Density Functional Studies on Secondary Amides: Role of Steric Factors in Cis/Trans Isomerization
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molecules Article Density Functional Studies on Secondary Amides: Role of Steric Factors in Cis/Trans Isomerization Balmukund S. Thakkar * , John Sigurd M. Svendsen and Richard A. Engh * Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø, Norway; [email protected] * Correspondence: [email protected] (B.S.T.); [email protected] (R.A.E.); Tel.: +47-96-950-477 (B.S.T.); +47-77-644-073 (R.A.E.) Received: 1 September 2018; Accepted: 21 September 2018; Published: 25 September 2018 Abstract: Cis/trans isomerization of amide bonds is a key step in a wide range of biological and synthetic processes. Occurring through C-N amide bond rotation, it also coincides with the activation of amides in enzymatic hydrolysis. In recently described QM studies of cis/trans isomerization in secondary amides using density functional methods, we highlighted that a peptidic prototype, such as glycylglycine methyl ester, can suitably represent the isomerization and complexities arising out of a larger molecular backbone, and can serve as the primary scaffold for model structures with different substitution patterns in order to assess and compare the steric effect of the substitution patterns. Here, we describe our theoretical assessment of such steric effects using tert-butyl as a representative bulky substitution. We analyze the geometries and relative stabilities of both trans and cis isomers, and effects on the cis/trans isomerization barrier. We also use the additivity principle to calculate absolute steric effects with a gradual increase in bulk. The study establishes that bulky substitutions significantly destabilize cis isomers and also increases the isomerization barrier, thereby synergistically hindering the cis/trans isomerization of secondary amides. These results provide a basis for the rationalization of kinetic and thermodynamic properties of peptides with potential applications in synthetic and medicinal chemistry. Keywords: density functional theory; cis/trans isomerization; secondary amides; dipeptides; steric effects; tert-butyl; additivity principle 1. Introduction The chemistry of the amide bond has attracted the interest of chemists with diverse specializations. Its unique characteristics arise from the delocalization of electrons from nitrogen to the carbonyl group, which confers a partial double-bond character to the C-N bond and stabilizes a planar geometry with a relatively high energy rotational barrier that hinders the free rotation, giving rise to cis and trans isomers [1–3]. The resonance effect also protects the amide moiety against nucleophilic attacks at the carbonyl carbon (e.g., it is virtually immune to hydrolysis at ambient temperature and pH in non-enzymatic conditions); hence, it is a common practice to activate amides using Lewis acids for chemical transformation. However, studies on enzymatic hydrolysis of amides have revealed that distortion in the amide bond planarity via C-N bond rotation also results in amide bond activation, increasing susceptibility to nucleophilic attack [4–6]. Cis/trans isomerization is one phenomenon whereby the amide moiety loses its planarity, as significant geometric and hybridizational changes occur throughout C-N bond rotation [7]. Therefore, information regarding the stabilities of cis and trans forms of amides, C-N bond rotation in terms of cis/trans isomerization, and relevant energy barriers can be useful for understanding the activation by deformation for a variety of amides, especially peptides. Molecules 2018, 23, 2455; doi:10.3390/molecules23102455 www.mdpi.com/journal/molecules Molecules 2018, 23, x 2 of 20 MoleculesMolecules 20182018,, 2323,, x 2455 2 2of of 20 19 While 3°-amides (e.g., prolyl peptide bonds) have often been observed to undergo cis/trans While 3°-amides (e.g., prolyl peptide bonds) have often been observed to undergo cis/trans isomerization◦ due to small energy differences between cis and trans isomers [8–10], 2°-amides also isomerizationWhile 3 -amidesdue to small (e.g., energy prolyl differences peptide bonds) betw haveeen cis often and beentrans observedisomers [8–10], to undergo 2°-amides cis/trans also undergo cis/trans isomerization via higher energy states in diverse important phenomena,◦ such as undergoisomerization cis/trans due isomerization to small energy via higher differences energy between states in cis divers ande trans important isomers phenomena, [8–10], 2 -amidessuch as chemo-mechanical cycling of motor proteins [11], the protein folding [12–14] and catalytic activity chemo-mechanicalalso undergo cis/trans cycling isomerization of motor proteins via higher [11], the energy protein states folding in diverse [12–14] important and catalytic phenomena, activity [15] of enzymes (such as cyclophilin A), cascade dissociation of peptide cation radicals for peptide [15]such of as enzymes chemo-mechanical (such as cyclophilin cycling of A), motor cascade proteins dissociation [11], the of protein peptide folding cation [radicals12–14] and for catalyticpeptide sequencing [16], and cyclization reactions of peptides (e.g. as in the formation of piperazine-2,5- sequencingactivity [15 ][16], of enzymesand cyclization (such as reactions cyclophilin of peptides A), cascade (e.g. dissociationas in the formation of peptide of piperazine-2,5- cation radicals diones) [17]. diones)for peptide [17]. sequencing [16], and cyclization reactions of peptides (e.g., as in the formation of With advances in computational capabilities since the 1990s, theoretical studies on trans and cis piperazine-2,5-diones)With advances in computational [17]. capabilities since the 1990s, theoretical studies on trans and cis isomers of 2°-amides and their interconversion have revealed diverse phenomena, such as: effects of isomersWith of advances2°-amides in and computational their interconversion capabilities have since revealed the 1990s, diverse theoretical phenomena, studies such on transas: effects and cisof pyramidalization◦ of the amide and geometries of transition states [18]; the role of conjugation [19]; pyramidalizationisomers of 2 -amides of the and amide their and interconversion geometries haveof tran revealedsition states diverse [18]; phenomena, the role of suchconjugation as: effects [19]; of simulated solvent effects with molecular dynamics [20]; comparison of theoretically obtained simulatedpyramidalization solvent of effects the amide with andmolecular geometries dynamics of transition [20]; comparison states [18]; the of roletheoretically of conjugation obtained [19]; rotational barrier values with experimental values [21,22]; and the generation of ensembles of rotationalsimulated solventbarrier effectsvalues with with molecular experimental dynamics valu [20es ];[21,22]; comparison and ofthe theoretically generation obtained of ensembles rotational of transition state geometries [23]. Recently, we have conducted theoretical studies [7,24] on secondary transitionbarrier values state withgeometries experimental [23]. Recently, values [we21, 22have]; and conducted the generation theoretical of ensembles studies [7,24] of transition on secondary state amides using density functional methods and molecular dynamics to provide a detailed account of amidesgeometries using [23 density]. Recently, functional we have methods conducted and molecular theoretical dynamics studies [ 7to,24 provide] on secondary a detailed amides account using of geometry changes during cis/trans isomerization, as well as the effects of solvent models, using geometrydensity functional changes methods during andcis/trans molecular isomerization, dynamics toas providewell as athe detailed effects account of solvent of geometry models, changes using glycylglycine methyl ester (GGMe, Figure 1) as an example. We described that cis/trans isomerization glycylglycineduring cis/trans methyl isomerization, ester (GGMe, as well Figure as the 1) as effects an example. of solvent We models, described using that glycylglycine cis/trans isomerization methyl ester can occur via either of the two paths: one via the anti-type transition state, and one via the syn-type can(GGMe, occur Figure via either1) as an of example.the two paths: We described one via that the cis/transanti-type isomerization transition state, can occurand one via via either the of syn the-type two transition state (Figure 2). We also showed that the salient features of the cis/trans isomerization transitionpaths: one state via the (Figureanti-type 2). transitionWe also showed state, and that one th viae salient the syn features-type transition of the statecis/trans (Figure isomerization2). We also remained consistent when the studies were extended from N-methylacetamide to the peptidic remainedshowed that consistent the salient when features the of studies the cis/trans were isomerizationextended from remained N-methylacetamide consistent when to the the studies peptidic were scaffolds of GGMe, thus serving as a simple peptide prototype to study conformational flexibilities scaffoldsextended of from GGMe,N-methylacetamide thus serving as to a thesimple peptidic peptide scaffolds prototype of GGMe, to study thus conformational serving as a simple flexibilities peptide and complexities relevant to larger molecular backbones. In the present work, we extend our studies andprototype complexities to study relevant conformational to larger flexibilities molecular andback complexitiesbones. In the relevant present towork, larger we molecular extend our backbones. studies to substituted derivatives