Thermal Deprotection Research Articles

Selective Thermal Deprotection of N-Boc Protected Amines in Continuous Flow.

Thermal N-Boc deprotection of a range of amines is readily effected in continuous flow, in the absence of an acid catalyst. While the optimum results were obtained in methanol or trifluoroethanol, deprotection can be effected in a range of solvents of different polarities. Sequential selective deprotection of N-Boc groups has been demonstrated through temperature control, as exemplified by effective removal of an aryl N-Boc group in the presence of an alkyl N-Boc group. As a proof of principle, a telescoped sequence involving selective deprotection of an aryl N-Boc group from 9h followed by benzoylation and deprotection of the remaining alkyl N-Boc group to form amide 13 proved successful.

Precise control of thermal deprotection behavior and dismantlable adhesion property of the acrylate copolymers containing BOC-protected hydroxy group

The acrylate copolymers consisting of 4-hydroxybutyl acrylate (HBA), 2-(tert-butoxy-carbonyloxy)ethyl acrylate (BHEA) or 4-(tert-butoxycarbonyloxy)butyl acrylate (BHBA), and 2-ethylhexyl acrylate (2EHA) as the repeating units were synthesized by radical copolymerization. The performance as the pressure-sensitive adhesives (PSAs) used for a dismantlable adhesion system was investigated. The glass transition temperatures and the adhesive properties were precisely controlled by the comonomer composition of the copolymers. It was confirmed that the deprotection of the tert-butoxycarbonyl (BOC) group rapidly proceeded for the BOC-containing acrylate copolymers as the PSAs. It resulted in the decrease of the adhesion strength during a debonding process by heating. The thermal stability during use and the quick response for on-demand debonding were simultaneously achieved by the use of alkyl p-toluenesulfonates as the thermally latent acids (TLAs).

Controlled deprotection of poly(2-(tert-butoxycarbonyloxy)ethyl methacrylate) using p-toluenesulfonic esters as thermally latent acid catalysts

Poly(2-(tert‑butoxycarbonyloxy)ethyl methacrylate) (PBHEMA) is converted to poly(2-hydroxyethyl methacrylate) with the release of isobutene and carbon dioxide gasses when it is heated at a high temperature over 200 °C. The deprotection of PBHEMA is accelerated by the addition of an acid, but it is simultaneously disadvantageous for the storage and handling of the polymer at an ambient temperature. In this study, we propose the use of thermal acid generators, i.e., thermally latent acids (TLAs) as the catalysts to control a reaction rate and a working temperature for the deprotection of PBHEMA. We investigated the thermal deprotection behavior of some sulfonates including isopropyl p-toluenesulfonate (IPTS) and cyclohexyl p-toluenesulfonate (CHTS). The kinetic parameters for the deprotection, which provides p-toluenesulfonic acid (TsOH) as the reaction product, were determined by thermogravimetric (TG) analysis under the isothermal condition. A remarkable auto-catalytic effect actually resulted in a rapid deprotection to produce TsOH in a narrow temperature range under the non-isothermal conditions. The additive effect of the TLAs on the deprotection of the BOC groups contained in the side chain of PBHEMA was similarly investigated. It was revealed that the deprotection of PBHEMA rapidly proceeded by the addition of IPTS and CHTS under the heating conditions over 100 °C. PBHEMA was stable at a temperature below the onset temperature of the deprotection of the TLAs. The deprotection kinetics of PBHEMA and a detailed mechanism for the control of the reactions in the presence of the TLAs were clarified.

Taking a different road: following Ag25 and Au25 cluster activation via in situ differential pair distribution function analysis.

Synchrotron X-ray total scattering measurements and accompanying pair distribution function (PDF) analyses are an excellent characterization technique to complement both transmission electron microscopy (TEM) and extended X-ray absorption fine structure (EXAFS) spectroscopy methods for detailed structural studies of atom-precise metal clusters. Herein, we study the thermal activation of Au25(SR)18- and Ag25(SR)18- clusters on alumina supports via in situ differential PDF (dPDF) analyses to compare structural changes in the metal clusters upon thermal activation in air. The metal-metal interatomic distances in Au25(SR)18- and Ag25(SR)18- clusters as measured by the dPDF method are comparable with those measured via single-crystal crystallographic and EXAFS methods. Compared to EXAFS analysis, in situ dPDF data can also provide high-temperature, non-element specific, longer range structural information with excellent temporal resolution. TEM and dPDF results show that Ag25(SR)18 systems behave significantly differently than analogous Au25(SR)18 systems upon thermal activation. Atom-precise Au clusters on alumina supports show continuous growth in particle size with increasing activation temperature due to particle coalescence upon thermal deprotection, and grow to an average size of 11.2 ± 2.1 nm for samples thermally activated at 650 °C. Conversely, analogous Ag clusters on alumina supports show particle size growth to mid-sized particles (3.2 ± 0.4 nm) at activation temperatures of 450 °C, beyond which the Ag particles then undergo thermal degradation to give smaller Ag clusters with an average size of 1.4 ± 0.2 nm for samples thermally activated at 650 °C. The significant difference in the behaviours of atom-precise, thiolate-protected Au and Ag clusters upon thermal activation emphasizes the development of distinct activation protocols for different metal cluster systems.

Preparation of the 5-(4-((4-[18F] fluorobenzyl) oxy)- 3-methoxybenzyl) pyrimidine-2, -diamine as a radioligand for positron emission tomography scanning of the tyrosine kinase b/C receptor

Objective: The present research describes a new radiosynthesis of 5-(4-((4-[18F]fluorobenzyl)oxy)-3-methoxybenzyl)pyrimidine- 2,4-diamine as a potential radioligand for colony-stimulating factor 1 receptor (CSF-1R) and tyrosine kinase B/C (TrkB/C) neuroreceptors. Methods: Radiofluorination of a boronic acid precursor followed by thermal deprotection of Boc-protecting groups avoided acidcatalyzed protodeboronation in 8.7 ± 2.8% radiochemical yield. Results: Competitive autoradiographic binding research indicated a high unspecific binding, and that binding to TrkB/C could be blocked while binding to CSF-1R was not. In a rat model, a positron emission tomography (PET) scan indicated a moderate brain uptake and slow clearance rate. Conclusion: Moreover, the poor pharmacokinetic features of 5-(4-((4-[18F]fluorobenzyl)oxy)-3-methoxybenzyl)pyrimidine-2,4- diamine prevented its utilization as a PET radioligand in brain scanning, but 1-pot synthesis (which is a strategy to improve the effectiveness of the chemical reaction occurring by the use of copper, 18F-fluorination, and Boc deprotection) is an approach to the radio-synthesis of PET tracers (which are sensitive to acid).

High-yield synthesis of a tau PET radioligand and its nonradioactive ligand using an alternative protection and deprotection strategy.

Recently developed tau imaging radiopharmaceuticals show specific uptake in tau protein-rich regions in human brains without off-target binding. These radiopharmaceuticals and their nonradioactive reference ligands are generally obtained in low (radio)chemical yields. In the present study, we investigated high-yield synthesis of 18 F-RO948 ([18 F]1) and its nonradioactive ligand (1). The ligand 1 was synthesized by a Suzuki-Miyaura coupling reaction between 9-(4-methoxybenzyl)-9H-pyrrolo[2,3-b:4,5-c']dipyridin-2-yl trifluoromethanesulfonate (3) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4), followed by oxidative removal of the para-methoxybenzyl (PMB) group with ceric ammonium nitrate (CAN). This two-step reaction gave 1 in 55.8% yield. The precursor for [18 F]1 was synthesized from 3 and 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6). The resulting PMB-protected precursor 8 was obtained in 74.5% yield. [18 F]1 was synthesized by radiofluorination of 8 (radiochemical conversion (RCC): 95.7 ± 1.7%), followed by deprotection of the PMB group with CAN. This one-pot, two-step radiochemical synthesis followed by HPLC purification gave [18 F]1 in high decay-corrected radiochemical yield (54-60%). The RCC of [18 F]fluoride to [18 F]1 in our two-step synthesis method was similar to that in a one-step radiofluorination reaction of a tert-butoxycarbonyl (BOC)-protected precursor 10 that proceeds with concomitant thermal deprotection of the BOC group. Taken together, the results of this study suggest that this high-yield synthesis method is useful for the synthesis of 18 F-labeled (NH)heteroarene compounds.

Efficient radiosynthesis and preclinical evaluation of [18 F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging.

Herein we report an efficient radiolabeling of a 18 F-fluorinated derivative of dual inhibitor GW2580, with its subsequent evaluation as a positron emission tomography (PET) tracer candidate for imaging of two neuroreceptor targets implicated in the pathophysiology of neurodegeneration: tropomyosin receptor kinases (TrkB/C) and colony stimulating factor receptor (CSF-1R). [18 F]FOMPyD was synthesized from a boronic acid pinacolate precursor via copper-mediated 18 F-fluorination concerted with thermal deprotection of the four Boc groups on a diaminopyrimidine moiety in an 8.7±2.8% radiochemical yield, a radiochemical purity >99%, and an effective molar activity of 187±93 GBq/μmol. [18 F]FOMPyD showed moderate brain permeability in wild-type rats (SUVmax = 0.75) and a slow washout rate. The brain uptake was partially reduced (ΔAUC40-90 = 11.6%) by administration of the nonradioactive FOMPyD (up to 30 μg/kg). In autoradiography, [18 F]FOMPyD exhibits ubiquitous distribution in rat and human brain tissues with relatively high nonspecific binding revealed by self-blocking experiment. The binding was blocked by TrkB/C inhibitors, but not with a CSF-1R inhibitor, suggesting selective binding to the former receptor. Although an unfavorable pharmacokinetic profile will likely preclude application of [18 F]FOMPyD as a PET tracer for brain imaging, the concomitant one-pot copper-mediated 18 F-fluorination/Boc-deprotection is a practical technique for the automated radiosynthesis of acid-sensitive PET tracers.

Sub-10 nm Resolution Patterning of Pockets for Enzyme Immobilization with Independent Density and Quasi-3D Topography Control.

The ability to precisely control the localization of enzymes on a surface is critical for several applications including biosensing, bionanoreactors, and single molecule studies. Despite recent advances, fabrication of enzyme patterns with resolution at the single enzyme level is limited by the lack of lithography methods that combine high resolution, compatibility with soft, polymeric structures, ease of fabrication, and high throughput. Here, a method to generate enzyme nanopatterns (using thermolysin as a model system) on a polymer surface is demonstrated using thermochemical scanning probe lithography (tc-SPL). Electrostatic immobilization of negatively charged sulfonated enzymes occurs selectively at positively charged amine nanopatterns produced by thermal deprotection of amines along the side-chain of a methacrylate-based copolymer film via tc-SPL. This process occurs simultaneously with local thermal quasi-3D topographical patterning of the same polymer, offering lateral sub-10 nm resolution, and vertical 1 nm resolution, as well as high throughput (5.2 × 104 μm2/h). The obtained single-enzyme resolution patterns are characterized by atomic force microscopy (AFM) and fluorescence microscopy. The enzyme density, the surface passivation, and the quasi-3D arbitrary geometry of these patterned pockets are directly controlled during the tc-SPL process in a single step without the need of markers or masks. Other unique features of this patterning approach include the combined single-enzyme resolution over mm2 areas and the possibility of fabricating enzymes nanogradients.

Diketopyrrolopyrrole latent pigment-based bilayer solar cells

Abstract Two Diketopyrrolopyrrole based latent pigment donor materials were fabricated into thin film bilayer photovoltaic devices featuring PCBM as the acceptor. Thermal deprotection of the thin film, carried out at 200∘ C, returns the dye-like small molecule to the corresponding pristine pigment quantitatively. The connected evolution of electrical and morphological features of pure thin films and blends are examined. A significant decrease in extinction coefficient was noted and correlated both to intrinsic changes of the electronic structure upon cleavage and to an increase in internal scattering due to extensive crystallization. Power conversion efficiencies of 0.33% were achieved for bilayer devices, nearly doubling previous results with latent pigment DPP devices, under comparable experimental conditions.

Products of low-temperature pyrolysis of nanocellulose esters and implications for the mechanism of thermal stabilization

Esterification was used to improve the thermal stability of nanocellulose to extend its application as reinforcing filler to polymer matrices with high melting point. The effect of the structure of ester groups on thermal stability was studied in detail. Various types of nanocellulose esters (straight-chain, C2–C14; cyclic adamantoyl, ADM; aromatic benzoyl, BNZ; and branched pivaloyl, PIV) with degree of substitution values in the range of 0.40–0.47 were prepared from bacterial cellulose nanofibers and nanocrystals. The reaction conditions used to prepare the esters maintained the viscosity-average degree of polymerization (DPv) and crystallinity of the starting materials. Thermogravimetric analysis showed that the temperature at maximum weight loss rate (Tmax) increased after esterification. The structure of the ester groups and the DPv, however, showed no varying effect on Tmax. The 5 % weight loss temperature (WLT) which was used to assess the thermal stability at the onset of thermal degradation varied with the type of ester. Lower 5 % WLT was observed in straight-chain esters than those of the bulky esters of ADM, BNZ and PIV; which also showed high resistance to weight loss when subjected to isothermal heating. To understand the event at the onset of thermal degradation, low temperature pyrolysis was conducted. The evolved gases were separated and identified by gas chromatography–mass spectrometry technique. Results showed that at the onset of thermal degradation, levoglucosan (LG) is produced from the untreated BC nanocrystals. After esterification, LG formation was inhibited. The removal of the ester groups or deprotection is the main event at the onset of thermal degradation of nanocellulose esters. From the structure of the pyrolysis products, the mechanism of thermal deprotection of nanocellulose esters is proposed for the first time.

Functional modification of poly(vinyl alcohol) with maleimide compounds

A new synthetic way for obtaining poly(vinyl alcohol) functionalized with maleimide by the acetalization of poly(vinyl alcohol) with 4-formylphenyl-4-maleimidobenzoate and its cycloadducts with furan or anthracene to give the corresponding acetal was studied in detail. The deprotection of modified poly(vinyl alcohol) leaves the double bond of maleimide available for subsequent photocross-linking, “thiol click” or Diels–Alder reactions. The synthesized structures were confirmed by the Fourier transform infrared and the nuclear magnetic resonance (NMR) spectroscopy. The thermal deprotection of modified poly(vinyl alcohol) was investigated by the means of differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), NMR spectroscopy and TG-DSC/FTIR/mass spectrometer system.

Modulating the Stability of 2-Pyridinyl Thermolabile Hydroxyl Protecting Groups via the "Chemical Switch" Approach.

A novel and effective method is presented for modulating the stability of 2-Pyridinyl Thermolabile Protecting Groups (2-Py TPGs) in the "chemical switch" approach. The main advantage of the discussed approach is the possibility of changing the nucleophilic character of pyridine nitrogen using different switchable factors, which results in an increase or decrease in the thermal deprotection rate. One of the factors is transformation of a nitro into an amine group via reduction with a low-valent titanium in mild conditions. The usefulness of our approach is corroborated using 3'-O-acetyl nucleosides as model compounds. Their stability in various solvents and temperatures before and after reduction is also examined. Pyridine N-oxide and pH are other factors responsible for the nucleophilicity and stability of 2-Pyridinyl Thermolabile Protecting Groups in thermal deprotection. Protonation of 4-amino 2-Pyridinyl Thermolabile Protecting Groups is demonstrated by (1)H-(15)N HMBC and HSQC NMR analysis.

Poly(methacrylic acid)‐l‐Polyisobutylene Amphiphilic Conetworks by Using an Ethoxyethyl‐Protected Comonomer: Synthesis, Protecting Group Removal in the Cross‐Linked State, and Characterization

A series of poly(methacrylic acid)‐l‐polyisobutylene anionic amphiphilic conetworks with hydrophobic polyisobutylene (PIB) content between 33% and 70% (w/w) is synthesized by the macromonomer method using a new approach by applying ethoxyethyl‐protected methacrylic acid (EEMA) comonomer. To remove the protecting group after copolymerization of EEMA with PIB‐dimethacrylate, acidic hydrolysis and thermal treatment are attempted, and the success of the deprotection is monitored by different techniques. Comparing the two protective group removal steps, it is found that, in contrast to homopolymers of EEMA, the acidic hydrolysis is more favorable than the thermal deprotection due to anhydride formation during the latter process in the conetworks. Distinct glass transitions are obtained by differential scanning calorimetry (DSC) indicating phase separation in the resulting conetworks. The swelling ability of the obtained conetworks in polar and nonpolar solvents proves the amphiphilic nature of these materials. Due to the polyacidic component of the conetworks, their water swollen gels have pH‐sensitive, intelligent swelling behavior in aqueous media. Because of the relatively high stability of EEMA, the applied protection–deprotection strategy can be easily utilized in several other designed polymer syntheses. image

Proline functionalization of the mesoporous metal-organic framework DUT-32.

The linker functionalization strategy was applied to incorporate proline moieties into a metal-organic framework (MOF). When 4,4'-biphenyldicarboxylic acid was replaced with a Boc-protected proline-functionalized linker (H(2)L) in the synthesis of DUT-32 (DUT = Dresden University of Technology), a highly porous enantiomerically pure MOF (DUT-32-NHProBoc) was obtained, as could be confirmed by enantioselective high-performance liquid chromatography (HPLC) measurements and solid-state NMR experiments. Isotope labeling of the chiral side group proline enabled highly sensitive one- and two-dimensional solid-state (13)C NMR experiments. For samples loaded with (S)-1-phenyl-2,2,2-trifluoroethanol [(S)-TFPE], the proline groups are shown to exhibit a lower mobility than that for (R)-TFPE-loaded samples. This indicates a preferred interaction of the shift agent (S)-TFPE with the chiral moieties. The high porosity of the compound is reflected by an exceptionally high ethyl cinnamate adsorption capacity. However, postsynthetic thermal deprotection of Boc-proline in the MOF leads to racemization of the chiral center, which was verified by stereoselective HPLC experiments and asymmetric catalysis of aldol addition.

Chemical Reactions in Dense Monolayers: In Situ Thermal Cleavage of Grafted Esters for Preparation of Solid Surfaces Functionalized with Carboxylic Acids

The thermodynamics of a chemical reaction confined at a solid surface was investigated through kinetic measurements of a model unimolecular reaction. The thermal cleavage of ester groups grafted at the surface of solid silica was investigated together with complementary physicochemical characterization of the grafted species. The ester molecules were chemically grafted to the silica surface and subsequently cleaved into the carboxylic acids. A grafting process of a reproducible monolayer was designed using the reaction of monofunctional organosilane from its gas phase. The thermal deprotection step of the ester end-group was investigated. The thermal deprotection reaction behaves in quite a specific manner when it is conducted at a surface in a grafted layer. Different organosilane molecules terminated by methyl, isopropyl and tert-butyl ester groups were grafted to silica surface; such functionalized materials were characterized by elemental analysis, IR and NMR spectroscopy, and thermogravimetric analysis, and the thermodynamic parameters of the thermal elimination reaction at the surface were measured. The limiting factor of such thermal ester cleavage reaction is the thermal stability of grafted ester group according to the temperature order: tert-butyl < i-propyl < methyl. Methyl ester groups were not selectively cleaved by temperature. The thermal deprotection of i-propyl ester groups took place at a temperature close to the thermal degradation of the organofunctional tail of the silane. The low thermolysis temperature of the grafted tert-butyl esters allowed their selective cleavage. There is a definite influence of the surface on the reaction. The enthalpy of activation is lower than in the gas phase because of the polarity of the reaction site. The major contribution is entropic; the negative entropy of activation comes from lateral interactions with the neighbor grafted molecules because of the high grafting density. Such reaction is an original strategy to functionalize the silica surface by carboxylic acid groups by means of a simple, reproducible, and efficient process involving in situ thermolysis of ester groups.

SiO2 nanodot arrays using patterned functionalization of self-assembled block copolymer and selective adsorption of amine-terminated polydimethylsiloxane

Silicon dioxide (SiO2) nanodot arrays were fabricated by the selective adsorption of amine-terminated polydimethylsiloxane on functionalized block copolymer thin films. A polystyrene-b-poly(acrylic acid/acrylic anhydride) thin film was created by the acid-catalyzed thermal deprotection of polystyrene-b-poly(tert-butyl acrylate). The amine-terminated polydimethylsiloxane selectively adsorbed on poly(acrylic acid) (PAA)/(acrylic anhydride) (AN) spherical nanodomains using a simple dipping method. Patterned SiO2 nanodot arrays were also fabricated using polystyrene-b-poly(tert-butyl acrylate) coated on the patterned SU-8 film. The final SiO2 nanodot arrays were obtained by the calcination of an organosilicon film.

Effects of Reactive Annealing on the Structure of Poly(methacrylic acid)–Poly(methyl methacrylate) Diblock Copolymer Thin Films

We monitor the structural evolution of a poly(tert-butyl methacrylate)-poly(methyl methacrylate) (PtBMA–PMMA) diblock copolymer thin film undergoing conversion via reactive annealing to yield poly(methacrylic acid)–poly(methyl methacrylate) (PMAA–PMMA). Using grazing-incidence small-angle X-ray scattering (GISAXS) and atomic force microscopy (AFM), we confirm the generation of well-ordered cylindrical microdomains in the PtBMA–PMMA precursor film after solvent annealing. After initiating thermal deprotection, the high degree of ordering can be maintained up to 25% conversion of the diblock into PMAA–PMMA. Beyond this point, a significant decrease in the overall film thickness associated with the conversion process cannot accommodate the hexagonal lattice adopted by the cylindrical microdomains. At the same time, rearrangement of PMMA cores in a PtBMA matrix that is becoming progressively glassier presents further difficulties in maintaining a reasonable structure. The fully converted PMAA–PMMA film contains a system of cylindrical microdomains that lack good ordering.

Ordering and microdomain orientation in block copolymer films by thermal deprotection

Ordering and microdomain orientation for the films of symmetric polystyrene- b-poly( tert-butyl methacrylate)s (PS- b-P tBMAs) was investigated by in-situ grazing incidence small-angle X-ray scattering (GISAXS) and the electron microscopy. During thermal deprotection at higher temperature (200 °C), functional tert-butyl ester units in the P tBMA block component are integrated into inter- or intra-molecular anhydride linkages. It was observed that this process causes an increase in the Flory–Huggins interaction parameter ( χ) between the two block components for disordered PS- b-P tBMA film, leading to a modulated nonequilibrium structure. Interestingly, for lamella-forming PS- b-P tBMA film, a significant chain stretching in lateral direction during thermal deprotection resulted in a characteristic strain-induced perpendicular orientation in the middle of the film confined between two parallel orientations of lamellar microdomains.

Synthesis of Cyclic (Co)polymers by Atom Transfer Radical Cross-Coupling and Ring Expansion by Nitroxide-Mediated Polymerization

A novel approach to prepare cyclic polymers via a combination of atom transfer radical polymerization (ATRP) and atom transfer radical cross-coupling (ATRC) is presented. A functional ATRP initiator possessing an alkoxyamine group was synthesized and used to prepare well-defined linear telechelic α-nitroxy,ω-bromo homo- and block copolymers via ATRP and subsequent thermal deprotection of the α-terminal nitroxide function. Cyclization reactions were achieved by intramolecular ATRC under high dilution. Ring expansion of a cyclic polystyrene alkoxyamine prepared by ATRC was conducted via nitroxide-mediated polymerization (NMP) of styrene and yielded a mixture of linear and cyclic polycondensates. This result is discussed in detail and explained by the persistent radical effect (PRE), thermal initiation, and the occurrence of radical crossover reactions during chain extension via NMP.

Investigation of Thermally Responsive Block Copolymer Thin Film Morphologies Using Gradients

We report the use of a gradient library approach to characterize the structure and behavior of thin films of a thermally responsive block copolymer (BCP), poly(styrene-b-tert-butyl acrylate) (PS-b-PtBA), which exhibits chemical deprotection and morphological changes above a thermal threshold. Continuous gradients in temperature and film thickness, as well as discrete substrate chemistry conditions, were used to examine trends in deprotection, nanoscale morphology, and chemical structure. Thermal gradient annealing permitted the extraction of transformation rate constants (k(t)) for the completion of thermal deprotection and rearrangement of the film morphology from a single BCP library on hydroxyl and alkyl surfaces, respectively. The transformation rate constants ranged from 1.45 × 10(-4) s(-1) to 5.02 × 10(-5) s(-1) for temperatures between 185 and 140 °C for hydroxyl surfaces. For the same temperature range, the alkyl surfaces yielded k(t) values ranging from 4.76 × 10(-5) s(-1) to 5.73 × 10(-6) s(-1), an order of magnitude slower compared to hydroxyl surfaces. Activation energies of the thermal deprotection and film transformation on these surfaces were also extrapolated from linear fits to Arrhenius behavior. Moreover, we noted a morphology shift and orientation transformation from parallel lamellae to perpendicular cylinders at the free surface because of changes in volume fraction and surface energetics of the initially symmetric BCP. Using gradient techniques, we are able to correlate morphological and chemical structure changes in a rapid fashion, determine kinetics of transitions, and demonstrate the effect of surface chemistry on the deprotection reaction in thermally responsive BCP thin films.