Elucidating the Impact of Molecular Structure on the 19F NMR

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Letter Cite This: ACS Macro Lett. 2018, 7, 921−926

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Elucidating the Impact of Molecular Structure on the 19F NMR Dynamics and MRI Performance of Fluorinated Oligomers Cheng Zhang,†,‡ Dong Sub Kim,§ Jimmy Lawrence,§,∥ Craig J. Hawker,*,§ and Andrew K. Whittaker*,†,‡

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Australian Institute for Bioengineering and Nanotechnology and ‡ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, Brisbane, Queensland 4072, Australia § Materials Research Laboratory, Materials Department and Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States ∥ Cain Department of Chemical Engineering, Louisiana State University, Baton Rouge, Louisiana 70803, United States S Supporting Information *

ABSTRACT: To understand molecular factors that impact the performance of polymeric 19F magnetic resonance imaging (MRI) agents, a series of discrete fluorinated oligoacrylates with precisely defined structure were prepared through the combination of controlled polymerization and chromatographic separation techniques. These discrete oligomers enabled thorough elucidation of the dependence of 19F NMR and MRI properties on molecular structure, for example, the chain length. Importantly, the oligomer size and dispersity strongly influence NMR dynamics (T1 and T2 relaxation times) and MR imaging properties with higher signal-to-noise ratio (SNR) observed for oligomers with longer chain length and shorter T1. Our approach enables an effective pathway and thus opportunities to rationally design effective polymeric 19F MR imaging agents with optimized molecular structure and NMR relaxivity.

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imaging,14,15 and cell tracking.16,17 These studies collectively demonstrate the importance of fluorinated group placement and overall polymer structure on 19F NMR dynamics and MR imaging performance. Access to a library of discrete fluorinated oligomers provides an exciting entry point to further understand the impact of molecular structure on NMR dynamics and MRI performances at a more precision level. To achieve this, a fluorinated chain transfer agent was employed in the RAFT polymerization of tert-butyl acrylate (TBA) leading to oligomers with fluorinated chain ends and various average degrees of polymerizations (DPs; Scheme 1 and Figure S1). The ratio of initiator to chain transfer agent (CTA) was set at 0.1 to obtain narrow dispersity oligoTBA samples with high chain-end fidelity (see Supporting Information, Figure S1). These disperse samples were transformed into a library of discrete oligomers using the recently reported chromatographic separation technique.1,2 Following the isolation process, the discrete oligomers were exposed to light to replace the trithiocarbonate end group with a hydrogen.18 Deprotection of the tert-butyl groups using trifluoroacetic acid (TFA) was conducted subsequently to afford chain-end-fluorinated oligo(acrylate acid) samples in

he rational design of polymeric 19F magnetic resonance imaging (MRI) agents depends on an understanding of the contributions from each molecular factor of the fluorinated polymer: chain length, dispersity, and topology, etc. Equally important is the availability of robust synthetic methods to control such parameters with high precision. In contrast to the well-established methods of preparation of inorganic nanoparticles with discrete sizes, facile and scalable preparation of discrete polymeric materials (Đ approaching 1.0) has been a longstanding challenge. Encouragingly, a versatile and efficient strategy for the synthesis of a range of discrete functional oligomers has been developed. The method exploits the use of scalable automated chromatography systems to purify lowmolecular weight polymers derived from controlled polymerization techniques (e.g., atom transfer radical polymerization), thereby enabling the isolation of a library of discrete polymeric species (Đ = 1.0) at multigram scale. Furthermore, this method is applicable to a wide range of monomer families, such as acrylates, styrenics, siloxanes, and thiophenes.1−4 Motivated by the potential of this method to enable detailed studies of structure-performance relationships, we prepared a library of discrete oligo(acrylic acid)s with a terminal trifluoromethyl group (oligoAAn-CF3) for 19F NMR and MRI studies. Over the past decade, we and others have examined the potential of partly fluorinated polymeric nanoparticles (NPs) as 19F MRI agents5−9 and demonstrated the application of these molecules for measuring changes in biological conditions such as pH, ionic strength,10−13 in vivo © XXXX American Chemical Society

Received: June 7, 2018 Accepted: July 11, 2018

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ACS Macro Letters Scheme 1. Synthetic Route for Discrete OligoAAn-CF3 (n = 3, 5, 7, 9, and 11)

Figure 1. 1H NMR (left) and MALDI-ToF-MS (right) spectra of (a) CTA-oligoTBA7-CF3, (b) H-oligoTBA7-CF3 after end-group removal, and (c) H-oligoAA7-CF3 after deprotection.

final oligoAA-CF3 samples. Peak d in the 1H NMR spectrum corresponding to the tert-butyl groups disappears, while in the MS a mass loss of 392 a.m.u. was observed, corresponding to the quantitative removal of seven tert-butyl groups (Figure 1c). To confirm the structures of the final products (oligoAACF3), high-resolution 1D and 2D 1H COSY, 1H TOCSY, 13C DEPT135, 1H−13C HSQC, and HMBC spectroscopies were conducted and the results are shown in Figures S5−S16. The 1 H NMR spectrum of the discrete trimer, displayed in Figure S5, shows sharp resonances typical of small molecules in solution. The multiple splittings of the resonances are the result of J coupling and the presence of different individual stereoisomers.1,2 As the series progresses toward the undecamer, resonances in the 1H and 13C NMR spectra broaden, especially those due to protons and carbons on the oligomeric backbone, until the spectrum becomes similar to high molecular weight poly(acrylic acid) (PAA). The 1H NMR spectra of the disperse oligomers, shown in Figure S6, display similar line broadening with increasing chain length, and no

excellent yields (discrete and disperse oligoAAn-CF3, 3-, 5-, 7-, 9-, and 11-mer). A combination of 1H NMR and mass spectroscopy was employed to monitor transformation of the chain end and confirm the purity of both the disperse and discrete libraries (Figures 1 and S2−S4). As an illustrative example, the peak integral intensities in the 1H NMR spectrum of the discrete heptamer sample (CTA-oligoTBA7-CF3) are in excellent agreement with the number of protons in the structure (Figure 1). Following removal of the RAFT end group from the discrete heptamer (H-oligoTBA7-CF3), the 1H signals from the two methylene protons (Figure 1a, peak c, δ = 3.3 ppm) adjacent to the trithiocarbonate group disappear (Figure 1b), while the methylene protons (Figure 1a, peak b, δ = 4.5 ppm) adjacent to the CF3 chain end remain intact. This quantitative removal of trithiocarbonate chain ends could also be observed in the mass spectral (MS) analysis, where a decrease in mass of 276 a.m.u. was observed, confirming removal of the trithiocarbonate group. The tert-butyl groups of the discrete heptamer were removed by treatment with TFA to give the 922

DOI: 10.1021/acsmacrolett.8b00433 ACS Macro Lett. 2018, 7, 921−926

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ACS Macro Letters significant differences were observed in 1H NMR spectra of the disperse and discrete oligomeric species. The proton-decoupled 19F NMR spectra of the oligomers were measured to obtain detailed molecular structural information, that is, chain length and stereochemistry. Multiple 19 F resonances can be clearly observed in all discrete samples with resonances for oligomers with longer chain lengths broadening and moving to higher chemical shifts (Figure 2a).

discrete oligoAA11-CF3 undecamer. Figure S16 shows the expansion of the region in the 13C NMR spectrum due to the CH groups of the polymer backbone. The peaks were assigned based on published spectra for high molecular weight PAA.19 The chain tacticity of the undecamer, quantified by integration of the CH-based triads is rr/mr/mm = 0.38/0.49/0.13, which agrees with the analysis of the 19F NMR spectra, as described below (Table S1 and Figure S18, rr/mr/mm = 0.41/0.47/ 0.12). By means of the established triad populations, we can test whether the propagation of the polymer chain obeys Bernoullian statistics. Pr/m is the probability that the monomeric unit added to a polymer chain terminated by a racemic dyad will generate a meso dyad and is given by Pr/m = (mr)/(2rr + mr) and similarly Pm/r = (mr)/(2mm + mr). When Pr/m + Pm/r = 1, the chain propagation obeys Bernoullian statistics.20 For the discrete oligoAA-CF3 undecamer, the above equations yield Pr/m and Pm/r to be 0.36 and 0.66 from 19 F NMR and 0.39 and 0.65 from 13C NMR. The sum of the placement probabilities is equal to one within experimental error indicating that the polymerization of TBA under the current conditions obeys Bernoullian statistics, as seen in previously reported studies.20,21 The populations of meso and racemic diads in the discrete undecamer were calculated to be 0.37 and 0.63 from 13C NMR and 0.36 and 0.64 from 19F NMR, respectively, indicating higher racemic content of TBA units formed during the RAFT polymerization, once again in agreement with literature data for the controlled polymerization of TBA.21 Based on the spectra assignment for the discrete undecamer, the 1H-decoupled 19F NMR spectrum of the discrete oligoAA-CF3 pentamer, heptamer and nonamer were also assigned to the triad level. The proportions of rr, mr, and mm triads were calculated to be 0.23, 0.67, and 0.10 for the pentamer, 0.37, 0.52, and 0.11 for the heptamer and 0.41, 0.48, and 0.11 for the nonamer (Figures S19−21 and Table S1). The 1H-decoupled 19F and 13C NMR spectra of the discrete oligoAA-CF3 trimer were also measured. The two resonances in the proton-decoupled 19F NMR spectrum of the discrete trimer (Figure 3a,b) could be assigned to racemic (−75.036

Figure 2. 1H-decoupled 19F NMR spectra of (a) discrete oligoAA-CF3 3-, 5-, 7-, 9-, and 11-mer and (b) disperse and discrete oligoAA-CF3 3mer. TFA was added to the solution as an internal NMR chemical shift reference at −76.55 ppm.

Of particular note is the difference between discrete and low dispersity samples which is illustrated by seven major peaks being observed in the proton-decoupled 19F NMR spectrum of the disperse oligoAA-CF3 trimer, while only two peaks were observed in the spectrum of the discrete oligoAA-CF3 trimer (Figure 2b). The splitting of the 19F NMR resonances of the discrete trimer is attributed to the different stereochemical arrangements of the monomeric units adjacent to the chain ends. However, contributions from other oligomers (primarily n = 2−4) are apparent in the spectrum of the disperse trimer. To clarify the contribution of chain length to the observed multiple peaks in the 19F NMR spectrum of the disperse trimer derivative, 19F diffusion-ordered spectroscopy (DOSY) was conducted. The diffusion coefficients associated with each peak allowed identification of those due to dimeric, trimeric and tetrameric species and the corresponding peak assignments are shown in Figure 2b. The diffusion coefficients of the dimer, trimer and tetramer in methanol-d4 were 9.9 × 10−12, 8.6 × 10−12 and 7.8 × 10−12 m2/s, respectively, in line with the increasing chain length (Figure S17). The results indicate that there are three sets of resonances in the 19F NMR spectrum of the disperse trimer with the peak from the dimer at −75.079 ppm, peaks from the trimer at −75.045 and −75.036 ppm and the tetramer at −75.031, −75.027, −75.018, and −75.005 ppm. This is consistent with electrospray ionization (ESI) analysis of the disperse trimer, where three species can be observed with the dimer at m/z 315, the trimer at m/z 409 and the tetramer at m/z 481, respectively ([M + Na]+, Figure S4). It is clearly observed that the 19F NMR chemical shift is subtly sensitive to the chain length. The content of dimer, trimer and tetramer in the disperse trimer sample can be further calculated to be 10%, 52%, and 38%, respectively, by integration of the corresponding 19F NMR peaks (Figure 2b). The extensive splitting in the 19F NMR spectra is evidence that the 19F NMR chemical shift of the oligoAA-CF3 is sensitive to the stereochemistry of the short chains. To examine this further, 13C NMR and 1H-decoupled 19F NMR spectra were measured for the highest molecular weight,

Figure 3. (a) Proposed stereochemical configurations for the oligoAA-CF3 trimer: racemic and meso. (b) 1H-decoupled 19F NMR, (c, d) quantitative 13C NMR spectra of the discrete trimer.

ppm, 61%) and meso (−75.045 ppm, 39%) diads. Again the populations of meso and racemic diads of the discrete trimer are close to those of the discrete undecamer. The quantitative 13C NMR spectrum of the discrete trimer (Figure 3c) also shows similar splitting of the peak due to the methine carbon in the main chain (C6 and C6′) with nearly equivalent integral values 923

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Figure 4. 19F NMR dynamics and MRI properties of the discrete oligomers. (a) 19F NMR T1 and (b) T2 relaxation times of discrete oligoAA-CF3 samples. 19F MRI SNRs of (c) discrete and (d) disperse oligoAA-CF3 samples with different T1/T2 ratios from trimer to undecamer in water. The fluorine concentration was kept constant at 20 mM for all oligomers. Data are expressed as means ± SD (n = 3).

Figure 5. (a) 19F MR images and (b) signal-to-noise ratios of solutions of discrete trimer and undecamer oligoAA-CF3 at fluorine concentrations from 2 to 20 mM in water. 19F MRI was performed using the RARE sequence at 9.4 T, with TR = 1500 ms and TE = 11 ms.

when compared to the 19F NMR analysis (62% and 38% for racemic and meso, respectively, Figure 3c). In addition, the peaks in the 13C NMR spectrum of the trimer due to the two methyl groups at the chain end are well-defined (C8 and C8′ + C8′′) with the two methyl carbons being inequivalent due to the presence of the stereocenter at the terminal monomeric unit. The resonances from these methyl carbons are further split due to the presence of two stereoisomers in the terminal dyads, and the peaks at lower chemical shift show a more pronounced splitting (peaks C8′ + C8′′, Figure 3d). The proportion of racemic and meso dyads in the discrete oligoAA3CF3 trimer sample can be calculated from the integration of the two peaks and again ∼64% racemic (C8′) and 36% meso dyad (C8′′) populations are observed. The resonances of the oligoAA-CF3 tetramer can be also assigned successfully (Figure 2b). These results indicate that the 19F NMR analysis provides similar information to 13C NMR spectroscopy in terms of structure and stereochemistry with the higher natural abundance providing a significant advantage in terms of dramatically shorter acquisition times (13C: 26 h, 19F: 1.63 min). We next examined 19F NMR relaxation times for discrete and disperse oligoAA-CF3 samples in aqueous solution. The hydrodynamic diameters of the oligomers up to 11-mer were determined by 19F DOSY NMR. The results confirm that the fluorinated oligomers are present as unimers in solution and

that their molecular size increases in proportion to the chain length (Figures S22 and S23, Tables S2 and S3). 19F NMR longitudinal and transverse T1 and T2 relaxation times of aqueous solutions of the oligomers with an overall content of 20 mM “fluorine atoms” in solution were then measured at 9.4 T at 25 °C. The 19F NMR T1 and T2 relaxation times of the disperse samples decrease with increasing chain length (Figure S24), indicating the mobility of fluorinated segments decreases as the chain length is increased. However, in the case of the discrete oligomers, 19F NMR T1 and T2 relaxation times decrease as the chain length increases to nonamer (Figure 4a,b). As the chain length further progresses to 11-mer, the 19F NMR T1 of the discrete undecamer increases slightly while the 19 F NMR T2 plateaus at around 1.1 s, suggesting a transition of the molecular motion from the fast to the slow motion regime.13,22 Given this difference in 19F NMR dynamics between disperse and discrete derivatives of different chain lengths, next we examined the MRI performance of these molecules. Among several commonly employed MRI imaging sequences, we found that the rapid acquisition with refocused echoes (RARE) sequence to be particularly well-suited for imaging these fluorinated oligomers (see Supporting Information Figure S24). The 19F MRI signal-to-noise ratios (SNRs) were measured from the RARE images and displayed in Figures 4c,d and S25c,d. The SNR of images of the oligomers 924

DOI: 10.1021/acsmacrolett.8b00433 ACS Macro Lett. 2018, 7, 921−926

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increases as the degree of polymerization increases from three to seven, while the SNR reaches a plateau as the chain length increases further (Figure S25c,d). It was previously reported that SNR is directly related to both T1 relaxation time and the ratio of T1/T2 with smaller T1 and T1/T2, resulting in higher SNR.23,24 However, in contrast, we observe that the SNR is proportional to the ratio of T1/T2 (Figure 4c). This observation leads us to conclude that, under the imaging conditions used here, changes in T1 have a more pronounced influence on the SNR compared with changes in T1/T2. The SNR of the undecamer sample was always higher than the trimer (increased by 74% vs 24% for discrete and disperse samples respectively), primarily due to the shorter 19F NMR T1 relaxation time of the longer oligomer. In addition, the SNR of the discrete undecamer is approximately 21% higher that the disperse sample, and the relationship between SNR and T1/T2 is not as clear as for the discrete samples (Figure 4d). Differences in 19F MRI SNR of the discrete samples compared to the disperse oligomers are due to additional contributions from the various species in the disperse samples. 19 F MR images of solutions of the trimer and undecamer having fluorine atom concentrations from 2 to 20 mM were also acquired using the RARE sequence and a linear dependence of intensity on concentration was noted (Figure 5, R2 = 0.99 and Figure S26, R2 ≈ 0.95 for discrete and disperse samples, respectively). We conclude that quantitative MR imaging of the discrete oligoAA-CF3 oligomers is possible, and therefore they have potential as quantitative 19F MR tracers.5,8,14,25,26 These observations are important as it provides useful insights into the structural design of discrete fluorinated oligomers and polymers, where a trade-off exists between structure, dynamics and MRI performance. In summary, we have successfully prepared a series of partly fluorinated oligo(acrylic acid) derivatives (oligoAA-CF3) with discrete chain lengths from trimer to undecamer. Detailed studies have provided an understanding of the structural dependence of their 19F NMR and MRI properties. The length of the oligomeric chain and dispersity in chain length were shown to have a strong effect on magnetic resonance properties, revealed through studies of NMR relaxation times and MRI performance. Under the conditions of these studies the 19F MRI signal-to-noise ratio increased with increasing degree of oligomerization, primarily as a result of a decrease in T1 relaxation time with increasing chain length. Overall, the results presented here provide a powerful strategy for designing discrete fluorinated oligomers as effective 19F MR imaging agents with optimized molecular structure and NMR dynamics.

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Cheng Zhang: 0000-0002-2722-7497 Jimmy Lawrence: 0000-0003-4455-6177 Craig J. Hawker: 0000-0001-9951-851X Andrew K. Whittaker: 0000-0002-1948-8355 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the Australian Research Council (CE140100036, DP0987407, DP110104299, LE0775684, LE0668517, and LE0882357), the National Health and Medical Research Council (APP1021759), and the UCSB MRSEC (NSF DMR 1720256) for funding of this research. The Australian National Fabrication Facility, Queensland Node, is also acknowledged for access to some items of equipment. C.Z. acknowledges the University of Queensland for his Early Career Researcher Grant (UQECR1720289).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.8b00433. Describes in detail the synthetic procedures and characterization (NMR, DLS, MRI) of the discrete and disperse oligomers (PDF).

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. 925

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