Cyclohexanecarbonitriles: Assigning Configurations at Quaternary Centers from ¹³C NMR CN Chemical Shifts

Abstract

Abstract13 C NMR chemical shifts of the nitrile carbon in cyclohexanecarbonitriles directly correlate with the configuration of the quaternary, nitrile-bearing stereocenter. Comparing 13 C NMR chemical shifts for over 200 cyclohexanecarbonitriles reveals that equatorially oriented nitriles resonate 3.3 ppm downfield, on average, from their axial counterparts. Pairs of axial/equatorial diastereomers varying only at the nitrile-bearing carbon consistently exhibit downfield shifts of δ 0.4-7.2 for the equatorial nitrile carbon, even in angularly substituted decalins and hydrindanes.Cyclic nitriles are versatile synthetic intermediates 2 that are readily transformed into an array of bioactive targets. 3 Cylcohexanecarbonitriles in particular have a long and distinguished history as versatile synthetic intermediates, 2,4 partly because of the prevalence of 6-membered rings in nature 5 and partly because of the nitrile's small steric demand. 6 The miniscule steric demand of the nitrile group, a mere 0.2 kcal mol −1,6 allows efficient installation of hindered quaternary carbons through alkylations 7 and conjugate cyanations, 8 even in cases where other methods fail. 9Assigning the configuration of nitrile-bearing, quaternary centers is challenging. 10 X-ray crystallography provides an excellent method for crystalline nitriles whereas axial and equatorial orientations of liquid cyclohexanecarbonitrile diastereomers can be differentiated by their infrared CN bond intensity. 11 In contrast, using mechanistic arguments to assign the configuration of cyclic nitriles resulting from conjugate cyanations 12 or alkylations 13 is not always reliable. An illustrative case is the alkylation of 1 in which deprotonations with iPrMgBr or LDA/BuLi and methylation leads to different nitrile diastereomers (Scheme 1, 1→2→3 and 1→4→5). The divergent stereoselectivity is consistant with alkylations via Cor N-metalated cyclohexanecarbonitriles 2 and 4, respectively. 14 Correspondence to: Fraser F. Fleming. During the synthesis of several diastereomeric cyclohexanecarbonitriles, the 13 C chemical shift of the nitrile carbon was found to correlate with the orientation of the nitrile group (Scheme 1, compare 3 and 5). The attraction of using a simple NMR method to assign the stereochemistry of quaternary nitrile-bearing carbons stimulated an extensive examination of 13 C NMR shifts in a diverse population of substituted cyclohexanecarbonitriles. Comparison of the chemical shifts revealed distinct regions depending on the configuration at the quaternary center. Equatorially oriented nitriles on fully substituted carbons typically resonate downfield, between δ 126.8-124.4, whereas the axially oriented counterparts resonate further upfield, between δ 124.6-118.6. Equatorial cyclohexanecarbonitrile diastereomers consistently resonate downfield from their axial counterparts, even for angular nitriles embedded within cis-and trans-decalins. The 13 C NMR chemical shift provides a rapid, useful method for assigning the configuration of quaternary, nit...

Stereoselective Synthesis of a 4-⍺-Glucoside of Valienamine, Inhibition, and X-Ray Structural Studies Involving a Bacterial Glycoside Hydrolase-Like Enzyme of The GH13 Family

“…34 The C-atoms carrying an equatorial substituent, especially oxy groups, resonate at a higher eld than those with axial substituents, justifying the 13 C NMR chemical shifts for C(4) of 28A (73.10 ppm) and 28B (75.07 ppm) ( Table 3). 46 A similar trend in the 13 C NMR chemical shift values was also observed in the glucosyl diastereomers The synthesis continued with the protection of the tertiary alcohol of 28A with trichloroacetyl isocyanate in dichloromethane (DCM) at 0 °C, followed by hydrolysis with K 2 CO 3 in aqueous MeOH giving an 85% yield of the carbamate 29. Compound 29 was subjected to an Ichikawa rearrangement 40 that proved useful in the synthesis of valienamine (6).…”

Isolation of the Metalated Ylides [Ph3P−C−CN]M (M=Li, Na, K): Influence of the Metal Ion on the Structure and Bonding Situation

“…The 13 C NMR shift of the nitrile carbon atom proved to be most indicative to distinguish between N‐ versus C‐metalation in α‐metalated nitriles, because the chemical shift is highly sensitive to the local environment . Typically, N‐metalated nitriles show signals between δ ( 13 C) = 140 and 157 ppm, whereas the carbon in the corresponding C‐metalated nitriles resonates at higher field between δ ( 13 C)=115 and 138 ppm .…”

“…[19] The 13 CNMR shift of the nitrile carbon atom proved to be most indicative to distinguish between N-versus C-metalation in a-metalated nitriles, because the chemical shifti sh ighly sensitivet ot he local environment. [20] Typically,N -metalated nitriles show signals between d( 13 C) = 140 and 157 ppm, whereas the carbon in the corresponding C-metalated nitriles resonates at higher field between d( 13 C) = 115a nd 138 ppm. [21] Yet, comparison of the 13 CNMR shifts of the different metal salts of 1 andt heir crown-ether complexess hows no clear evidence for either coordination mode ( Table 1).…”

Colorimetric Cyanide Chemosensor Based on 1′,3,3′,4-Tetrahydrospiro[chromene-2,2′-indole]

“…The IR spectrum of 10 contains an absorption band at 2222 cm −1 , characteristic for nitriles . The heteronuclear multiple bond coherence (HMBC) spectrum revealed three bonds range coupling between the methylidene protons at 2.15 and 2.30 ppm and the nitrile carbon at 118.49 ppm . These protons also interact with the quaternary carbon at 76.75 ppm, separated by two bonds, and with the quaternary carbons at 46.76 and 128.16 ppm, separated by three bonds.…”

“…30 The heteronuclear multiple bond coherence (HMBC) spectrum revealed three bonds range coupling between the methylidene protons at 2.15 and 2.30 ppm and the nitrile carbon at 118.49 ppm. 31 , 32 These protons also interact with the quaternary carbon at 76.75 ppm, separated by two bonds, and with the quaternary carbons at 46.76 and 128.16 ppm, separated by three bonds. The full assignments presented in Figure 3 were based on the combined application of standard NMR techniques such as COSY, NOESY, ROESY, APT, DEPT, HSQC and HMBC spectra.…”