Proton grease: an acid catalyzed acceleration of a molecular rotor

Transcription

1 Journal of American Chemical Society Supplementary Information for Proton grease: an acid catalyzed acceleration of a molecular rotor Authors: Brent E. Dial, a Perry J. Pellechia, a Mark D. Smith a and Ken. D. Shimizu a a Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC Fax: (803) ; Tel: (803) ; shimizu@mail.chem.sc.edu 1) General Experimental All chemicals were purchased from commercial suppliers and used as received unless otherwise specified. Flash chromatography was carried out using silica (Sorbent Technologies, silica gel 60 Å, mesh). Thin layer chromatography (TLC) was performed on precoated TLC plates (Merck precoated 0.25 mm silica gel 60 F254 plates). NMR spectra were recorded on a Varian 300 or 400 MHz spectrometer. Chemical shifts are reported in ppm (δ) referenced to TMS (δ, 0.00 ppm) in 1 H NMR. 2) Synthesis S1

2 R R O O O 4a R = CH 3 4b R = H 5 N NH 2 N O! 150 o C, neat N N N O 6 O NH 2 N! 150 o C, neat O 7 NH 2 O! 150 o C, neat N O R R R R 1a R = CH 3 (95%) 1b R = H (95%) R 2 R = CH 3 (95%) R 3 R = CH 3 (95%) 3,3-dimethyl-1-(quinolin-8-yl)pyrrolidine-2,5-dione 1a 2,2-dimethylsuccinic anhydride 4a (133 µl, 1.18 mmol) and 8-aminoquinoline 5 (190 mg, 1.30 mmol) were dissolved in tetrahydrofuran (5 ml). The solvent was removed in vacuo and the residue was heated at 150 C overnight. No further purification was necessary. The product was a black solid (290 mg, 97%). 1 H NMR (300 MHz, CDCl 3 ) δ: 8.86 (dd, J = 1.7 Hz, J = 4.3 Hz, 1 H), 8.18 (dd, J = 1.7 Hz, J = 8.3 Hz, 1 H), 7.92 (dd, J =2.2 Hz, J = 7.5 Hz, 1 H), (m, 2 H), 7.43 (dd, J = 4.2 Hz, J = 8.3 Hz, 1 H), 2.96 (d, J = 18.0 Hz, 1 H), 2.82 (d, J = 18.0 Hz, 1 H), 1.61 (s, 3 H), 1.50 (s, 3 H); 13 C NMR (75 MHz, CDCl 3 ) δ: 25.4, 26.2, 41.0, 44.2, 121.9, 126.0, 129.2, 129.4, 129.6, 130.3, 136.0, 143.6, 151.0, HRMS (EI): calculated for C 15 H 14 N 2 O 2 : ; observed: S2

3 Figure S1. 1 H NMR spectrum of 1a (CDCl 3, 300 MHz). S3

4 Figure S2. 13 C NMR spectrum of 1a (CDCl 3, 75 MHz). The synthesis of the other N-arylimide rotors 1b 3 were carried out by the same procedure used above in the synthesis of 1a with their respective reactants. 1-(quinolin-8-yl)pyrrolidine-2,5-dione 1b The product obtained from condensation of anhydride 4b (52 mg, 0.52 mmol) and amine 5 (82 mg, 0.57 mmol) was a tan solid (116 mg, 99%). 1 H NMR (400 MHz, CDCl 3 ) δ: 8.88 (dd, J = 1.6 Hz, J = 4.2 Hz, 1 H), 8.20 (dd, J = 1.6 Hz, J = 8.3 Hz, 1 H), 7.93 (dd, J = 2.1 Hz, J = 7.4 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 4 H); 13 C NMR (100 MHz, CDCl 3 ) δ: 29.0, 122.0, 126.1, S4

5 129.3, 129.5, 129.8, 130.1, 136.3, 143.4, 151.0, HRMS (EI): calculated for C 13 H 10 N 2 O 2 : ; observed: Figure S3. 1 H NMR spectrum of 1b (CDCl 3, 400 MHz). S5

6 Figure S4. 13 C NMR spectrum of 1b (CDCl 3, 100 MHz). 1-(isoquinolin-5-yl)-3,3-dimethylpyrrolidine-2,5-dione 2 The product obtained from condensation of anhydride 4a (88 µl, 0.79 mmol) and 5-aminoisoquinoline 6 (113 mg, 0.79 mmol) was a brown powder (198 mg, 99%). 1 H NMR (400 MHz, TCE-d 2 ) δ: 9.35 (s, J = 1.0 Hz, 1 H), 8.59 (d, J = 6.0, 1 H), 8.13 (dt, J = 1.0 Hz, J = 8.3 Hz, 1 H), 7.74 (dd, J = 7.4 Hz, J = 7.4 Hz, 1 H), 7.60 (dd, J = 1.2 Hz, J = 6.0 Hz, 1 H), 7.27 (dt, J = 1.0 Hz, J = 8.3 Hz, 1 H), 2.94 (d, J = 18.3 Hz, 1 H), 2.85 (d, J = 18.3 Hz, 1 H), 1.59 (s, 3 H), 1.52 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ: 25.5, 26.5, 40.9, 44.1, 114.8, 126.9, 127.8, 129.3, 129.5, 130.6, 132.2, 144.1, 153.1, HRMS (EI): calculated for C 15 H 14 N 2 O 2 : ; observed: S6

7 Figure S5. 1 H NMR spectrum of 2 (TCE-d 2, 400 MHz). S7

8 Figure S6. 13 C NMR spectrum of 2 (CDCl 3, 100 MHz). 3,3-dimethyl-1-(naphthalen-1-yl)pyrrolidine-2,5-dione 3 The product obtained from condensation of anhydride 4a (88 µl, 0.79 mmol) and 1-aminonaphthalene 7 (113 mg, 0.79 mmol) was a light purple solid (198 mg, 99%). 1 H NMR (300 MHz, CDCl 3 ) δ: (m, 2 H), (m, 4 H), 7.33 (d, J = 7.3 Hz, 1 H), 2.94 (d, J = 18.2 Hz, 1 H), 2.84 (d, J = 18.2 Hz, 1 H), 1.60 (s, 3 H), 1.51 (s, 3 H); 13 C NMR (75 MHz, CDCl 3 ) δ: 25.6, 26.4, 40.7, 44.1, 121.6, 125.4, 126.3, 126.5, 127.2, 128.7, 129.4, 130.0, , HRMS (EI): calculated for C 16 H 14 NO 2 : ; observed: S8

9 Figure S7. 1 H NMR spectrum of 3 (CDCl 3, 300 MHz). S9

10 Figure S8. 13 C NMR spectrum of 3 (CDCl 3, 75 MHz). 3) Rotational Barrier Studies 3.1) via VT NMR Rotational barriers of rotors 1 3 lower than 20 kcal/mol were measured via variable temperature 1 H NMR (on a Varian 400 MHz spectrometer) by monitoring the broadening of the rotors methyl and methylene protons as they approached coalescence. The methyl and methylene protons appeared as diastereotopic singlets and a diastereotopic AB quartet on NMR spectrum, respectively. 1 Rates of 1 Abraham, R. J.; Fisher, J.; Loftus, P. Application of NMR Spectroscopy. Introduction to NMR Spectroscopy, John Wiley & Sons Ltd.: New York, 1988; Chapter 8. S10

11 exchange (k ex = π(h- h o )) were then obtained by line width analysis, which involves deconvolution of each methyl and methylene peak at each temperature step (h = width of peak at half height, h o = width of peak at slow or no exchange). Spectra were taken at 3 to 5 degree intervals within a 30 to 50 degree temperature range in 1,1,2,2-tetrachloroethane-d 2 (TCE-d 2 ). Each peak signal was analyzed and plotted individually in Arrhenius and Eyring plots and the average of the measured slopes and x- intercepts were used to calculate energy parameters of ΔG, ΔH, ΔS and E a (Note: the E a was only calculated using the Arrhenius analysis method). Line width analysis is only accurate in the intermediate exchange region. Thus, the measured slopes were restricted to this exchange region. The following is an example of a typical rotational barrier study. Figure S9. Rational barrier study overlay of rotor 2 in TCE-d 2 via VT NMR ( 1 H NMR 400 MHz). Left peak: methylene peaks were diastereotopic AB quartet. Right peak: methyl peaks were diastereotopic singlets. S11

12 y = x R 2 = ln(k/t) y = x R 2 = /Temperature (K -1 ) Figure S10. Eyring plot of the rates of exchange obtained from line width analysis of methyl protons on rotor 2. The barrier (ΔG = 19.4 kcal/mol) was calculated from the slope (ΔH = 23.6 kcal/mol) and x-intercept (ΔS = 29.3 cal/mol). VT studies was carried out between 66 C 115 C y = x R 2 = ln(k) y = x R 2 = /Temperature (K -1 ) Figure S11. Arrhenius plot of the rates of exchange obtained from line width analysis of methyl protons on rotor 2. The barrier (ΔG = 19.7 kcal/mol), enthalpy (ΔH = 23.5 kcal/mol), and entropy (ΔS = 28.8 cal/mol) were calculated from the slope or activation energy (E a = 24.3 kcal/mol). VT studies was carried out between 66 C 110 C. S12

13 3.2) via 2D Exchange Spectroscopy For rotational barriers higher than 20 kcal/mol, rotors 1 3 barriers were obtain by monitoring the exchange rates of the dynamic systems via two-dimensional exchange spectroscopy (2D EXSY). 2D EXSY can be applied qualitatively to map exchange pathways or quantitatively the measure rate constants. An identical pulse sequences used in 2D NOESY to monitor spin relaxation can be applied to measure exchange rates. Thus, the exchange rate is calculated from a single 2D EXSY NMR spectrum by the cross peak to diagonal peak intensity ratio (Equation 1). These rates must be observable on the NMR timescale, meaning that the rates can not be so slow that the relaxation process occurs during the mixing time erasing memory of the exchange process or so fast that the exchanging resonance can not be resolved. For this reason, 2D EXSY is most accurate when the exchange rate is between k ex s -1. k ex = (1/t m ) ln [(r +1)/(r 1)] where (1) r = (I AA +I BB )/(I AB +I BA ) From the exchange rate the energy barriers can be calculated using the Eyring equation. Below is an example of typical 2D EXSY spectrum S13

14 Figure S12. EXSY NMR (400 MHz) spectrum of rotor 1a at 78 C in TCE-d 2. The barrier calculated by this method was ΔG = 22.2 kcal/mol 4) Rotational Barrier Studies with Guest NMR samples were prepared by dissolving rotors 1-3 in TCE-d 2 (700 µl). To each sample were added sequential additions of 0.5, 1.0, 1.5, 2.0, and 4.0 equiv of methanesulfonic acid. Rotational barriers were obtained as discussed previously via VT and 2D EXSY NMR. Below is a titration overlay of 1a with MeSO 3 H (Figure S13). S14

15 Figure S13. Full 1 H NMR (400 MHz) spectra of 1a when titrated with various equivalence of MeSO 3 H in TCE-d 2 at rt. Figure S14. 1 H NMR (400 MHz) spectra of the diastereotopic methyl groups of rotor 3 at 0.0, 1.0, and 2.0 equiv of MeSO 3 H in TCE-d 2 at rt. Analysis of rotor 1a titration overlay provides support of a protonation event. Upon the addition of guest the coupling constant of the methylene peaks increased dramatically as a result of the chemical environment of the two conformers becoming more divergent due to the protonated nitrogen s proximity to the chiral axis. Succeeding additions of guest result in broadening and coalescence of the diastereotopic peaks. The quinoline aromatic protons initially overlap but are nicely resolved upon S15

16 consecutive additions of the acid guest (Figure S13). At 3.0 equiv of the guest a broad peak representing the protonated quinoline nitrogen (N + -H) appears between ppm ln(k/t) y = x R 2 = y = x R 2 = /Temperature (K -1 ) Figure S15. Eyring plot of the rates of exchange obtained from line width analysis of methyl protons on rotor 1a with 1.5 equiv of guest. The barrier (ΔG = 14.5 kcal/mol) was calculated from the slope (ΔH = 18.0 kcal/mol) and x-intercept (ΔS = 29.7 cal/mol). VT studies was carried out between -12 C 22 C. S16

17 Figure S16. EXSY spectrum of rotor 1a with 0.5 equiv of acid guest at 35 C in TCE-d 2 ( 1 H NMR 400 MHz). The barrier determine by this method was ΔG = 16.9 kcal/mol. The following table illustrates both methods, VT and 2D ESXY NMR, used to measure the guest catalyzed rotational barriers produced similar values. For example, at 0.5 equiv of MeSO 3 H the rotational barriers of rotor 1a measured by VT and 2D ESXY NMR were kcal/mol and 16.9 kcal/mol, respectively. Also, the barriers of 2 measured by both methods at 0 equiv of the guest were similar, kcal/mol and 20.0 kcal/mol. S17

18 Table S1. Energy parameters of rotors 1 3. Eyring Plot Arrhenius Plot 2D EXSY NModeling Sample Equiv. Acid E a!g!h!s!g!h!s!g!g 1a a b c a a a Base Study d e b f Base study was carried titrating rotor a solution of 3.0 equiv of MeSO 3 H and 1a with 2,6-lutidine. a the ΔG barrier was measured at 78 C. b the ΔG barrier was measured at 35 C. c the ΔG barrier was measured at 40 C. d the ΔG barrier was measured at -40 C. e the ΔG barrier was measured at 0 C. f the ΔG barrier was measured at 110 C. 5) Reversibility Study To test the reversibility of the guest catalyzed rotation event, a sample of rotor 1a with 3.0 equiv of methanesulfonic acid was titrated with 1.0, 2.0 and 3.0 equiv of 2,6-lutidine (Figure S18, Table 1) in TCE-d 2 (700 µl) and rotational barriers were measured via VT and EXSY NMR. S18

19 Figure S17. 1 H NMR spectra of 1a with 3.0 equiv of acid guest titrated with various equivalence of 2,6-lutidine in TCE-d 6 at rt. 2,6-lutidine was selected for this study because it is a mild base with a similar pka as quinoline (6.67 and 4.9, respectively) and its methyl peaks did not overlap the rotor s methyl peaks on the NMR spectrum (Figure S17). When 2,6-lutidine was added to a solution of the rotor the coalesced methyl peaks began to decoalesce and sharpen into diastereotopic singlets again (Table 1). At low temperatures a new peak representing the protonated lutidine (d, 16.5 ppm) grew in while the protonated quinoline nitrogen peak decreased at each base addition. S19

20 Table S2. Reversibility study of rotors 1a rotational barrier in TCE-d 6. O EXSY NMR VT NMR Acid equiv Base equiv!g (kcal/mol) EXSY Temp. ( o C)!G (kcal/mol) VT Temp. ( o C) %"!#$ %"(#$! (ppm) %"'#$ %"&#$ %"##$!"!#$ #"#$ )"#$ &"#$ *"#$ Equiv of MeSO 3 H Figure S18. Plot of the changes in the chemical shift of the aromatic proton adjacent to the quinoline nitrogen upon titration of varying equiv of MeSO 3 H. The 1 H NMR spectra were taken in TCE-d 6 at rt. S20

21 6) Crystal Information X-Ray Structure Determination, C 15 H 14 N 2 O 2 rotor 1a X-ray intensity data from a light brown needle crystal were measured at 100(2) K using a Bruker SMART APEX diffractometer (Mo Ka radiation, l = Å). 1 Raw area detector data frame processing was performed with the SAINT+ and SADABS programs. 1 Final unit cell parameters were determined by least-squares refinement of 7624 reflections from the data set. Direct methods structure solution, difference Fourier calculations and full-matrix least-squares refinement against F 2 were performed with SHELXTL. 2 The compound crystallizes in the space group P2 1 /n as determined uniquely by the pattern of systematic absences in the intensity data. The asymmetric unit consists of one molecule. Nonhydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were located in difference maps before being placed in geometrically idealized positions and included as riding atoms. Figure S19. X-ray crystal structure of 1a, head-on view. S21

22 Crystal data and structure refinement for rotor 1a. Identification code Empirical formula rotor 1a Formula weight Temperature Wavelength Crystal system C15 H14 N2 O2 100(2) K Å Monoclinic Space group P 21/n Unit cell dimensions a = (4) Å a= 90. b = (6) Å b= (10). c = (5) Å g = 90. Volume (10) Å 3 Z 4 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 536 Crystal size 0.46 x 0.24 x 0.18 mm 3 Theta range for data collection 2.38 to Index ranges Reflections collected <=h<=10, -16<=k<=16, -14<=l<=14 Independent reflections 2651 [R(int) = ] Completeness to theta = % Absorption correction None Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 2651 / 0 / 174 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Largest diff. peak and hole and e.å -3 S22

23 X-Ray Structure Determination, (C 13 H 10 N 2 O 2 )(H 2 O) Hydrate 1b X-ray intensity data from a colorless needle crystal were measured at 100(2) K using a Bruker SMART APEX diffractometer (Mo Ka radiation, l = Å). 1 Raw area detector data frame processing was performed with the SAINT+ program. 1 Final unit cell parameters were determined by least-squares refinement of 1260 reflections from the data set. Direct methods structure solution, difference Fourier calculations and full-matrix least-squares refinement against F 2 were performed with SHELXTL. 1 The compound crystallizes in the space group Pbca as determined uniquely by the pattern of systematic absences in the intensity data. The asymmetric unit consists of one C 13 H 10 N 2 O 2 molecule and one H 2 O molecule. Non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms bonded to carbon were placed in geometrically idealized positions and included as riding atoms. The water hydrogens were located in a difference map and refined isotropically with d(o-h) = 0.85(2) Å distance restraints. Figure S20. The hydrate X-ray crystal structure of rotor 1c. Dimer formation was hydrogen bond assistant. Hydrogen bonds drawn as blue dashed lines. S23

24 Crystal data and structure refinement for rotor 1b. Identification code Empirical formula rotor 1b Formula weight Temperature Wavelength Crystal system Space group C13 H12 N2 O3 100(2) K Å Orthorhombic P b c a Unit cell dimensions a = (3) Å a= 90. b = (12) Å b= 90. c = (3) Å g = 90. Volume (7) Å 3 Z 8 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 1024 Crystal size 0.46 x 0.10 x 0.06 mm 3 Theta range for data collection 2.21 to Index ranges Reflections collected <=h<=19, -8<=k<=8, -20<=l<=20 Independent reflections 1671 [R(int) = ] Completeness to theta = % Absorption correction None Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 1671 / 2 / 171 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Largest diff. peak and hole and e.å -3 S24

25 X-Ray Structure Determination, (C 13 H 10 N 2 O 2 )(C 13 H 11 N 2 O 2 )(Cl)(H 2 O) Rotor 1b X-ray intensity data from a colorless crystal were measured at 100(2) K using a Bruker SMART APEX diffractometer (Mo Ka radiation, l = Å). 1 Raw area detector data frame processing was performed with the SAINT+ and SADABS programs. 1 Final unit cell parameters were determined by least-squares refinement of 5108 reflections from the data set. Direct methods structure solution, difference Fourier calculations and full-matrix least-squares refinement against F 2 were performed with SHELXTL. 2 The compound crystallizes in the orthorhombic system. The space groups Pna2 1 and Pnma were indicated by the pattern of systematic absences in the intensity data. The acentric space group Pna2 1 was eventually confirmed by obtaining a reasonable and stable solution of the structure, by close examination of the packing, and by use of the ADDSYM program (in EXACT mode).error! Bookmark not defined. The crystal is pseudosymmetric. There is a false center of symmetry present relating the C 13 H 10 N 2 O 2 and C 13 H 11 N 2 O + 2 species (ignoring the proton H2). However this symmetry is broken by the inequivalence of the chloride and water molecules, whose positions are also related by the center. The asymmetric unit of the crystal consists of one C 13 H 10 N 2 O 2 molecule, one C 13 H 11 N 2 O + 2 ion, one water molecule and one chloride ion. All non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms bonded to carbon were placed in geometrically idealized positions and included as riding atoms. Hydrogen atoms bonded to nitrogen and oxygen were located in difference maps. H2 was refined freely; the water hydrogens H5A and H5B were refined isotropically with their O-H distances restrained to be similar. The crystal was refined as an inversion twin based on the value of the Flack parameter. S25

26 Figure S21. X-ray crystal structure of rotor 1b. Asymmetric unit of the crystal. Displacement ellipsoids drawn at the 60% probability level. One neutral C 13 H 10 N 2 O 2 molecule, one HCl salt of a C 13 H 10 N 2 O 2 molecule and one water molecule. Hydrogen bonds drawn as blue dashed lines. S26

27 Crystal data and structure refinement for rotor 1b. Identification code Empirical formula rotor 1b Formula weight Temperature Wavelength Crystal system C26 H23 Cl N4 O5 100(2) K Å Orthorhombic Space group P n a 21 Unit cell dimensions a = (8) Å a= 90. b = (4) Å b= 90. c = (8) Å g = 90. Volume (19) Å 3 Z 4 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 1056 Crystal size 0.40 x 0.24 x 0.02 mm 3 Theta range for data collection 2.22 to Index ranges Reflections collected <=h<=22, -9<=k<=9, -20<=l<=20 Independent reflections 4779 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 4779 / 2 / 338 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter 0.37(7) Largest diff. peak and hole and e.å -3 S27

28 6) Molecular Modeling In Spartan10, the transition and ground state energies and geometry were calculated for the protonated and protonated rotors 1 3. The geometry of the GS and TS were identified using the equilibrium geometry and TS geometry commands on starting structures with dihedral angles of 90 and 0 between the planes of the succinimide and quinoline rings. The TS and GS geometries of the rotors were minimized at low level B3LYP 6-31 and then refined at a higher level of theory (B3LYP 6-311G++**). The difference between the TS and GS energies was equal to the barrier of rotation. In the TS, the protonated quinoline nitrogen is in close proximity with the imide carbonyl (distance between N + -H-- O=C = Å) forming an intramolecular hydrogen bond. The hydrogen bond stabilizes the TS, relieving the steric strain in the planar TS. 1 SMART Version 5.630, SAINT+ Version 6.45 and SADABS Version Bruker Analytical X-ray Systems, Inc., Madison, Wisconsin, USA, Sheldrick, G.M. Acta Cryst. 2008, A64, S28