

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A proposed catalytic cycle that accounts for all observations is shown in Scheme 2. The kinetic profiles suggest that the generation of the key σ-acetylide from the terminal alkyne 1 (step 1) is rate limiting and would be aided by the high concentration of terminal alkyne at early time points. The subsequent coordination of the iodoalkyne 2 (step 2) now provides two possible pathways: Exchange of the alkynyl fragment at copper (step 3) yields the exchange product 1’. Next, protonolysis of the newly generated copper acetylide generates the other exchange product 2’ (step 4). Alternatively, coordination of the iodoalkyne to the copper-acetylide species can lead to the oxidative addition of iodoalkyne generating a CuIII diacetylide species (step 3’); irreversible reductive elimination then gives the dimeric byproducts and regenerates CuI (step 4’). As a final comment, it must be noted that this proposed catalytic cycle does not explicitly depict π-coordination of the terminal alkyne prior to deprotonation; however, we surmise that this also serves as a mode of activation to help facilitate the exchange. While we have ruled out complete ligand substitution of TCPTA by TEA, the stark contrast between the early (< 20 min) and later behaviors suggests some type of ligand rearrangement or catalyst reformatting.

The initial copper species tends to facilitate rapid alkyne coupling.

However, after a threshold amount of exchange has occurred, the active catalyst now affords dimers at a significantly reduced rate. Conclusion In summary, we have reported the detailed kinetic profiles of the exchange equilibrium between terminal and 1-iodoalkynes.

This information yields practical considerations for

reaction environments in which terminal and iodoalkynes are present. A direct connection involves the family of Cu-catalyzed couplings of alkynes, including Glaser-Hay, CadiotChodkiewicz, and others that have been plagued by undesired byproducts. 13 ACS Paragon Plus Environment

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ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Experimental procedures, characterization data, reaction progress graphs, and kinetic parameters (PDF). AUTHOR INFORMATION Corresponding Author * [email protected] ORCID Ryan Chung: 0000-0001-7242-1195 Jason E. Hein: 0000-0002-4345-3005 Notes The authors declare no competing financial interests. Funding Sources The authors gratefully acknowledge Mettler-Toledo Autochem for the donation of process analytical equipment (React-IR and EasyMax). Financial support for this work was provided by the University of British Columbia and the Natural Sciences and Engineering Resource Council


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of Canada (Engage, 2016-RGPIN-04613). Additionally, we thank Pfizer Worldwide Research and Development for a student research fellowship (to R.C.). REFERENCES (1) (a) Wu, W.; Jiang, H. Acc. Chem. Res. 2014, 47, 2483-2504. (b) Jiang, H.; Zhu, C.; Wu, W., Reactions of Haloalkynes. In Haloalkyne Chemistry, Springer Berlin Heidelberg: Berlin, Heidelberg, 2016; pp 9-76. (2) (a) Ye, M.; Wen, Y.; Li, H.; Fu, Y.; Wang, Q. Tetrahedron Lett. 2016, 57, 4983-4986. (b) Zeng, M.; Huang, R.-X.; Li, W.-Y.; Liu, X.-W.; He, F.-L.; Zhang, Y.-Y.; Xiao, F. Tetrahedron 2016, 72, 3818-3822. (c) Zou, H.; He, W.; Dong, Q.; Wang, R.; Yi, N.; Jiang, J.; Pen, D.; He, W. Eur. J. Org. Chem. 2016, 2016, 116-121. (d) Xie, L.; Wu, Y.; Yi, W.; Zhu, L.; Xiang, J.; He, W. J. Org. Chem. 2013, 78, 9190-9195. (3) (a) Zeng, X.; Liu, S.; Shi, Z.; Xu, B. Org. Lett. 2016, 18, 4770-4773. (b) Liu, G.; Kong, L.; Shen, J.; Zhu, G. Org. Biomol. Chem. 2014, 12, 2310-2321. (c) Yamagishi, M.; Okazaki, J.; Nishigai, K.; Hata, T.; Urabe, H. Org. Lett. 2012, 14, 34-37. (4) (a) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2009, 48, 8018-8021. (b) Lehnherr, D.; Alzola, J. M.; Lobkovsky, E. B.; Dichtel, W. R. Chem. Eur. J. 2015, 21, 18122-18127. (c) Oakdale, J. S.; Sit, R. K.; Fokin, V. V. Chem. Eur. J. 2014, 20, 11101-11110. (d) Gao, Y.; Yin, M.; Wu, W.; Huang, H.; Jiang, H. Adv. Synth. Catal. 2013, 355, 2263-2273. (e) Garcia-Alvarez, J.; Diez, J.; Gimeno, J. Green Chem. 2010, 12, 2127-2130. (f) García-Álvarez, J.; Díez, J.; Gimeno, J.; Suárez, F. J.; Vincent, C. Eur. J. Inorg. Chem. 2012, 5854-5863.


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(5) (a) Yamamoto, K.; Bruun, T.; Kim, J. Y.; Zhang, L.; Lautens, M. Org. Lett. 2016, 18, 2644-2647. (b) Delaunay, T.; Genix, P.; Es-Sayed, M.; Vors, J.-P.; Monteiro, N.; Balme, G. Org. Lett. 2010, 12, 3328-3331. (c) Ye, Q.; Cheng, T.; Zhao, Y.; Zhao, J.; Jin, R.; Liu, G. ChemCatChem 2015, 7, 1801-1805. (d) González-Liste, P. J.; Francos, J.; García-Garrido, S. E.; Cadierno, V. J. Org. Chem. 2017, 82, 1507-1516. (6) Abe, H.; Suzuki, H. Bull. Chem. Soc. Jpn. 1999, 72, 787-798. (7) (a) Dewanji, A.; Mück-Lichtenfeld, C.; Studer, A. Angew. Chem., Int. Ed. 2016, 55, 6749-6752. (b) Tanaka, R.; Zheng, S.-Q.; Kawaguchi, K.; Tanaka, T. J. Chem. Soc., Perkin Trans. 2 1980, 1714-1720. (8) Lal, S.; Rzepa, H. S.; Diez-Gonzalez, S. ACS Catal 2014, 4, 2274-2287. (9) Chung, R.; Yu, D.; Thai, V. T.; Jones, A. F.; Veits, G. K.; Read de Alaniz, J.; Hein, J. E. ACS Catal 2015, 5, 4579-4585. (10) (a) Smith, P. K.; Krohn, R. I.; Hermanson, G. T.; Mallia, A. K.; Gartner, F. H.; Provenzano, M. D.; Fujimoto, E. K.; Goeke, N. M.; Olson, B. J.; Klenk, D. C. Anal. Biochem. 1985, 150, 76-85. (b) Walker, J. M., The Bicinchoninic Acid (BCA) Assay for Protein Quantitation. In The Protein Protocols Handbook, Walker, J. M., Ed. Humana Press: Totowa, NJ, 2009; pp 11-15. (c) Wiechelman, K. J.; Braun, R. D.; Fitzpatrick, J. D. Anal. Biochem. 1988, 175, 231-237. (11) Bagchi, P.; Morgan, M. T.; Bacsa, J.; Fahrni, C. J. J. Am. Chem. Soc. 2013, 135, 18549-18559.


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(12) See Supporting Information for details on quench preparation and reaction sampling protocol. (13) Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Angew. Chem., Int. Ed. 2005, 44, 22102215. (14) These are conditions nearly identical to those in the original cycloaddition report, Ref. 4a. We have substituted the tert-butyl azide-derived tris(triazolylmethyl)amine ligand for the cyclopentyl azide variant. Cyclopentyl azide is much more easily synthesized than tert-butyl azide and we notice similar if not greater acceleratory behavior from this ligand. (15) (a) Buckley, B. R.; Dann, S. E.; Heaney, H. Chem. Eur. J. 2010, 16, 6278-6284, S6278/6271-S6278/6222. (b) Chui, S. S.; Ng, M. F.; Che, C. M. Chem. Eur. J. 2005, 11, 17391749. (c) Lang, H.; Köhler, K.; Blau, S. Coord. Chem. Rev. 1995, 143, 113-168. (d) Bai, R.; Zhang, G.; Yi, H.; Huang, Z.; Qi, X.; Liu, C.; Miller, J. T.; Kropf, A. J.; Bunel, E. E.; Lan, Y.; Lei, A. J. Am. Chem. Soc. 2014, 136, 16760-16763. (e) Straub, B. F. Chem. Commun. 2007, 3868-3870. (f) Makarem, A.; Berg, R.; Rominger, F.; Straub, B. F. Angew. Chem., Int. Ed. 2015, 54, 7431-7435. (g) Evano, G.; Jouvin, K.; Theunissen, C.; Guissart, C.; Laouiti, A.; Tresse, C.; Heimburger, J.; Bouhoute, Y.; Veillard, R.; Lecomte, M.; Nitelet, A.; Schweizer, S.; Blanchard, N.; Alayrac, C.; Gaumont, A. C. Chem. Commun. 2014, 50, 10008-10018. (h) Mykhalichko, B. M.; Oleg, N. T.; Mys'kiv, M. G. Russ. Chem. Rev. 2000, 69, 957. (16) All graphs and selected overlays can be found in the Supporting Information. (17) See Supporting Information for fitting details and parameters.


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(18) Reaction conditions for the independent synthesis and characterization of diyne products are detailed in the Supporting Information. (19) (a) Hua, R., Copper-Catalyzed Alkynylation and Alkenylation Reactions of Alkynyl Derivatives: New Access to Diynes and Enynes. In Copper-Mediated Cross-Coupling Reactions, John Wiley & Sons, Inc.: 2013; pp 455-483. (b) Cadiot, P.; Chodkiewicz, W., In Chemistry of Acetylenes, Viehe, H. G., Ed. M. Dekker: New York, 1969; pp 597–647. (c) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632-2657. (d) Sindhu, K. S.; Thankachan, A. P.; Sajitha, P. S.; Anilkumar, G. Org. Biomol. Chem. 2015, 13, 6891-6905. (e) Chinta, B. S.; Baire, B. RSC Adv. 2016, 6, 54449-54455. (20) The kobs values are within the same order of magnitude and overlay of the reaction progress graphs for the relevant entries displays excellent agreement. (21) Vilhelmsen, M. H.; Jensen, J.; Tortzen, C. G.; Nielsen, M. B. Eur. J. Org. Chem. 2013, 2013, 701-711.


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ACS Catalysis

TOC Graphic X

H

Keq = 1 X

I

Y

I

Y

H

X, Y = H, CH3, or CF3


Iodine Exchange in ... - ACS Publications

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