CH2F Group Research Articles

The Synthesis and F-18 Labeling of a Cinacalcet Analogue Based on α-(Monofluoromethyl)arylmethylamine Structure

AbstractThe fluorine-containing drug Cinacalcet is the only oral calcimimetic agent for the management of hyperparathyroidism in China and targets calcium sensitive receptor (CaSR) in organ tissues. The monofluoromethyl (CH2F) motif, found in many drug molecules and bioactive molecules, is particularly valuable as the CH2F functional group can mimic the methyl (CH3) motif frequently encountered in bioactive molecules. Replacing CH3 group of Cinacalcet with CH2F group will both bring new opportunities for the development of Cinacalcet generic drugs and provide a new option for the F-18 labeling synthesis of Cinacalcet. A Cinacalcet analogue has been successfully synthesized using commercial 2-amino-2-(naphthalen-1-yl)ethan-1-ol and 3-(3-(trifluoromethyl)phenyl)propanal as raw materials in a total yield of 24% in five steps and achieved the F-18 labeling synthesis of this analogue. This strategy is simple and efficient, paving the way for PET imaging of CaSR related diseases and inspiring development of new drugs based on Cinacalcet­.

1.3 Å Crystal Structure of E. coli Peptidyl-Prolyl Isomerase B with Uniform Substitution of Valine by (2S,3S)-4-Fluorovaline Reveals Structure Conservation and Multiple Staggered Rotamers of CH2F Groups.

(2S,3S)-4-Fluorovaline (FVal) is an analogue of valine, where a single CH3 group is substituted by a CH2F group. In the absence of valine, E. coli valyl-tRNA synthetase uses FVal as a substitute, enabling the production of proteins uniformly labeled with FVal. Here, we describe the production and analysis of E. coli peptidyl-prolyl isomerase B where all 16 valine residues have been replaced by FVal synthesized with a 13C-labeled CH2F group. Although the melting temperature is lower by about 11 °C relative to the wild-type protein, the three-dimensional protein structure is almost completely conserved, as shown by X-ray crystallography. The CH2F groups invariably populate staggered rotamers. Most CH2F groups populate two different rotamers. The increased space requirement of fluorine versus hydrogen does not prohibit rotamers that position fluorine next to a backbone carbonyl carbon. 19F NMR spectra show a signal dispersion over 25 ppm. The most high-field shifted 19F resonances correlate with large 3JHF coupling constants, confirming the impact of the γ-gauche effect on the signal dispersion. The present work is the second experimental verification of the effect and extends its validity to fluorovaline. The abundance of valine in proteins and structural conservation with FVal renders this valine analogue attractive for probing proteins by 19F NMR spectroscopy.

Fluorination Promotes Lithium Salt Dissolution in Borate Esters for Lithium Metal Batteries

Lithium metal batteries promise higher energy densities than current lithium-ion batteries but require novel electrolytes to extend their cycle life. To promote electrolyte stability against lithium metal and improve the reversibility of lithium deposition/stripping, several electrolyte design strategies have been pursued. For example, high concentration electrolytes (HCEs) and localized high concentration electrolytes (LHCEs) produce solvation structure rich in salt aggregates and ion pairs, which can increase lithium metal cycling Coulombic efficiency to as high as 99.5%. Recently, molecular design of fluorinated ether solvents also leads to high lithium metal Coulombic efficiency of up to 99.9% in single-solvent-single-salt ~ 1 M electrolytes. In addition, fluorinated acetals, fluorinated carbonates, and fluorinated sulfonamides are also reported to enable efficient lithium metal cycling. Among those novel electrolytes, fluorinated solvents or diluents are frequently used because fluorinated moieties are known to yield LiF as a preferable component in solid electrolyte interphase (SEI). However, fluorinated groups are believed to weaken ion solvation as most fluorinated solvents show poorer solvation ability or lower ionic conductivity compared to their nonfluorinated counterparts. The trade-off between SEI passivation and ion solvation limits further optimization of fluorinated electrolytes.In this work, we synthesize tris(2-fluoroethyl) borate (TFEB) as a new fluorinated borate ester solvent. Interestingly, moderately fluorinated TFEB shows unexpectedly high lithium salt solubility (~1 M LiFSA) while the nonfluorinated triethyl borate (TEB) and heavily fluorinated tris(2,2,2-trifluoroethyl) borate (TTFEB) can hardly dissolve lithium salt. Through density functional theory (DFT) calculations and ab-initio molecular dynamics (AIMD) simulations, we show that the partially fluorinated -CH2F group in TFEB acts as primary coordination site that promotes lithium salt dissolution. The electrochemical property of TFEB electrolyte is then compared to the methoxy polyethyleneglycol borate esters reported in literature. Owing to the fluorinated solvent structure, TFEB electrolyte passivates lithium metal with LiF-rich SEI and supports compact lithium deposition morphology, high lithium metal Coulombic efficiency, and stable cycling of lithium metal/LiFePO4 cells. This work ushers in a new electrolyte design paradigm where partially fluorinated moieties enable salt dissolution and can serve as primary ion coordination sites for next-generation electrolytes. Figure 1

(2S,4S)-5-Fluoroleucine, (2S,4R)-5-Fluoroleucine, and 5,5'-Difluoroleucine in Escherichia coli PpiB: Protein Production, 19F NMR, and Ligand Sensing Enhanced by the γ-Gauche Effect.

Global substitution of leucine for analogues containing CH2F instead of methyl groups delivers proteins with multiple sites for monitoring by 19F nuclear magnetic resonance (NMR) spectroscopy. The 19 kDa Escherichia coli peptidyl-prolyl cis-trans isomerase B (PpiB) was prepared with uniform high-level substitution of leucine by (2S,4S)-5-fluoroleucine, (2S,4R)-5-fluoroleucine, or 5,5'-difluoroleucine. The stability of the samples toward thermal denaturation was little altered compared to the wild-type protein. 19F nuclear magnetic resonance (NMR) spectra showed large chemical shift dispersions between 6 and 17 ppm. The 19F chemical shifts correlate with the three-bond 1H-19F couplings (3JHF), providing the first experimental verification of the γ-gauche effect predicted by [Feeney, J. J. Am. Chem. Soc. 1996, 118, 8700-8706] and establishing the effect as the predominant determinant of the 19F chemical shifts of CH2F groups. Individual CH2F groups can be confined to single rotameric states by the protein environment, but most CH2F groups exchange between different rotamers at a rate that is fast on the NMR chemical shift scale. Interactions between fluorine atoms in 5,5'-difluoroleucine bias the CH2F rotamers in agreement with results obtained previously for 1,3-difluoropropane. The sensitivity of the 19F chemical shift to the rotameric state of the CH2F groups potentially renders them particularly sensitive for detecting allosteric effects.

Conformational Preferences of the Non-Canonical Amino Acids (2S,4S)-5-Fluoroleucine, (2S,4R)-5-Fluoroleucine, and 5,5'-Difluoroleucine in a Protein.

Proteins produced with leucine analogues, where CH2F groups substitute specific methyl groups, can readily be probed by 19F NMR spectroscopy. As CF and CH groups are similar in hydrophobicity and size, fluorinated leucines are expected to cause minimal structural perturbation, but the impact of fluorine on the rotational freedom of CH2F groups is unclear. We present high-resolution crystal structures of Escherichia coli peptidyl-prolyl cis-trans isomerase B (PpiB) prepared with uniform high-level substitution of leucine by (2S,4S)-5-fluoroleucine, (2S,4R)-5-fluoroleucine, or 5,5'-difluoroleucine. Apart from the fluorinated leucine residues, the structures show complete structural conservation of the protein backbone and the amino acid side chains except for a single isoleucine side chain located next to a fluorine atom in the hydrophobic core of the protein. The carbon skeletons of the fluorinated leucine side chains are also mostly conserved. The CH2F groups show a strong preference for staggered rotamers and often appear locked into single rotamers. Substitution of leucine CH3 groups for CH2F groups is thus readily tolerated in the three-dimensional (3D) structure of a protein, and the rotation of CH2F groups can be halted at cryogenic temperatures.

Monofluoromethylation of N-Heterocyclic Compounds.

The review focuses on recent advances in the methodologies for the formation or introduction of the CH2F moiety in N-heterocyclic substrates over the past 5 years. The monofluoromethyl group is one of the most versatile fluorinated groups used to modify the properties of molecules in synthetic medical chemistry. The review summarizes two strategies for the monofluoromethylation of N-containing heterocycles: direct monofluoromethylation with simple XCH2F sources (for example, ICH2F) and the assembly of N-heterocyclic structures from CH2F-containing substrates. The review describes the monofluoromethylation of pharmaceutically important three-, five- and six-membered N-heterocycles: pyrrolidines, pyrroles, indoles, imidazoles, triazoles, benzothiazoles, carbazoles, indazoles, pyrazoles, oxazoles, piperidines, morpholines, pyridines, quinolines and pyridazines. Assembling of 6-fluoromethylphenanthridine, 5-fluoromethyl-2-oxazolines, C5-monofluorinated isoxazoline N-oxides, and α-fluoromethyl-α-trifluoromethylaziridines is also shown. Fluoriodo-, fluorchloro- and fluorbromomethane, FCH2SO2Cl, monofluoromethyl(aryl)sulfoniummethylides, monofluoromethyl sulfides, (fluoromethyl)triphenylphosphonium iodide and 2-fluoroacetic acid are the main fluoromethylating reagents in recent works. The replacement of atoms and entire functional groups with a fluorine atom(s) leads to a change and often improvement in activity, chemical or biostability, and pharmacokinetic properties. The monofluoromethyl group is a bioisoster of -CH3, -CH2OH, -CH2NH2, -CH2CH3, -CH2NO2 and -CH2SH moieties. Bioisosteric replacement with the CH2F group is both an interesting task for organic synthesis and a pathway to modify drugs, agrochemicals and useful intermediates.

Molecular dynamics investigation on the interaction of nitrile-based ionic liquids in the separation of azeotropic refrigerant R-513A

The reclamation of mixed refrigerants stands as a potent measure to substantially mitigate the emission of fluorinated gases (F-gases). In the separation of the azeotropic refrigerant R-513A (comprising 56 wt% R-1234yf, 2,3,3,3-Tetrafluoropropene, and 44 wt% R-134a, 1,1,1,2-Tetrafluoroethane), the extractive distillation process using ionic liquids (ILs) was employed. The molecular structure of nitrile-based ILs ([C4C1im][SCN], [C4C1im][N(CN)2], [C4C1im][C(CN)3], [C4C1im][B(CN)4]) exerts a regular impact on the solubility of refrigerants, thereby necessitating molecular dynamics simulation to ascertain the law of refrigerant solubility in ILs concurrent with the augmentation in the number of –CN in the anion. Additionally, an analysis was conducted to elucidate the mechanism underlying the high selectivity of nitrile-based ILs. The results revealed pronounced interactions between R-1234yf and R-134a, predominantly occurring between carbon atoms (-CF3 groups in R-134a and R-1234yf), and chiefly van der Waals interactions. An enhancement in the number of –CN in anion led to the fortification of the van der Waals interaction between R-134a/R-1234yf and the anion. The stronger nonbonding interaction energy between R-134a and the anion, as well as the higher radial distribution function (RDF) peak height between R-134a and the anion, signified a more robust interaction between R-134a and the anion compared to R-1234yf and the anion. Concurrently, the variance in the RDFs in the anion-C atom (-CH2F group in R-134a and -CF group in R-1234yf) revealed the selectivity of the four ILs to R-134a and R-1234yf. Among the four anions, [B(CN)4]− exhibited the most interaction sites with R-134a. This investigation contributes significantly to comprehending the interaction mechanism of azeotropic refrigerants and the interaction mechanism between refrigerants and nitrile-based ILs.

Genome-Wide Expression Analysis Unravels Fluoroalkane Metabolism in Pseudomonas sp. Strain 273.

Pseudomonas sp. strain 273 grows with medium-chain terminally fluorinated alkanes under oxic conditions, releases fluoride, and synthesizes long-chain fluorofatty acids. To shed light on the genes involved in fluoroalkane metabolism, genome, and transcriptome sequencing of strain 273 grown with 1,10-difluorodecane (DFD), decane, and acetate were performed. Strain 273 harbors three genes encoding putative alkane monooxygenases (AlkB), key enzymes for initiating alkane degradation. Transcripts of alkB-2 were significantly more abundant in both decane- and DFD-grown cells compared to acetate-grown cells, suggesting AlkB-2 catalyzes the attack on terminal CH3 and CH2F groups. Coordinately expressed with alkB-2 was an adjacent gene encoding a fused ferredoxin-ferredoxin reductase (Fd-Fdr). Phylogenetic analysis distinguished AlkB that couples with fused Fd-Fdr reductases from AlkB with alternate architectures. A gene cluster containing an (S)-2-haloacid dehalogenase (had) gene was up-regulated in cells grown with DFD, suggesting a possible role in the removal of the ω-fluorine. Genes involved in long-chain fatty acid biosynthesis were not differentially expressed during growth with acetate, decane, or DFD, suggesting the bacterium's biosynthetic machinery does not discriminate against monofluoro-fatty acid intermediates. The analysis sheds first light on genes and catalysts involved in the microbial metabolism of fluoroalkanes.

The Synthesis and Acid-base Properties of α-(Fluoromethyl)- and α-(Difluoromethyl)-substituted Cyclobutane Building Blocks

Aim. To synthesize cyclobutane-derived amines and carboxylic acids bearing CH2F or CHF2 groups in the α position; to determine the regularities of the effect of fluoroalkyl substituents on the acid-base properties of the title compounds.Results and discussion. Synthetic approaches to 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanamines, 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanecarboxylic acids have been developed. It has been found that the pKa (pKa(H)) values measured for the title compounds, as well as for their non-substituted and CF3-substituted analogues, are consistent with the electron-withdrawing effect of the corresponding fluoroalkyl substituents.Experimental part. The synthesis of the title compounds commenced from the known ethyl 1-(hydroxymethyl)cyclobutanecarboxylate or the product of its Swern oxidation (the corresponding aldehyde) and included fluorination, alkaline ester hydrolysis (for carboxylic acids), and modified Curtius rearrangement (for amines). The pKa value was determined from the pre-equivalence point part of the titration curve using the standard acid-base titration.Conclusions. A newly developed synthetic approach to 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanamines, 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanecarboxylic acids allows to obtain the title compounds in multigram quantities (up to 97 g). With a single exception, the acid-base properties of these products, as well as their parent non-substituted and CF3-substituted analogues, change in a monotonous manner in accordance with inductive electronic effect of the fluorine atom(s).

Front Cover: 3‐Fluoroalkyl (CF3, CHF2, CH2F) Cyclobutane‐Derived Building Blocks for Medicinal Chemistry: Synthesis and Physicochemical Properties (Eur. J. Org. Chem. 24/2023)

The Front Cover shows the main building of the Vernadsky National Library of Ukraine located in Kyїv, as well as two constellations depicting novel cis- and trans-1,3-disubstituted cyclobutane building blocks bearing CF3, CHF2, or CH2F groups. The photo was taken by Bohdan Vashchenko in late 2022 when the synthetic part of this work had been finalized. Despite the building being located deep in the city, the night stars were clearly visible even in the unedited version of the picture due to the special circumstances of that period. The invaluable help of Vladyslava Prykhodko with artwork preparation is appreciated. More information can be found in the Research Article by O. O. Grygorenko et al.

Evidence for and evaluation of fluorine-tellurium chalcogen bonding.

In the field of noncovalent interactions, chalcogen bonding (ChB) involving the tellurium atom is currently attracting much attention in supramolecular chemistry and in catalysis. However, as a prerequisite for its application, the ChB should be studied in solution to assess its formation and, if possible, to evaluate its strength. In this context, new tellurium derivatives bearing CH2F and CF3 groups were designed to exhibit Te⋯F ChB and were synthesized in good to high yields. In both types of compounds, Te⋯F interactions were characterized in solution by combining 19F, 125Te and HOESY NMR techniques. These Te⋯F ChBs were shown to contribute to the overall JTe-F coupling constants (94-170 Hz) measured in the CH2F- and CF3-based tellurium derivatives. Finally, a variable temperature NMR study allowed us to approximate the energy of the Te⋯F ChB, from 3 kJ mol-1 for the compounds with weak Te σ-holes to 11 kJ mol-1 for Te σ-holes activated by the presence of strong electron withdrawing substituents.

Fluoromethyl-2,4,6-trinitrophenylsulfonate: A New Electrophilic Monofluoromethylating Reagent.

Fluoromethyl-2,4,6-trinitrophenylsulfonate has been prepared for the first time and qualified as a simple to use monofluoromethylating reagent. Its molecular structure in the solid state has been determined by single-crystal X-ray diffraction studies. This reagent proves to be effective for the electrophilic introduction of a CH2F group into selected chalcogen and nitrogen nucleophiles. Monofluoromethyl derivatives of various bifunctional N,O-nucleophiles have been synthesized using fluoromethyl-2,4,6-trinitrophenylsulfonate. Due to the good crystallizing properties of the anion, the fluoromethylated products as well as side products that are difficult to identify by nuclear magnetic resonance spectroscopy can readily be characterized by X-ray crystallographic techniques.

Reagents for Selective Fluoromethylation: A Challenge in Organofluorine Chemistry.

The introduction of a monofluoromethyl moiety has undoubtedly become a very important area of research in recent years. Owing to the beneficial properties of organofluorine compounds, such as their metabolic stability, the incorporation of the CH2F group as a bioisosteric substitute for various functional groups is an attractive strategy for the discovery of new pharmaceuticals. Furthermore, the monofluoromethyl unit is also widely used in agrochemistry, in pharmaceutical chemistry, and in fine chemicals. The problems associated with climate change and the growing need for environmentally friendly industrial processes mean that alternatives to the frequently used CFC and HFBC fluoromethylating agents (CH2FCl and CH2FBr) are urgently needed and also required by the Montreal Protocol. This has recently prompted many researchers to develop alternative fluoromethylation agents. This Minireview summarizes both the classical and new generation of fluoromethylating agents. Reagents that act via electrophilic, nucleophilic, and radical pathways are discussed, in addition to their precursors.

Divergent, Stereospecific Mono‐ and Difluoromethylation of Boronic Esters

AbstractThere is considerable interest in incorporating fluorine into agrochemicals and pharmaceuticals to improve their biological properties. Whilst a number of methods have been reported for installing CH2F and CHF2 groups, they are mainly limited to radical reactions, which are invariably racemic. Herein, we report the divergent, stereospecific reaction of fluoroiodomethyllithium with boronic esters to give α‐fluoro‐boronic esters. These unique intermediates can be readily transformed into the corresponding mono‐ or difluoromethylated compounds through proto‐ or fluorodeboronation, respectively. The use of the highly unstable fluoroiodomethyllithium was key to allowing rapid 1,2‐migration over competing decomposition of the carbanion. DFT calculations informed and supported the experimental findings.

Imaging of transition charge densities involving carbon core excitations by all X-ray sum-frequency generation.

X-ray diffraction signals from the time-evolving molecular charge density induced by selective core excitation of chemically inequivalent carbon atoms are calculated. A narrowband X-ray pulse selectively excites the carbon K-edge of the -CH3 or -CH2F groups in fluoroethane (CH3-CH2F). Each excitation creates a distinct core coherence which depends on the character of the electronic transition. Direct propagation of the reduced single-electron density matrix, using real-time time-dependent density functional theory, provides the time-evolving charge density following interactions with external fields. The interplay between partially filled valence molecular orbitals upon core excitation induces characteristic femtosecond charge migration which depends on the core-valence coherence, and is monitored by the sum-frequency generation diffraction signal. This article is part of the theme issue 'Measurement of ultrafast electronic and structural dynamics with X-rays'.

Catalytic enantioselective synthesis of cyclopropanes featuring vicinal all-carbon quaternary stereocenters with a CH2F group; study of the influence of C–F⋯H–N interactions on reactivity

A highly diastereo- and enantioselective synthesis of cyclopropanes with adjacent all-carbon quaternary stereocenters featuring a CH2F group is reported.

Predicting the phase behavior of fluorinated organic molecules using the GC-SAFT-VR equation of state

Fluorinated molecules such as perfluoroalkanes (PFA), perfluoroalkylalkanes (PFAA), fluoroalkanes, and hydrofluoroethers (HFE) possess attractive physical properties that have resulted in their use in a wide range of applications. However, while there is an abundance of thermophysical data for hydrocarbons in the literature, only limited studies have been performed that report the properties of the corresponding fluorinated species. Predictive approaches are therefore needed to accurately and reliably determine the physical properties of these molecules. The statistical associating fluid theory (SAFT) is a commonly used molecular-based equation of state that in its various forms has been applied to study a wide range of fluid systems. In recent work, several group contribution (GC) SAFT equations of state have been proposed, such as the GC-SAFT-VR equation that combines the SAFT equation for potentials of variable range (VR) with a group contribution approach that uniquely allows for the description of hetero-segmented chains. The GC-SAFT-VR equation has been shown to provide an excellent description of the phase behavior of pure associating and non-associating fluids and their mixtures, with a minimal reliance on fitting the model parameters to experimental data. Specifically, parameters for key functional groups (such as CH3, CH2, CH, CH2=CH, C=O, C6H5, ether and ester, OH, NH2, CH=O, COOH) have been obtained by fitting to experimental vapor pressure and saturated liquid density data for selected low molecular weight fluids and then used to predict the phase behavior of pure fluids and their mixtures without further adjusting the group parameters. To expand upon this effort, here we report parameters for the CF3, CF2, CF, CH2F, CHF2, and CHF functional groups and their cross interactions. The theoretical predictions are compared with experimental data for pure PFAs, PFAAs, and HFEs, as well as binary mixtures of alkanes, alkenes, PFAs, PFAAs, and CO2 in order to test the transferability of the new group parameters. The GC-SAFT-VR approach is found to accurately predict the phase behavior of the systems studied.

Quantum chemical studies on solvents for post-combustion carbon dioxide capture: calculation of pKa and carbamate stability of disubstituted piperazines.

Piperazine is a widely studied solvent for post-combustion carbon dioxide capture. To investigate the possibilities of further improving this process, the electronic and steric effects of -CH(3), -CH(2)F, -CH(2)OH, -CH(2)NH(2), -COCH3 , and -CN groups of 2,5-disubstituted piperazines on the pKa and carbamate stability towards hydrolysis are investigated by quantum chemical methods. For the calculations, B3LYP, M11L, and spin-component-scaled MP2 (SCS-MP2) methods are used and coupled with the SMD solvation model. The experimental pK(a) values of piperazine, 2-methylpiperazine, and 2,5-dimethylpiperazine agree well with the calculated values. The present study indicates that substitution of -CH(3), -CH(2) NH(2), and -CH(2) OH groups on the 2- and 5-positions of piperazine has a positive impact on the CO(2) absorption capacity by reducing the carbamate stability towards hydrolysis. Furthermore, their higher boiling points, relative to piperazine itself, will lead to a reduction of volatility-related losses.

Theoretical investigation of atmospheric chemistry of volatile anaesthetic sevoflurane: reactions with the OH radicals and atmospheric fate of the alkoxy radical (CF3)2CHOCHFO: thermal decomposition vs. oxidation

Reaction profile (kcal mol−1) for (CF3)2CHOCHFO radical at the M06-2X/6-311++G(d,p) level.

Establishment of a kinetic model for the intramolecular catalyzed hydrolysis of [18 F]-benzylfluoride containing amino acid analogues by linking experimental and DFT studies

In an earlier publication, we suggested that the faster radiodefluorination kinetics of no-carrier-added (S)-3-(2-[18F]fluoromethyl-phenyl)-2-amino-propionic acid (2-[18F]FMLP), as compared to 4-[18F]-fluoromethyl-l-phenylalanine (4-[18F]FMLP), was caused by an intramolecular interaction between the CH2F group on the 2-position of the phenyl ring and the ammonium group of the amino acid. As the presence of nonradioactive (S)-3-(2-fluoromethyl-phenyl)-2-amino-propionic acid (2FMLP) in a concentration up from 10−6 mol/L reduces considerably the defluorination rate due to the formation of dimers, conventional experimental methods, like spectroscopy, cannot be performed for the study of the hydrolysis in no-carrier-added conditions occurring at a concentration range of about 5.0 10−10 mol/L. In the present study, we aim to provide a proof that supports aforementioned hypothesis as well as to establish a kinetic model and to put forward accompanying rate equations for this hydrolysis reaction by combining ab initio quantum chemical calculations and kinetic data. The calculations of the optimized geometries and the corresponding energies of the reactants involved in the hydrolysis of 2-[18F]FMLP and 4-[18F]FMLP were performed at the DFT[B3LYP/6-31++G**] level of theory. Interpretation of these data reveals that in 2-[18F]FMLP three intramolecular hydrogen bond interactions can be identified that are not present in 4-[18F]FMLP. The most important interaction is the one between the amino acid ammonium group and the benzylic fluorine atom, rendering the rupture of the CF bond much more favorable. These findings align with the experimental data and enabled us to put forward the rate expressions that define the unexpected pseudo–zero-order defluorination reaction of 2-[18F]FMLP at neutral pH. This study also proves that in the development of [18F]-benzylfluoride containing tracers present-day quantum chemical calculations are capable of predicting intramolecular interactions, affecting their reactivity toward hydrolysis at the no-carrier-added level. © 2012 Wiley Periodicals, Inc. Int J Chem Kinet 44: 705–711, 2012