Asymmetric Azidation under Hydrogen Bonding Phase ...

Asymmetric Azidation under Hydrogen Bonding Phase-TransferCatalysis A Combined Experimental and Computational StudyJimmy Wang Matthew A Horwitz Alexander B Durr Francesco Ibba Gabriele Pupo Yuan GaoPaolo Ricci Kirsten E Christensen Tejas P Pathak Timothy D W Claridge Guy C Lloyd-JonesRobert S Paton and Veacuteronique Gouverneur

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ABSTRACT Asymmetric catalytic azidation has increased inimportance to access enantioenriched nitrogen containingmolecules but methods that employ inexpensive sodium azideremain scarce This encouraged us to undertake a detailed study onthe application of hydrogen bonding phase-transfer catalysis (HB-PTC) to enantioselective azidation with sodium azide So far thisphase-transfer manifold has been applied exclusively to insolublemetal alkali fluorides for carbonminusfluorine bond formation Hereinwe disclose the asymmetric ring opening of meso aziridiniumelectrophiles derived from β-chloroamines with sodium azide inthe presence of a chiral bisurea catalyst The structure of novel hydrogen bonded azide complexes was analyzed computationally inthe solid state by X-ray diffraction and in solution phase by 1H and 14N15N NMR spectroscopy With N-isopropylated BINAM-derived bisurea end-on binding of azide in a tripodal fashion to all three NH bonds is energetically favorable an arrangementreminiscent of the corresponding dynamically more rigid trifurcated hydrogen-bonded fluoride complex Computational analysisinforms that the most stable transition state leading to the major enantiomer displays attack from the hydrogen-bonded end of theazide anion All three H-bonds are retained in the transition state however as seen in asymmetric HB-PTC fluorination the H-bondbetween the nucleophile and the monodentate urea lengthens most noticeably along the reaction coordinate Kinetic studiescorroborate with the turnover rate limiting event resulting in a chiral ion pair containing an aziridinium cation and a catalyst-boundazide anion along with catalyst inhibition incurred by accumulation of NaCl This study demonstrates that HB-PTC can serve as anactivation mode for inorganic salts other than metal alkali fluorides for applications in asymmetric synthesis

INTRODUCTION

Griess Curtius and Tiemann were the first to investigate thechemistry of metal and organic azides at the end of the 19thcentury1 with greater interest in azidation chemistry emergingin the 1960s2 Today organic azides have establishedthemselves as highly versatile intermediates for syntheticmaterial and biological applications because they participate indiverse transformations including 13-dipolar cycloadditionsaza-Wittig reactions Staudinger reductions and ligations aswell as CminusH bond aminations3 Various protocols forasymmetric azidation have been developed often requiringtoxic and volatile reagents such as hydrazoic acid orazidotrimethylsilane4 Crystalline 1-azido-12-benziodoxol-3(1H)-one has also been used but this azide source is ofpoor atom economy and is prepared from azidotrimethylsi-lane5 In contrast only a few enantioenriched organic azidesare obtainable directly from sodium azide an inexpensivereagent compared to all aforementioned azide sources Phase-transfer catalysis with chiral ammonium salts is the mostsuccessful approach for azidation with sodium azide although

details on how the azide ion interacts with the catalyst-substrate complex are scarce6

In biology the azide ion serves as an inhibitor of manyenzymes including cytochrome oxidases involved in theelectron transport chain and formate dehydrogenase for CO2fixation or nicotinamide recycling (Figure 1A)7 Enzymeinhibition results from coordination of the azide ion to themetal or through H-bonding interactions as observed in theazide-bound NAD-dependent dehydrogenase complex (PDBID 2NAD) The terminal nitrogen atoms of the azide anioncan engage in H-bond contacts with several residues of theenzyme a binding profile that enables azide to serve as abridging ion between molecular fragments As well as acting asan inhibitor the azide ion has been used as a nucleophile in

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biocatalytic azidations Janssen and co-workers reported thekinetic resolution of racemic epoxides by azidolysis with NaN3in the presence of the halohydrin dehalogenase fromAgrobacterium radiobacter AD1 an enzyme class that typicallypromotes (de)halogenation with the exception of fluoride inepoxide chemistry8 This enzyme displays nucleophilepromiscuity for a range of monovalent linear anions otherthan N3

including cyanide cyanate and isocyanate ions Morerecently CminusH azidation at aliphatic carbons enabled by aniron-dependent halogenase was disclosed a process high-lighting coordination of the azide anion to the enzymersquos Fe(II)cofactor9

The metal-coordinating ability of the azide anion has beenamply exploited for catalytic azidation10 For example Grovesand co-workers have reported a manganese-catalyzed aliphaticCminusH azidation reaction featuring a Mn-bound intermediate inthe azido transfer step11 In contrast the ability of the azideanion to engage in H-bonding interactions has not beenharnessed for catalytic azidation with NaN3 We however notethat theoretical studies have suggested that H-bonds inmethylpentynol-azide clusters may influence the regiochemicaloutcome of 13-dipolar cycloaddition reactions12

This state of play encouraged an in-depth investigation intothe coordination chemistry of the azide ion with hydrogenbond donors (HBD) for applications in asymmetric catalysis(Figure 1B) The study detailed herein focuses on the H-bonding of azide with ureas a class of HBD widely used in

catalysis for a wide range of (asymmetric) transformationsother than azidations Mechanistically we envisaged a scenariobased on anion binding catalysis whereby the urea-bound azideion would intercept a cationic electrophile (E+) in theenantiodetermining step In this approach H-bondinginteractions to the azide anion would enable the HBD ureato function as a phase-transfer catalyst and bring NaN3 intosolution These interactions would attenuate the nucleophil-icity of the azide In our previous work applying thismechanistic scenario for enantioselective fluorination back-ground reactivity was suppressed by using an insoluble metalalkali fluoride with the urea HBD serving as phase-transfercatalyst (hydrogen bonding phase-transfer catalysis HB-PTC)13 This manuscript addresses whether HB-PTC is viablefor enantioselective azidation with NaN3 Specifically wedemonstrate C(sp3)minusN3 bond formation under catalyticconditions and report the successful application of a chiralBINAM-derived bisurea catalyst to promote asymmetricazidation with sodium azide for the synthesis of enantioen-riched β-amino azides Detailed information is provided on thestructure and characterization of a diverse range of (a)chiralurea-azide complexes in the solid state and in solutionMoreover X-ray diffraction analysis quantum chemicalcalculations and NMR spectroscopy provide insight on thecoordination chemistry of the azide ion to a chiral BINAM-derived bisurea catalyst The catalytic cycle has beeninterrogated using a combination of kinetics and computa-tional studies

RESULTS AND DISCUSSION1 Catalytic Azidation under HB-PTC We started our

investigation by employing β-chloroamines as substrates asthese were previously found to be reactive under HB-PTCconditions with alkali metal fluorides13 When treated withNaN3 in 12-difluorobenzene in the absence of a hydrogenbond donor model substrate (plusmn)-2a afforded (plusmn)-3a in lessthan 10 yield after 1 h (Scheme 1) When 10 mol ofSchreinerrsquos urea 1a14 was added to the reaction mixture andunder otherwise identical conditions the yield of this reactionincreased to 90

The demonstration that the hydrogen bond donor urea 1acatalyzes azidation of (plusmn)-2a prompted the development of anenantioselective variant of this reaction We selected the chiralBINAM-derived bisurea catalyst (S)-1k that was highlysuccessful for fluorination well aware that the strength andbinding mode of azide anion with (S)-1k may differsignificantly from fluoride (Table 1) The reaction of (plusmn)-2awith NaN3 in 12-difluorobenzene in the presence of (S)-1k (5mol ) at room temperature provided 3a in 80 yield and8515 er thereby demonstrating the feasibility of enantiose-lective azidation under HB-PTC (Table 1 entry 1) Thenonalkylated (S)-BINAM catalyst (S)-1l with four instead of

Figure 1 Molecular principles of catalysis and inhibition featuringhydrogen bonding interactions in natural enzymes translationaldesign strategies for synthetic organocatalysts (A) Azide binding innatural enzymes (B) Azidation with sodium azide under hydrogenbonding phase-transfer catalysis (this work)

Scheme 1 Azidation of β-Chloroamine (plusmn)-2a Using NaN3in 12-Difluorobenzene with(out) Schreinerrsquos Urea 1a

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three sites for hydrogen bonding with azide afforded β-aminoazide 3a in 74 yield but with significantly decreaseder a result highlighting the crucial effect of N-alkylation onenantiocontrol (Table 1 entry 2)13 N-Methylated catalyst (S)-1m (Table 1 entry 3) or a switch to other solvents (Table 1entries 4 and 5) led to decreased enantiocontrol Enantiose-lectivity was improved by reducing the temperature althoughthis required increasing both the azide and catalyst loading toachieve full conversion Use of catalyst (S)-1k (10 mol ) with24 equiv NaN3 at minus20 degC for 72 h yielded β-amino azide(SS)-3a in 74 yield and 93565 er (Table 4 entry 6)15

The reaction of soluble tetrabutylammonium azide in thepresence of (S)-1k (5 mol ) resulted in racemic productsuggesting that phase-transfer is essential for enantioinduction(Table 1 entry 7)The optimized conditions were successfully applied to a

range of meso-aziridinium precursors (Scheme 2) Productscontaining pharmaceutically relevant saturated heterocycles 16

including substituted piperidines 3aminusc pyrrolidine 3dmorpholine 3e piperazine 3fminusg and tetrahydroisoquinoline3h motifs were all formed with high enantioselectivityUnsymmetrically substituted amine derivatives also performedwell in this reaction to give 3hminusi despite the possibility forformation of two diastereomeric meso-aziridinium intermedi-ates The reaction was found to be tolerant of meta- and para-halogen substituents (3l 3m 3o) trifluoromethyl groups (3n3q) and larger alkyl groups (3p) The absolute configurationof 3o was determined by single-crystal X-ray diffraction andwas used to assign the absolute configuration of 3aminusn and 3pminusr by analogy The bis-pyridyl azide 3r was obtained in goodyield and enantioselectivity A cycloalkyl amino chloridesuccessfully furnished product 3s in high yield but with noenantiocontrol The model reaction was carried out on gramscale yielding 123 g of (SS)-3a in 80 yield and 93565 erNo measures were taken to avoid moisture or oxygenemphasizing the operational simplicity of reactions performedunder HB-PTC Reduction of azide (SS)-3a by hydrogenationand subsequent bis-alkylation with 15-dibromopentane

afforded 11 g of enantioenriched Kv15 blocker 4 from(plusmn)-2a17

The successful application of HB-PTC to NaN3 encourageda detailed analysis of how the azide ion interacts with hydrogenbond donors such as ureas in the solid state and in solutionand further mechanistic investigation based on kineticscombined with computational studies

2 Insight on the Structure of Urea-Azide Complexesfrom Experimental and Computational Studies Studieson H-bonded azide complexes have been reported18 with asingle example of azide anion encapsulated in a ureareceptor18l This limited knowledge on the binding modes of

Table 1 Optimization of the Reaction Conditions

entry cat azide source solventyielda

() erb

1 (S)-1k NaN3 (12 equiv) 12-DFB 80 85152 (S)-1l NaN3 (12 equiv) 12-DFB 74 58423 (S)-1m NaN3 (12 equiv) 12-DFB 80 83174 (S)-1k NaN3 (12 equiv) CHCl3 86 77235 (S)-1k NaN3 (12 equiv) CH2Cl2 91 81196c (S)-1k NaN3 (24 equiv) 12-DFB 74 935657 (S)-1k Bu4NmiddotN3 (12 equiv) 12-DFB 90 5050

aYield determined by 1H NMR with Ph3CH (05 equiv) internalstandard ber determined after prep TLC c(S)-1k (10 mol ) 72 hminus20 degC 12-DFB = 12-difluorobenzene

Scheme 2 Substrate Scope Scale-up and Derivatization

a109 mmol scale bAbsolute configuration of major enantiomer notdetermined

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azide with urea motifs prompted us to prepare and characterizeH-bonded azide complexes derived at first instance from arange of achiral hydrogen bond donors19 A set of variouslysubstituted 13-diarylureas was selected to examine how stericand electronic effects may influence the structures of azidecomplexes in the solid-state well aware that hydrogen bonddirectionality andor packing effects may be at play Allcomplexes were synthesized from either tetrabutylammonium(TBA) azide or a combination of sodium azide and 15-crown-5(gt95 yield) The azide salt was stirred overnight with anequimolar amount of hydrogen bond donor in acetonitrile (01M) followed by evaporation of solvent to dryness Theresulting complexes were characterized by 1H NMR 13CNMR and IR spectroscopy and subsequently recrystallized toobtain samples suitable for X-ray analysis15 A diverse set ofstructures was obtained revealing distinct binding modeswhich were categorized depending on (i) the type of donorminusacceptor interaction (side-on or end-on)20 (ii) whether thecomplex exists as a bridged or nonbridged structurein theend-on binding mode the azide could act as a bridging ionbetween two hydrogen bond donors and (iii) thestoichiometry of the complex with a HBDazide ratio of either11 or 21 Figure 2 illustrates the coordination diversity of the

urea-azide complexes that were successfully characterized bysingle-crystal X-ray diffraction analysis and distinguishesbetween 11 nonbridged side-on (type I Figure 2A) 11nonbridged end-on (type II Figure 2B) and 21 bridged end-on (type III Figure 2C) complexes Figure 3 and Table 2highlight some key parameters for these complexes such asdonorminusacceptor (DminusA) distances and the angles θ and Φwhich indicate the extent to which the azide lies outside of theurea NC(O)N plane in end-on and side-on complexes19

The [1amiddotN3]middotTBA complex derived from Schreinerrsquos urea 1a(entry 1 Table 2) features two crystallographically distinctmotifs (see Supporting Information for details) and is a 11complex with the azide bound side-on This arrangement islikely favored due to the electron-deficient 35-bis-(trifluoromethyl)phenyl groups which allow for an additionalinteraction between the two terminal nitrogens of the azideand the weakly acidic aryl ortho CminusH bonds (DminusA distance3364(4) Aring) An additional point of interest resides in weaklong-range interactions between the azide and α-CminusH bondsof the tetrabutylammonium countercation17 In both crystallo-graphic motifs the azide lies in the plane of the NC(O)Nmotif of the urea (115(14)deg 1579(7)deg) When the same ureawas bound to azide but featured Na+(15-crown-5) as thecountercation an end-on 11 complex of type II was obtainedwith the azide out of the urea plane (θ = 6240(30)deg ([1amiddot

azide]middot[Na(15-crown-5)] entry 2 Table 2) This resultunderlines the role of the cation in influencing thecoordination mode of the azide in the solid-state Complex[1amiddotazide]middot[Na(15-crown-5)] features the shortest and longestDminusA distances observed among all complexes examined in thisstudy (2780(9) Aring and 3332(9) Aring) Similar coordinationmodes were observed for [1bmiddotN3]middotTBA and [1cmiddotN3]middotTBA(entries 3 and 4 Table 2) derived from symmetrical urea 1bfeaturing 3-Cl substituents and unsymmetrical urea 1csubstituted with 35-bis(trifluoromethyl) group on a singlearyl ring respectively Complexes formed with 1dminus1gpresented two different packing arrangements a dimericstructure whereby the urea NminusH bonds point toward eachother with two linking azides (entries 5 and 6 Table 2 [1dmiddotN3]middotTBA and [1emiddotN3]middotTBA) and a structure in which the NHsof each urea point in the same direction thus forming anextended chain (entries 7 and 8 Table 2 [1fmiddotN3]middotTBA and[1gmiddot N3]middotTBA) Interestingly [1fmiddotN3]middotTBA revealed thepossibility of halogen bond interactions (3140(2) and3131(2) Aring) between the CminusBr and the terminal nitrogen ofthe azide21 Both urea 1f and 1g led to the formation ofsymmetry-related interdigitated antiparallel chains For com-plexes derived from 1dminus1g the azide is out of the NC(O)Nplane of the urea with angles in the range of θ = 24minus62deg but toa lesser extend for [1emiddot N3]middotTBA (θ = 743(14)) A single 21urea-azide complex was obtained which included water ofcrystallization (type III entry 9 [1h]2middot N3middot2H2OmiddotTBA) Inthis complex each urea with one of its NH binds the azidewhile the other NH is coordinated to water which presumablyoriginated from TBAFmiddot3H2OGiven the range of structures that are accessible within a

narrow family of urea-derived complexes the question ofwhether the urea unit could be replaced by another hydrogenbonding entity arose These queries encouraged the synthesisof additional azide complexes two of which successfullycrystallized The guanidine-based complex [1imiddotN3]middotTBA (typeII entry 10) crystallized as the amino rather than iminotautomer whereby both NH2 and NH interact with N3

minus withNH2 binding significantly more weakly than NH (DminusAdistance 3202(2) Aring versus 2842(2) Aring) The CNPh forcesthe phenyl ring to bend thus giving an angle between the twoaryls of sim63deg (average values for ureas in this set sim6minus30deg)Finally a near symmetrical complex [1j]middotN3middotTBA (entry 11)was obtained with diphenyloxalamide as HB donor In thisstructure the presence of two carbonyl groups sets the two arylunits of diphenyloxalamide in plane with the two NminusH bondsthat are oriented anti to each other This generates a 11bridged complex which is distinct from all others and in whicheach oxalamide unit binds a different terminal nitrogen of theazide anion (DminusA distance 2923(3) Aring)The binding properties of 1aminusi with N3

minus in solution werealso investigated by 1H NMR spectroscopy 1H NMR titrationswere carried out by adding increasing amounts of tetrabuty-lammonium azide (TBAmiddotN3) to a solution of HBD (CH3CNCD3CN 82 at 2 mM concentration) Deshielding andbroadening of 1H resonances ascribed to the NH groups wasobserved an indicator of H-bonding interactions betweenazide and urea The chemical shift variation of the aromaticsignals was plotted against the concentration of added TBAmiddotN3and association constants extrapolated from nonlinear least-squares regression using Bindfit23 Titration data were fitted to11 and 21 binding isotherms for 1a and 1d the fitting wasoptimal when accounting for the formation of a 21 complex

Figure 2 Coordination diversity of achiral urea-azide complexes M+

= tetrabutylammonium or Na[15-crown-5]

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while the 11 binding mode resulted in a better fit for 1c 1g1e and 1i15 The association constants (Ka(11)) for 11 urea-azide complexes ranged between 102minus103 Mminus1 with the moreelectron-deficient diarylureas resulting in stronger binding toazide which is consistent with the enhanced acidity of the NHgroups (Table 3) The two most acidic ureas 1a and 1dfeaturing 35-bis(trifluoromethyl) or 4-trifluoromethyl sub-

stituents gave binding constants Ka(11) = 157 plusmn 006 times 103

Mminus1 Ka(21) = 7 plusmn 3 times 101 Mminus1 and Ka(11) = 125 plusmn 012 times 103Ka(21) = 13 plusmn 05 times 102 respectively Ureas 1c (R1 = 35-CF3R2 = H) 1g (R1 = R2 = 4-F) and 1e (R1 = R2 = H) presentedprogressively reduced binding affinity as expected from theirelectronic properties Diphenyl guanidine 1i displayed theweakest binding among all receptors studied

Figure 3 Achiral hydrogen bonded donor-azide complexes Counter cations and crown ethers are omitted for clarity

Table 2 Main Structural Features of Achiral Hydrogen-Bonded Urea Complexes

entry HBD complex type complex DminusA distance22 θ or Φ22

1ab 1a R1 = R2 = 35-CF3 11 Non-bridged (side-on) [1amiddotN3]middotTBA 2966(4) 2974(4) 2962(4) 3069(4) 115(14) 1579(7)2c 1a R1 = R2 = 35-CF3 11 Non-bridged (end-on) [1amiddotN3]middot[Na(15-crown-5)] 2780(9) 3332(9) 6240(30)3 1b R1 = R2 = 3-Cl 11 Non-bridged (end-on) [1bmiddotN3]middotTBA 2876(4) 3000(4) 5190(14)4 1c R1 = 35-CF3 R

2 = H 11 Non-bridged (end-on) [1cmiddotN3]middotTBA 2852(9) 2946(9) 2834(9) 2940(9)c 2760(19) 3421(12)c

5 1d R1 = R2 = 4-CF3 11 Non-bridged (end-on) [1dmiddotN3]middotTBA 2838(5) 2905(5) 4653(8)6 1e R1 = R2 = H 11 Non-bridged (end-on) [1emiddotN3]middotTBA 2870(2) 2996(2) 743(14)7 1f R1 = R2 = 4-Br 11 Non-bridged (end-on) [1fmiddotN3]middotTBA 2909(8) 2923(8) 2490(3)8 1g R1 = R2 = 4-F 11 Non-bridged (end-on) [1gmiddotN3]middotTBA 2833(3) 2912(3) 3713(6)9d 1h R1 = R2 = 4-CN 21 Bridged (end-on) [1h]2middotN3middot2H2OmiddotTBA 2860(2) 2976(2) nd10e 1i R1 = R2 = H 11 Non-bridged (end-on) [1imiddotN3]middotTBA 2842(2) 3202(2) nd11f 1j R1 = R2 = 35-CF3 11 Bridged (end-on) [1j]2middotN3middotTBA 2923(3)d nd

aCalculated for the two crystallographically distinct motifs bThis complex is side-on The values correspond to N(1) to N(2) and N(1prime) to N(4)distances respectively cUnder slightly different crystallization conditions a 21 complex was also obtained (see Supporting Information for details)dThe second HB donor involves a single NminusH in binding (NminusHminusN3 = 2144(2) Aring) eThe hydrogen bond donor is a guanidine fThe hydrogenbond donor is an oxalyl amide and the terminal nitrogen of the azide anion is bound to each HB donor via a single NminusH TBA =tetrabutylammonium

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These data confirm the ability of azide to engage inhydrogen bonding interactions with dual HBD donors insolution The predominant binding mode is 11 with anadditional weaker 21 binding mode observed only for thestrongest donors 1a and 1d Compared with complexesderived from fluoride24 the binding affinity is substantiallyreduced a measure of the lower propensity of azide to engagein hydrogen bonding interaction (cf 1dmiddotFminus sim 105 Mminus1 1dmiddotN3

minus

sim 103 Mminus1) The weaker binding of azide compared to fluoridehas implications in the development of a catalytic methodaimed at bringing insoluble azide salts into solution viacomplexation with hydrogen bond donors while the phase-transfer of azide salts may differ from that of fluoride salts thenucleophilicity of soluble bound urea-azide complex isexpected to be less attenuated as a consequence of weakerbinding to the HBD catalyst Also urea 1a binds chloride(Ka(11) = 47 plusmn 16 times 104 Mminus1 Ka(21) = 17 plusmn 09 times 102 Mminus1)more effectively than azide (Ka(11) = 157 plusmn 006 times 103 Mminus1Ka(21) = 7 plusmn 3 times 101 Mminus1) raising awareness of a possibleinhibition pathwayNext we focused on the characterization of the chiral

BINAM-derived bisurea-azide complex that led to successfulenantioselective azidation with sodium azide The proposedhydrogen-bonded association between azide and (S)-1k wasinvestigated computationally and experimentally Conforma-tional analysis of the solution-phase structure of a 11 complexformed between (S)-1k and azide was performed computa-tionally While our previous studies on fluoride complexationfocused on the use of explicitly solvated classical moleculardynamics25 here we used semiempirical GFN2-xTB calcu-lations and the iMTD-GC workflow implemented in GrimmersquosCREST for sampling including implicit solvation for dichloro-methane26 followed by DFT optimizations of the low energyconformers27 Low-lying conformers were obtained with threeNH-azide H-bonding interactions which can be furthercategorized into three distinct catalyst-azide binding-modes(i) Type A conformers show side-on binding in which theazide termini form H-bonds with proximal NminusH groups in thecatalyst (ii) Type B conformers show side-on binding in whichthe azide termini form H-bonds to distal NminusH groups (iii)Type C conformers show end-on binding in a tripodal fashionto all three NminusH bonds in 1k (Figure 4) The synanti-conformation with respect to the catalyst N-isopropylated ureais found in these low-lying conformersThe end-on binding mode in Type C conformers is

energetically most favorable by over 10 kJmiddotmolminus1 displaying

the shortest average NminusH distance (202 Aring) Additionally thequadrupole moment of the azide anion is polarized uponbinding with the terminus coordinated to the highest possiblenumber of NminusH bonds (3 for end-on 2 for side-on) and NAbearing the largest residual negative charge In the Type Cconformation this effect is largestNext 1H NMR titrations were conducted using TBAmiddotN3

(CDCl3 at 2 mM concentration) Similar to achiral ureas 1aand 1d a 11 binding model was insufficient to provide anaccurate description of the system The inclusion of a 21complex ([(S)-1k]2middotN3

minus) resulted in improved fits leading to aKa(11) of 914 plusmn 09 times 103 Mminus1 and a Ka(21) of 10 plusmn 06 times 102

Mminus1 (Figure 5A) This finding is analogous to fluoride where21 urea-fluoride complexes were also observed in solution13d

The Ka(11) and Ka(21) for the complexes of (S)-1k with fluorideare 143 plusmn 004 times 106 Mminus1 and 31 plusmn 09 times 103 Mminus1 in CH2Cl2approximately 2 orders of magnitude higher than azide 14NNMR spectroscopy provided further insight The highlysymmetric environment of unbound TBAN3 (CDCl3 25mM) gives three signals in 14N NMR spectrum correspondingto the tetrabutylammonium cation (66 ppm) to the centralazide nitrogen (251 ppm) and to the terminal one (102 ppm)In an equimolar mixture of (S)-1k and TBAN3 (CDCl3 25mM) the central azide nitrogen appears significantly broaderand the signal of the terminal azide nitrogen is broadenedbeyond detection negligible change is observed for thetetrabutylammonium cation (Figure 5B) 14N is a quadrupolarnucleus which shows sharp signals only in symmetricenvironments28 the extreme line broadening observed for(S)-1kmiddotTBAmiddotN3 is thus consistent with a lack of symmetry ofthe azide anion likely resulting from an interaction with (S)-1kFurther analysis was performed using isotopically enrichedtetrabutylammonium [1-15N]azide (TBAmiddot[1-15N]N3) At room

Table 3 Association Constants for the Formation of 11Ka(11) and 21 Ka(21) Complexes between Receptor 1aminusiand TBAmiddotN3 (CH3CNCD3CN 2 mM) Ordered byDecreasing Strength

entry HBD Ka(11) (Mminus1) Ka(21) (M

minus1)

1 1a 157 plusmn 006 times 103 7 plusmn 3 times 101

2 1d 125 plusmn 012 times 103 13 plusmn 05 times 102

3 1c 94 plusmn 17 times 102 minus4 1g 482 plusmn 005 times 102 minus5 1e 314 plusmn 003 times 102 minus6 1i 14 plusmn 03 times 102 minus

Figure 4 DFT computed conformers and relative Gibbs energies (kJmiddotmolminus1) of the [(S)-1kmiddotN3]

minus complex NminusH distances (Aring) and naturalcharges on azide N atoms (au) also shown

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temperature a sample prepared by mixing TBAmiddot[1-15N]N3 and1 equiv of (S)-1k (CDCl3 25 mM) exhibited broad lines in 1HNMR supporting the existence of multiple equilibrating speciespresent in solution ascribed to the unbound ligand the 11[(S)-1k]middotN3

minus and 21 [(S)-1k]2middot complexes 15N NMR at roomtemperature shows one resonance at 1018 ppm Steady-stateheteronuclear 1Hminus15N NOE experiments provided evidence ofazide binding to the NH groups of (S)-1k Selective irradiationof the urea NH protons resulted in a decrease of 15N signalintensities whereas irradiation of the CH protons gave noevidence of heteronuclear NOEs supporting the proposal thatthe urea NH protons are responsible for azide coordination15

At 213 K a sample prepared using (S)-1k (CDCl3 25 mM)and two equivalents of TBA[1-15N]N3 shows sharp resonancesin 1H NMR with a major species assigned to the 11 complex1kmiddot[1-15N]azide and a minor species which is consistent withthe 21 complex [(S)-1k]2middotazide as noted in the course of the1H NMR titrations At this temperature applying a 1Hminus15NHMBC sequence it was possible to detect couplings acrosshydrogen bonding (1hJNH) between the three NH groups and[1-15N]N3

minus (Figure 5C) The magnitude of 1hJNH measuredusing 1D 1H15N HMBC was found to be around 5 Hzalthough accurate measurement was hindered by the line widthof the cross-peaks This value is consistent with those reportedfor 15N-labeled DNA duplex which are typically in the range of1minus4 Hz29 The data obtained by 1Hminus15N NOE and HMBCexperiments unambiguously indicate coordination of the azidewith all three NH hydrogen bond donors in solutionFurther insight on the nature of the complexation of (plusmn)-1k

with azide was obtained in the solid-state A sample of (plusmn)-1kcomplexed to TBAN3 (11 ratio) was prepared by stirring bothcomponents in MeCN (01 M) and subsequently evaporatingthe mixture to dryness Crystals of (plusmn)-1kmiddotTBAN3 suitable forsingle crystal X-ray diffraction were successfully grown by slowevaporation of a saturated solution of the amorphous solid inhot hexane and EtOAc In a single asymmetric unit cell bothenantiomers (R)- and (S)-1k were observed each complexedto azide In both enantiomeric complexes the azide anion iscoordinated at one terminus by three hydrogen bonds from theNH groups of one catalyst unit As previously observed for thecorresponding fluoride complex13aminusd the N-isopropylated ureaadopts a syn-anti conformation with the iPr group pointing

away from the chiral pocket thus allowing for azide to interactwith the three NHs (Figure 6A) Comparison with (S)-1kmiddot

tetrabutylammonium fluoride revealed similar geometriesalthough the donorminusacceptor distances22a for the azidecomplex were consistently longer (by sim02minus04 Aring) thanobserved for fluoride (Figure 6B Table 4) In (S)-1kmiddotTBAFthe relative N(H)middotmiddotmiddotF donorminusacceptor distances were NH(3)middotmiddotmiddotF sim NH(1)middotmiddotmiddotF lt NH(2)middotmiddotmiddotF a reversal of these distances isfound in (S)-1kmiddotTBAN3 with NH(1)middotmiddotmiddotN3 lt NH(2)middotmiddotmiddotN3 ltNH(3)middotmiddotmiddotN3 (Table 4) The crystal structure is analogous tothe computed Type C coordination mode which shows end-on binding of the azide (Figure 6C Table 4)

Figure 5 (A) Ka(11) and Ka(21) for the complexes of TBAmiddotN3 with (S)-1k in CDCl3 (2 mM) (B) 14N spectra of and TBAmiddotN3 complexed to 1 equivof (S)-1k in CDCl3 (25 mM) (C) 1D and 2D 1Hminus15N HMBC spectra of (S)-1kmiddot[1-15N]N3 (CDCl3 25 mM 213 K)

Figure 6 (A) Asymmetric unit of a Zprime = 2 crystal structure consistingof both (R)-1k and (S)-1k complexed to tetrabutylammonium azide(B) View of (S)-1k complexed to azide Distances provided inAringngstroms displacement ellipsoids drawn at 50 probability level(C) Overlay of [1kmiddotN3]

minus (DFT vs X-ray)

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G

3 Mechanistic Insight from Kinetic and Computa-tional Studies To shed light on the reaction mechanism weexplored the kinetics of the reaction of β-chloroamine (plusmn)-2awith NaN3 in 12-difluorobenzene in the presence and absenceof catalyst (S)-1k at ambient temperature The growth of thesubstitution product (3a) was monitored by in situ ATR-FT-IR analyzing the absolute intensity of the signal arising fromorganoazide stretching band at 2100 cmminus1 After some initialoptimization of conditions15 the reactions gave kinetics thatwere sufficiently reproducible for further analysis (Figure 7)The temporal concentration profiles for product 3a obtained ata series of different initial concentrations of 2a and 1k wereinvestigated using a series of simple models that included thenet enantioselectivity15 Detailed kinetic analysis was precludedby the absence of information on catalyst speciation from thein situ FT-IR spectra and by the solid-phase form of thesodium azide reactant and sodium chloride coproductNaN3s and NaCls from the overall reaction eq 1Nonetheless three key features that govern the reactionevolution emerged (i) the rate of turnover has a first-orderdependency on the initial concentration of catalyst [(S)-1k]0(ii) the rate of turnover has a fractional order (sim05)

dependency on the temporal concentration of the substrate[2a]t and (iii) as the reactions proceed the rate of turnover isattenuated to a greater degree than dictated by the progressivereduction in the quantities of the reactants (2a and NaN3s)The latter is consistent with inhibition by accumulation ofNaCls

15

+ rarr + 2a 3aNaN NaCl3 s s (1)

[ ] asymp [ ][ ‐ ]

++

Auml

Ccedil

AringAringAringAringAringAringAringAringAringAringAringAring

Eacute

Ouml

NtildeNtildeNtildeNtildeNtildeNtildeNtildeNtildeNtildeNtildeNtildeNtildeta S

c3a

2a1kd

d( )

1t b

r

05 01

(2)

The temporal concentration profiles for [3a] can besatisfactorily correlated (Figure 7A and B) using the simpleempirical relationship shown in eq 2 When aSSaRR = 794(er = 888112) and cSScRR = 100 (er = 5050) eq 2 alsocorrectly predicts the net enantioselectivity for (SS)-3a as afunction of catalyst loading (Figure 7C) eq 2 is consistent withtwo processes operating in parallel one enantioselective andone a background racemic reaction Their relative flux andthus the net enantioselectivity is governed by the initialconcentrations of substrate 2a and catalyst 1k the proportionsof reactants the extent of conversion and the magnitude ofconstants a b and c Two kinetically equivalent processes thatare consistent with the empirical eq 2 are shown in Figure 8Both processes involve competing complexation (KX X = N3or Cl) of catalyst 1k with either azide or chloride ion and apre-equilibrium (KiKIPD) involving 2a that generates ion-pairseparated aziridinium ([A]+) cation and chloride anion Thetwo pathways diverge in the sequence of their reaction of [1kmiddotX]minus[Na+] where X = N3 with [A]+ and [Cl]minus But in bothcases they lead to the same key species an aziridiniumcatalyst-bound azide ion pair [1kmiddotN3][A

+] This rapidly and

Table 4 DonorminusAcceptor N(H)middotmiddotmiddotXminus Bond Distances22a of1kmiddotTBAN3

NHmiddotmiddotmiddotXminusX-ray (plusmn)-1kmiddotN3

minus

d NmiddotmiddotmiddotN3minus (Aring)

X-ray (S)-1kmiddotFminusd NmiddotmiddotmiddotFminus (Aring)13a

DFT (S)-1kmiddotN3minus

d NmiddotmiddotmiddotN3minus (Aring)

1 281(2) (S)281(2) (R)

2667(2) 290(4)

2 294(2) (S)291(2) (R)

2690(2) 295(2)

3 298(2) (S)302(2) (R)

2662(2) 303(2)

Figure 7 In situ ATR-FTIR analysis of the reaction of 2a with NaN3s in 12-difluorobenzene catalyzed by (S)-1k Data open circles Kineticmodel (eq 2) solid red linescrosses (A) Temporal growth of [3a] from [2a]0 = 025 018 and 013 M at [(S)-1k]0 = 0025M (B) Temporalgrowth of [3a] from [2a]0 = 025 M at catalyst (S)-1k loadings (mol ) indicated (C) Net enantiomeric excess of (SS)-3a at catalyst (S)-1kloadings (06 13 26 77 10 and 20 mol ) Constants used for fitting eq 2 a = 0081(plusmn0018) Mminus05 sminus1 b = 21(plusmn09) c = 18(plusmn05) times 10minus5

M05 sminus1 r = NaN3sNaCls Enantioselectivity employed in all fits as aSSaRR = 794 (er = 888112) and cSScRR = 100 (er = 5050)

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H

irreversibly generates (kee) the product 3a in 8911 er Thefitting parameter ldquoardquo reflects the series of equilibria andreactions that lead to [1kmiddotN3][A

+] The fitting parameter ldquobrdquoreports the differential binding of chloride over azide to thecatalyst in an equilibrium that is limited by the common-ionNa+ The term ldquorrdquo reflects the evolving stoichiometry ratioNaN3sNaCls The fitting parameter ldquocrdquo reports on the rateof the competing background racemic (er = 5050) processinvolving direct reaction (krac) of the aziridinium ([A]+) cationwith azideAlternative approaches involving more complex models and

holistic simulations were also effective but did not proveadvantageous or allow elucidation of any discrete kineticconstants Conducting reactions in the presence of exogenousNaCl led to the expected changes in rate and enantioselectiv-ity15 Other general mechanisms where catalyst 1k interactsfirst with the substrate 2a in its neutral or ionized forms areinconsistent with eq 215 Overall the kinetics support a processwhere the turnover rate limiting event directly or indirectlyresults in the generation of an ion pair [1kmiddotN3][A

+]containing an aziridinium cation and a catalyst-bound azideanion The substitution product (SS)-3a is then generated inexcess over (RR)-3a through enantiocontrol by ligand ((S)-1k) that is coordinated to the azide being delivered to theaziridinium cation as the ion-pair collapsesComputationally we studied several elementary steps in the

proposed azidation mechanism First we considered theachiral transformation with catalyst 1a (Figure 9) andsubsequently the enantioselective reaction with 1k (Figure 10)Transition structures (TSs) were located for aziridinium

formation in the absence and presence of the achiral ureacatalyst 1a Little energetic difference (02 kJmiddotmolminus1) was foundbetween these pathways which corroborates previouscomputational studies13 Consistent with the kinetic modelabove aziridinium formation by autoionization is computed tobe feasible and reversible with ion-pair formation endergonicby 3 kJmiddotmolminus1 Azidation TSs were also located for the additionof the urea-bound azide anion Barrier heights are lower thanfor aziridinium formation by gt15 kJmiddotmolminus1 and the addition ofazide is computed to occur irreversibly with product formation

exergonic by 68 kJmiddotmolminus1 We also considered the relativestabilities of chloride and azide bound urea catalyst For 1a welocated three distinct azide binding modes of which the end-on structure is most stable Chloride binding however iscomputed to be more favorable by 15 kJmiddotmolminus1 (minus276 vsminus126 kJmiddotmolminus1) Interestingly the differential binding ofchloride over azide for catalyst 1k is reduced to 4 kJmiddotmolminus1since azide anion is able to form three NminusH bonds This valueis consistent with the kinetic model developed for 1kIn order to understand the origins of asymmetric induction

in azidation promoted by (S)-1k we computed the competingTSs for the enantiodetermining step We manually located aTS for the formation of major and minor enantiomer productsfollowed by a constrained conformational search with CRESTThis produced 168 major and 219 minor structures15 fromwhich we finally obtained eight DFT-optimized (using thesame methodology described above) energetically low-lyingTSs within 14 kJmiddotmolminus1 of the most stable structure (Figure10) The two most stable competing TSs (TS-A and TS-B)involve attack from the H-bonded end of the azide anion (NA)while the remaining six higher energy structures arecharacterized by the distal nitrogen NC as the reactive centerof the nucleophile of which TS-C is the most stable exampleAttack from NC results in a bridged structure in which there iscomparatively little geometric distortion of the catalyst andsubstrate in the TS (relative distortion energies are shown inFigure 10) However in the two most stable structures attackfrom NA results in more significant noncovalent interactionsbetween the substrate and catalystas can be seenqualitatively from the extent of the RDG isosurface producedby NCI plot in each of the TSs These arise from severaldispersive interactions between aromatic rings (both face-to-face and edge-to-face are evident) as well as CH(substrate)-π(catalyst) interactions All three H-bonds are retained in theTS however as seen in asymmetric HB-PTC fluorination the

Figure 8 Two pathways for generation of 3a from NaN3 and 2acatalyzed by 1k in competition with a racemic background reactionThe pathways are kinetically equivalent in the context of eq 215 xN3 isthe mole fraction of [1kmiddotX]minus[Na+]in which X is azide

Figure 9 DFT computed transition structures for aziridiniumformation azidation with 1amiddotN3

minus and binding of azide vs chlorideto catalysts 1a and 1k30 Distances in Aring and energies in kJmiddotmolminus1

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I

H-bond between nucleophile and the monodentate urea mostnoticeably lengthens along the reaction coordinate TheBoltzmann-averaged enantioselectivity arising from these low-lying structures is 6931 in favor of the major enantiomerobserved experimentally (Table 1 entry 5)

CONCLUSION

In this work we have described the expansion of hydrogen-bonding phase-transfer catalysis and the privileged BINAM-derived bisurea catalyst scaffolds to the recognition of an anionother than fluoride for applications in catalysis By employing alinear anion such as azide rather than the spherical charge-dense fluoride anion we have demonstrated that the bisureacatalyst acts as an azide receptor and enables enantioselectiveazidation of β-chloroamine-derived meso aziridinium electro-philes using sodium azide Kinetic studies support a processwith the turnover rate limiting event that directly or indirectlygenerates an ion pair containing an aziridinium cation and acatalyst-bound azide anion with catalyst inhibition incurred byaccumulation of NaCl Structural data in the solid state and insolution of a range of hydrogen bonded azide complexesinform that azide end-on binding is more often observed Forthe chiral monoalkylated bisurea catalyst 1Hminus15N NOE andHMBC experiments in solution as well as data in the solid statearising from single crystal X-ray diffraction analysis indicatecoordination of the azide with all three NH hydrogen bonddonors Computationally azide end-on bound to all three NHbonds of the BINAM urea in a tripodal fashion is found to beenergetically most favorable This binding mode inducespolarization of the azide ion with the bound nitrogen bearingthe largest negative charge which indicates that this nitrogen isamenable to electrophilic attack This analysis corroborateswith the features of the most stable transition state leading tothe major enantiomer More generally this study highlights thepotential of hydrogen bonding phase transfer (HB-PTC)catalysis beyond fluorination and as a general activation modefor abundant alkali metal salts as reagents in asymmetricsynthesis

ASSOCIATED CONTENTsı Supporting InformationThe Supporting Information is available free of charge athttpspubsacsorgdoi101021jacs1c13434

Additional data (TXT)

Experimental details kinetics characterization dataNMR spectra and full computational details (PDF)

Accession CodesCCDC 2129236minus2129248 contain the supplementary crys-tallographic data for this paper These data can be obtainedfree of charge via wwwccdccamacukdata_requestcif or byemailing data_requestccdccamacuk or by contacting TheCambridge Crystallographic Data Centre 12 Union RoadCambridge CB2 1EZ UK fax +44 1223 336033

AUTHOR INFORMATIONCorresponding Authors

Timothy D W Claridge minus Chemistry Research LaboratoryUniversity of Oxford Oxford OX1 3TA UK orcidorg0000-0001-5583-6460 Email timclaridgechemoxacuk

Guy C Lloyd-Jones minus School of Chemistry University ofEdinburgh Edinburgh EH9 3FJ UK orcidorg0000-0003-2128-6864 Email guylloyd-jonesedacuk

Robert S Paton minus Department of Chemistry Colorado StateUniversity Fort Collins Colorado 80528 United Statesorcidorg0000-0002-0104-4166 Email robertpaton

colostateeduVeacuteronique Gouverneur minus Chemistry Research LaboratoryUniversity of Oxford Oxford OX1 3TA UK orcidorg0000-0001-8638-5308 Email veroniquegouverneurchemoxacuk

AuthorsJimmy Wang minus Chemistry Research Laboratory University ofOxford Oxford OX1 3TA UK orcidorg0000-0002-4277-5248

Figure 10 Low-lying enantiodetermining azidation TSs with (S)-1k Relative distortion energies of aziridinium and [(S)-1kmiddotN3]minus fragment in each

TS shown The reduced density gradient isosurface (RDG = 03) around the substrate is shown to indicate qualitatively the extent of substrate-catalyst noncovalent interactions in each TS

Journal of the American Chemical Society pubsacsorgJACS Article

httpsdoiorg101021jacs1c13434J Am Chem Soc XXXX XXX XXXminusXXX

J

Matthew A Horwitz minus Chemistry Research LaboratoryUniversity of Oxford Oxford OX1 3TA UK

Alexander B Durr minus Chemistry Research LaboratoryUniversity of Oxford Oxford OX1 3TA UK

Francesco Ibba minus Chemistry Research Laboratory Universityof Oxford Oxford OX1 3TA UK orcidorg0000-0002-2739-4156

Gabriele Pupo minus Chemistry Research Laboratory Universityof Oxford Oxford OX1 3TA UK orcidorg0000-0003-3084-3888

Yuan Gao minus School of Chemistry University of EdinburghEdinburgh EH9 3FJ UK

Paolo Ricci minus Chemistry Research Laboratory University ofOxford Oxford OX1 3TA UK

Kirsten E Christensen minus Chemistry Research LaboratoryUniversity of Oxford Oxford OX1 3TA UK

Tejas P Pathak minus Novartis Institutes for Biomedical ResearchCambridge Massachusetts 02139 United Statesorcidorg0000-0003-3858-8770

Complete contact information is available athttpspubsacsorg101021jacs1c13434

Author ContributionsJW MAH and ABD contributed equally to this workNotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSThis work was supported by the EU Horizon 2020 Researchand Innovation Programme (Marie Skłodowska-Curie Agree-ment 675071 and 789553) the Engineering and PhysicalSciences Research Council (EPR010064 Centre for DoctoralTraining in Synthesis for Biology and Medicine EPL0158381) and the European Research Council (Agreement 832994)RSP acknowledges support from the National ScienceFoundation (CHE 1955876) the RMACC Summit super-computer which is supported by the National ScienceFoundation (ACI-1532235 and ACI-1532236) the Universityof Colorado Boulder and Colorado State University and theExtreme Science and Engineering Discovery Environment(XSEDE) through allocation TG-CHE180056 YG thanksEdinburgh University for an Edinburgh Global ResearcherScholarship We thank Mr Songshi Jing for preliminaryexperiments Dr John M Brown FRS for insightful discussionduring the course of this project Prof Paul Beer for a helpfulcomment and Dr Amber L Thompson for proofreading themanuscript

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K

Nakashima R Yoshikawa S X-Ray Structure of Azide-Bound FullyOxidized Cytochrome c Oxidase from Bovine Heart at 29 AringResolution Acta Crystallogr Sect D Biol Crystallogr 2000 56 (5)529minus535 (c) Guo Q Gakhar L Wickersham K Francis KVardi-Kilshtain A Major D T Cheatum C M Kohen AStructural and Kinetic Studies of Formate Dehydrogenase fromCandida Boidinii Biochemistry 2016 55 (19) 2760minus2771(d) Bowler M W Montgomery M G Leslie A G W WalkerJ E How Azide Inhibits ATP Hydrolysis by the F-ATPases ProcNatl Acad Sci U S A 2006 103 (23) 8646minus8649(8) (a) Hasnaoui-Dijoux G Majeric Elenkov M Lutje Spelberg JH Hauer B Janssen D B Catalytic Promiscuity of HalohydrinDehalogenase and Its Application in Enantioselective Epoxide RingOpening ChemBioChem 2008 9 (7) 1048minus1051 (b) Majeric Elenkov M Primozic I Hrenar T Smolko A Dokli I Salopek-Sondi B Tang L Catalytic Activity of Halohydrin Dehalogenasestowards Spiroepoxides Org Biomol Chem 2012 10 (26) 5063(9) Matthews M L Chang W Layne A P Miles L A KrebsC Bollinger J M Direct Nitration and Azidation of AliphaticCarbons by an Iron-Dependent Halogenase Nat Chem Biol 2014 10(3) 209minus215(10) Matthews M L Chang W Layne A P Miles L A KrebsC Bollinger J M Direct Nitration and Azidation of AliphaticCarbons by an Iron-Dependent Halogenase Nat Chem Biol 2014 10(3) 209minus215(11) Huang X Bergsten T M Groves J T Mangananese-Catalyzed Late-Stage Aliphatic CminusH Azidation J Am Chem Soc2015 137 (16) 5300minus5303(12) Hashemi M Taherpour A A Structural Assessment ofHydrogen Bonds on MethylpentynolminusAzide Clusters to AchieveRegiochemical Outcome of 13-Dipolar Cycloaddition ReactionsUsing Density Functional Theory ACS Omega 2020 5 (11) 5964minus5975(13) (a) Pupo G Ibba F Ascough D M H Vicini A C RicciP Christensen K E Pfeifer L Morphy J R Brown J M PatonR S Gouverneur V Asymmetric Nucleophilic Fluorination underHydrogen Bonding Phase-Transfer Catalysis Science 2018 360(6389) 638minus642 (b) Pupo G Vicini A C Ascough D M HIbba F Christensen K E Thompson A L Brown J M Paton RS Gouverneur V Hydrogen Bonding Phase-Transfer Catalysis withPotassium Fluoride Enantioselective Synthesis of β-Fluoroamines JAm Chem Soc 2019 141 (7) 2878minus2883 (c) Roagna G AscoughD M H Ibba F Vicini A C Fontana A Christensen K EPeschiulli A Oehlrich D Misale A Trabanco A A Paton R SPupo G Gouverneur V Hydrogen Bonding Phase-TransferCatalysis with Ionic Reactants Enantioselective Synthesis of γ-Fluoroamines J Am Chem Soc 2020 142 (33) 14045minus14051(d) Ibba F Pupo G Thompson A L Brown J M Claridge TD W Gouverneur V Impact of Multiple Hydrogen Bonds withFluoride on Catalysis Insight from NMR Spectroscopy J Am ChemSoc 2020 142 (46) 19731minus19744(14) (a) Schreiner P R Wittkopp A H-Bonding Additives ActLike Lewis Acid Catalysts Org Lett 2002 4 217minus220 (b) SchreinerP R Metal-free organocatalysis through explicit hydrogen bondinginteractions Chem Soc Rev 2003 32 289minus296(15) See the Supporting Information for full details including fulloptimization(16) Vitaku E Smith D T Njardarson J T Analysis of theStructural Diversity Substitution Patterns and Frequency of NitrogenHeterocycles among US FDA Approved Pharmaceuticals J MedChem 2014 57 (24) 10257minus10274(17) Bostroumlm J Symmetric Kv15 Blockers Discovered by FocusedScreening ACS Med Chem Lett 2012 3 (9) 769minus773(18) For selected examples of hydrogen bonded azide crystalstructures (a) Kimura E Anan H Koike T Shiro M AConvenient Synthesis of a Macrocyclic Dioxo Pentaamine and X-RayCrystal Structure of Its Monohydrazoic Acid Salt J Org Chem 198954 3998minus4000 (b) Lex J Linke K Beitrage Zur Chemie DesHydrazins Und Seiner Derivate LI Kristall- Und Molekulstruktur

von N N NprimeNprime-Tetraaminopiperazindiium-Bis(Azid) Chem Ber1976 109 2684minus2690 (c) Bushmarinov I S Nabiev O GKostyanovsky R G Antipin M Y Lyssenko K A The Azide Anionas a Building Block in Crystal Engineering from a Charge DensityPoint of View CrystEngComm 2011 13 2930 (d) Serpell C JCookson J Thompson A L Beer P D A Dual-FunctionalTetrakis-Imidazoliummacrocycle for Supramolecular Assembly ChemSci 2011 2 494minus500 (e) Christe K O Wilson W W Bau RBunte S W New Synthesis Crystal Structure and VibrationalSpectra of Tetramethylammonium Azide and Reactions of theFluoride Anion with Hydrazoic Acid and of the Azide Anion withHydrogen Fluoride J Am Chem Soc 1992 114 3411minus3414(f) Kang S O Day V W Bowman-James K Tricyclic Host forLinear Anions Inorg Chem 2010 49 8629minus8636 (g) Escuer AEsteban J Font-Bardia M Anion Coordination by Metallamacro-cycles A Cryptand-like Cavity Chem Commun 2012 48 9777(h) Esteban J Font-Bardia M Escuer A Anionic Guests inPrismatic Cavities Generated by Enneanuclear Nickel MetallacyclesInorg Chem 2014 53 1113minus1121 (i) Tuo D-H Ao Y-F WangQ-Q Wang D-X Benzene Triimide Cage as a Selective Containerof Azide Org Lett 2019 21 7158minus7162 (j) Ray S K Homberg AVishe M Besnard C Lacour J Efficient Synthesis of DitopicPolyamide Receptors for Cooperative Ion Pair Recognition inSolution and Solid States Chem Eur J 2018 24 2944minus2951(k) Evers J Goumlbel M Krumm B Martin F Medvedyev SOehlinger G Steemann F X Troyan I Klapoumltke T M EremetsM I Molecular Structure of Hydrazoic Acid with Hydrogen-BondedTetramers in Nearly Planar Layers J Am Chem Soc 2011 133 (31)12100minus12105 For a single example of a crystal structure of a urea-azide complex see (l) Wang X Jia C Huang X Wu B AzideAnion Encapsulation in a Tetraurea Receptor Inorg Chem Commun2011 14 (9) 1508minus1510(19) Low temperature single-crystal X-ray diffraction data werecollected using a Rigaku Oxford Diffraction SuperNova diffractom-eter Raw frame data were reduced using CrysAlisPro and thestructures were solved using ldquoSuperfliprdquo (a) Palatinus L Chapuis GSUPERFLIP - A Computer Program for the Solution of CrystalStructures by Charge Flipping in Arbitrary Dimensions J ApplCrystallogr 2007 40 786 Successive refinement was performed withCRYSTALS (b) Parois P Cooper R I Thompson A L CrystalStructures of Increasingly Large Molecules Meeting the Challengeswith CRYSTALS Software Chem Cent J 2015 9 30 (c) Cooper RI Thompson A L Watkin D J CRYSTALS EnhancementsDealing with Hydrogen Atoms in Refinement J Appl Crystallogr2010 43 1100 Full refinement details are given in the SupportingInformation Crystallographic data have been deposited with theCambridge Crystallographic Data Centre (CCDC 2129236minus2129248) and can be obtained via wwwccdccamacukdata_-requestcif(20) End-on binding implies hydrogen bonds from the hydrogenbond donor moieties are formed to the same terminal nitrogen of theazide whereas side-on binding indicates that one or more H-bondsare formed with both terminal nitrogens of the azide(21) For an example of halogen-bonding to azide in solution see(a) Lim J Y C Beer P D A Halogen Bonding 13-DisubstitutedFerrocene Receptor for Recognition and Redox Sensing of Azide EurJ Inorg Chem 2017 2017 220 And in the solid-state (b) RosokhaS V Stern C L Swartz A Stewart R Halogen Bonding ofElectrophilic Bromocarbons with Pseudohalide Anions Phys ChemChem Phys 2014 16 12968minus12979(22) DminusA distance relates to the distance expressed in Aring betweenthe nitrogen atom of the donor NH and the proximal nitrogen of theazide θ for end-on complexes is defined as the angle between thevector defined by the carbonyl of the urea and the vector defined bythe terminal nitrogen atoms of the azide ϕ for side-on complexes isdefined as the angle between the NminusN urea vector and the vectordefined by the terminal nitrogen atoms of the azide Both angles werecalculated using PLATON (a) Spek A L PLATON A MultipurposeCrystallographic Tool Utrecht the Netherlands 1998 (b) Spek A L

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Single-crystal structure validation with the program PLATON J ApplCrystallogr 2003 36 7minus13(23) (a) Supramolecularorg httpsupramolecularorg (accessedSeptember 18 2019) (b) Brynn Hibbert D Thordarson P TheDeath of the Job Plot Transparency Open Science and Online ToolsUncertainty Estimation Methods and Other Developments inSupramolecular Chemistry Data Analysis Chem Commun 2016 52(87) 12792minus12805 (c) Thordarson P Binding Constants and TheirMeasurement In Supramolecular Chemistry John Wiley amp Sons LtdChichester UK 2012 (d) Howe E N W Bhadbhade MThordarson P Cooperativity and Complexity in the Binding ofAnions and Cations to a Tetratopic Ion-Pair Host J Am Chem Soc2014 136 (20) 7505minus7516 (e) Thordarson P DeterminingAssociation Constants from Titration Experiments in SupramolecularChemistry Chem Soc Rev 2011 40 (3) 1305minus1323(24) Pfeifer L Engle K M Pidgeon G W Sparkes H AThompson A L Brown J M Gouverneur V Hydrogen-BondedHomoleptic FluorideminusDiarylurea Complexes Structure Reactivityand Coordinating Power J Am Chem Soc 2016 138 (40) 13314minus13325(25) Bickelhaupt F M Houk K N Analyzing Reaction Rates withthe DistortionInteraction-Activation Strain Model Angew ChemieInt Ed 2017 56 (34) 10070minus10086(26) Pracht P Bohle F Grimme S Automated Exploration of theLow-Energy Chemical Space with Fast Quantum Chemical MethodsPhys Chem Chem Phys 2020 22 (14) 7169minus7192(27) Energetics in the text refer to ωB97XD3(ma)-def2-TZVPPsingle point calculations on M06-2X geometries using a mixed def2-SVP (C H) def2-TZVP (F) and def2-TZVPD (N O) basis set withCPCM solvation (see Supporting Information for details)(28) Mason J Nitrogen In Multinuclear NMR Mason J EdSpringer US Boston MA 1987 pp 335minus367(29) (a) Yan X Kong X Xia Y Sze K H Zhu GDetermination of Internucleotide h J HN Couplings by the Modified2D J NN -Correlated [15N 1H] TROSY J Magn Reson 2000 147(2) 357minus360 (b) Pervushin K Ono A Fernandez C SzyperskiT Kainosho M Wuthrich K NMR Scalar Couplings acrossWatson-Crick Base Pair Hydrogen Bonds in DNA Observed byTransverse Relaxation-Optimized Spectroscopy Proc Natl Acad SciU S A 1998 95 (24) 14147minus14151 (c) Dingley A J Masse J EPeterson R D Barfield M Feigon J Grzesiek S InternucleotideScalar Couplings Across Hydrogen Bonds in WatsonminusCrick andHoogsteen Base Pairs of a DNA Triplex J Am Chem Soc 1999 121(25) 6019minus6027(30) The three barrier values correspond to different binding modesof the urea to the azide anion end-on azide reacting at the distal Natom shown in graphics (735 kJmiddotmolminus1) end-on azide reacting at theproximal N atom (754 kJmiddotmolminus1) side on bound azide (899 kJmiddotmolminus1)

Journal of the American Chemical Society pubsacsorgJACS Article

httpsdoiorg101021jacs1c13434J Am Chem Soc XXXX XXX XXXminusXXX

M