conformational studies of gas-phase ribose and 2 ...szolcsanyi/education/files/chemia%20...above,...

Carbohydrate Research 384 (2014) 20–36

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Carbohydrate Research

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Conformational studies of gas-phase ribose and 2-deoxyriboseby density functional, second order PT and multi-level methodcalculations: the pyranoses, furanoses, and open-chain structures

0008-6215/$ - see front matter Crown Copyright � 2013 Published by Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.carres.2013.10.013

⇑ Corresponding author. Mobile: +48 697013557.E-mail address: [email protected] (M. Szczepaniak).

Marek Szczepaniak ⇑, Jerzy MocFaculty of Chemistry, Wroclaw University, F. Joliot-Curie 14, 50-383 Wroclaw, Poland

a r t i c l e i n f o

Article history:Received 1 June 2013Received in revised form 9 September 2013Accepted 18 October 2013Available online 1 November 2013

Keywords:D-Ribose2-Deoxy-D-riboseMP2G4NBO

a b s t r a c t

We present an extensive computational study of a complex conformational isomerism of two gas phasepentoses of biological and potential astrobiological importance, D-ribose and 2-deoxy-D-ribose. Both cyc-lic (a- and b-pyranoses, a- and b-furanoses) and open-chain isomers have been probed using secondorder Møller–Plesset perturbation theory (MP2), M06-2X density functional, and multi-level G4 methods.This study revealed a multitude of existing minima structures. Numerous furanose conformers found aredescribed with the Altona and Sundaralingam pseudorotation parameters. In agreement with the recentgas-phase microwave (MW) investigation of Cocinero et al., the calculated free ribose isomers of lowestenergy are the two b-pyranoses with the 1C4 and 4C1 ring chair conformations. Both b-pyranoses liewithin 0.9 kJ/mol in terms of DG(298 K) (G4), thus challenge the computational methods used to predictthe ribose global minimum. The calculated most favoured ribofuranose is the a-anomer having the twist2T1 ring conformation, put 10.4 kJ/mol higher in DG than the global minimum. By contrast with D-ribose,the lowest energy 2-deoxy-D-ribose is the a-pyranose, with the most stable 2-deoxy-D-furanose (the a-anomer) being only 6.2 kJ/mol higher in free energy. For both pentoses, the most favoured open-chainisomers are significantly higher in energy than the low-lying cyclic forms. A good overall agreement isobserved between the M06-2X and MP2 results in terms of both the existing low-energy minima struc-tures and intramolecular H-bonding geometrical parameters. The natural orbital analysis confirms theoccuring of the endo- and exo-anomeric effects and maximization of intramolecular H-bonding in thelowest-lying pyranoses and furanoses of both sugars.

Crown Copyright � 2013 Published by Elsevier Ltd. All rights reserved.

1. Introduction 43(b-pyranose):42(a-pyranose):10(b-furanose):5(a-furanose) at

Five-carbon sugars or pentoses perform various biological func-tions. They are components of nucleotides, nucleosides, nucleicacids, certain vitamins, and coenzymes.1 D-Ribose and 2-deoxy-D-ribose being constituents of RNA and DNA, respectively, occur inthese molecules in the b-furanose form (comprising the five-mem-bered sugar ring, see Scheme 1). The occurrence of b-furanose in-stead of b-pyranose (the latter comprising the six-memberedsugar ring, Scheme 1) in nucleic acids is thought to be related tothe structural flexibility of the former conformation.2 Based onthe NMR spectroscopy studies it has been known3–6 however thatin aqueous solution both D-ribose and 2-deoxy-D-ribose exist as amixture of the a- and b-pyranoses. For instance, the followingequilibrium mixture for D-ribose was reported in Ref. 5: 62%(b-pyranose):20.3%(a-pyranose):11.6%(b-furanose):6.1%(a-furanose).For 2-deoxy-D-ribose, which pentose lacks hydroxyl group at car-bon C2, the aqueous solution percentage ratio of

0 �C and of 15(a-pyranose):15(b-pyranose):9(a-furanose):11(b-furanose) at 90 �C was reported.6 The distinction between a- andb-sugar ring conformers or anomers arises from the actual orienta-tion of the OH group at carbon C1 of the ring (Scheme 1). Evenmore complex conformational typology of D-ribose as well as 2-deoxy-D-ribose arises if one takes into account their open-chain(acyclic) structures, also shown in Scheme 1.

Simple sugars have been of interest in astrobiology (see e.g., Ref.7). In the interstellar space there have been found more than 140chemical compounds, including the sugar building block—glycolal-dehyde. Glycolaldehyde is considered a main component of organ-ic transformations leading to aldoses or ketoses.8 Currently,detecting pentoses in space encounters problems caused by thepaucity of reliable data concerning their molecular structures andspectroscopic properties.9

Compared to other common pentoses and hexoses, both D-ribose and 2-deoxy-D-ribose can be regarded as structurally under-explored. Indeed, for D-ribose, only recently its crystal10 structurehas been reported. Although the early work aiming at crystallizingribose was published already in 1956,11 there had been major

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M. Szczepaniak, J. Moc / Carbohydrate Research 384 (2014) 20–36 21

difficulties for many years to isolate crystals appropriate for X-rayanalysis.12 In 2010, the successful combined X-ray crystal diffrac-tion and solid state 13C MAS (magic angle spinning) NMR spectros-copy investigation of D-ribose by Sisak et al.10 was published. Itwas concluded from both structural analyses that the ribose crystalconsisted of the b- and a-pyranoses, with the b/a-pyranose ratio of1.7–2:1.

The condensed phase structural data are affected by possiblecontributions from crystal packing interactions and thus are notstrictly comparable to the lowest energy isolated species. In2012, the first successful gas-phase rotational study of D-ribosewas reported by Cocinero et al.9 (the earlier such attempts faileddue to a thermal instability of ribose). The Cocinero et al. investiga-tion, which is most relevant to the current theoretical study, wasaccomplished by combining microwave (MW) spectroscopy insupersonic jets with ultrafast UV laser vaporization.9 Theseauthors’ interpretation of the rotational transitions made withthe help of quantum chemical calculations and Watson semi-rigidrotor model led to the conclusion that six distinct conformers of D-ribose were present under the experimental conditions. Of these,the two lowest energy structures assigned as the distinct b-pyra-noses were found to be essentially isoenergetic. The other four freeribose species assigned included exclusively the pyranoses. Neitherfuranose nor open-chain structures of D-ribose have been observedsuggestive of their higher energies. Also, to our knowledge, noexperimental studies of the gas phase structure of 2-deoxy-D-ri-bose have been reported. We are aware of one experimental studyof 2-deoxy-D-ribose, published in 1960, where its structure in thecrystalline state was determined by X-ray crystallography andfound to be pyranose.13

In addition to the combined microwave spectroscopic andtheoretical investigation of D-ribose by Cocinero et al.9 mentionedabove, the computational quantum mechanical study of D-ribosestructures of Guler et al.14 appeared in the literature in 2002. For2-deoxy-D-ribose, a limited conformational analysis by Ghoshet al.15 was recently reported. In this work, we set out to studyextensively the potential energy surfaces (PESs) of the two ald-opentoses involving their pyranose, furanose, and open-chainstructures. To this end, density functional theory (DFT) and corre-lated ab initio as well as multi-level (composite) electronic struc-ture methods have been used. Main goals of this investigationare to elucidate a complex conformational isomerism of riboseand deoxyribose, to find their most stable conformers and to com-pare their structural, energetic, and bonding properties in the gasphase.

2. Computational methods

To predict low-energy conformations and conformational-en-ergy differences of D-ribose and 2-deoxy-D-ribose, the following

Scheme 1. Possible confo

search strategy was adopted. First, the molecular mechanics (MM)method was used for extensive mappings of their PESs includingboth cyclic (a- and b-pyranoses and a- and b-furanoses) andopen-chain structures (for the recent use of the MM method forthe initial conformational studies of various sugars, see for exam-ple, Refs. 16–18). The force field employed here was MM3, 19–21

implemented in Scigress code22 (for the recent comparative studyof saccharides using eighteen force fields, including MM3, see Ref.23). A few hundred structures were MM3 preoptimized. Based onthe relative energies of the MM3 calculated structures, a set of con-formers was selected for the subsequent quantum mechanical cal-culations after applying a cut-off at �62 kJ/mol. This MM3 followedby the quantum mechanical conformation search procedure wasemployed before, for example, for complex conformational energysurfaces of hexoses,24 including the structures with intramolecularO–H� � �O hydrogen bonds. In this respect we mention therecent application/validation of the MM3 method for systemscontaining various types of non-covalent interactions such asnon-conventional C–H� � �O hydrogen bonding and p� � �p stackinginteractions.25

All the conformers with relative energies662 kJ/mol (about 340structures) were reoptimized with both the M06-2X26 densityfunctional and second-order Møller–Plesset perturbation theory(MP2)27 methods, with the 6-311++G(d,p) basis set,28 using GAUSS-IAN 09 code.29 The choice of both the M06-2X and MP2 relied onthe recent test study of the relative energies of the gas phase hex-ose isomers where the performance of various computationalmethods was validated against the results of the coupled clusterCCSD(T) calculations extrapolated to the complete basis set limit(CBS).30 The importance of including diffuse functions in the basisset to minimize the basis set superposition error (BSSE) in systemswith intramolecular hydrogen bonding (present in both pentosesstudied here) is well known.31 Vibrational frequency analysis wascarried out at the DFT level to confirm the minima on the PES.All DFT calculations were carried out using a grid with 99 radialshells and 590 angular points per atom called ‘ultrafine’ in GAUSSIAN09 (instead of the standard (75,302) integration grid). This was tocomply with the recent findings32 that the M06 type functionals26

are sensitive to the integration-grid size. In fact, the choice of thegrid can matter for the M06-2X calculations of the lowest energyribopyranoses having minuscule energy differences (see below).

In addition to the relative energies (including zero-point energy(ZPE) corrections), DH(0 K), the 298 K free energy differences,DG(298 K), have been calculated at the M06-2X and MP2 levels.The thermodynamic values were obtained by computing the ZPE,thermal and entropic contributions with the help of the M06-2Xvibrational frequencies (used without scaling, except where scalingwas part of a multi-level method, see below). The thermal and en-tropy corrections were determined with the harmonic oscillatorand rigid rotor approximations and assuming an ideal gas at

rmations of D-ribose.

Scheme 2. Atom numbering scheme for pyranose and furanose conformers.

Scheme 4. Twist furanose ring conformations (the three atoms marked with asterisk make up the plane).

Scheme 3. Envelope furanose ring conformations (the four atoms marked with asterisk make up the plane).

22 M. Szczepaniak, J. Moc / Carbohydrate Research 384 (2014) 20–36

1pyr-1C4-b 2pyr-1C4-b 3pyr-

1C4-a

4pyr-4C1-b 5pyr-1C4-a 6pyr-

4C1-a

7pyr-1C4-a 8pyr-4C1-b 9pyr-

1C4-b


1C4-a

Figure 1. Structures of twenty four most stable pyranose conformers of D-ribose optimized at the M06-2X/6-311++G(d,p) and MP2/6-311++G(d,p) levels with the indicatedH� � �O distances of the possible HB interactions (in Å, the MP2 values are in parentheses).


1.0 atm. Additionally, the free energy differences for the most sta-ble conformers of both pentoses were also evaluated using theMP2 method with the aug-cc-pVTZ basis set33 (single point MP2/

aug-cc-pVTZ calculations) and multi-level G4 scheme.34

Recently,35,36 the encouraging multi-level versus coupled clusterCCSD(T) comparison for the prediction of the relative energies of


1C4-a

16pyr-1C4-a 17pyr-4C1-a 18pyr-

1C4-b


1C4-a


4C1-b

Fig. 1 (continued)


the gas phase n-butanol rotamers was obtained. The optimized su-gar structures were drawn with Chemcraft37 visualization soft-ware. Finally, the atom numbering scheme used for the pyranoseand furanose conformers is given in Scheme 2.

3. Labeling of conformers

Due to a large number of various type isomers of D-ribose and 2-deoxy-D-ribose presented in this work, their unambiguous labeling

1fur-2T1-a 2fur-2T1-a 3fur-

3T4-a

4fur-2E-a 5fur-E1-a 6fur-2E-a

7fur-2T1-a 8fur-E2-b 9fur-3T4-a

10fur-3T2-b 11fur-3T4-a 12fur-

3E-a

Figure 2. Structures of the twelve most stable furanose conformers of D-ribose optimized at the M06-2X/6-311++G(d,p) and MP2/6-311++G(d,p) levels with the indicatedH� � �O distances of the possible HB interactions (in Å, the MP2 values are in parentheses).


is of importance. Here, the conformational nomenclature em-ployed is defined. According to Scheme 1, pyranoses (pyr) whichcan assume either 1C4 or 4C1 chair ring conformations, can addi-tionally be either a (denoted a) or b (denoted b) anomers depend-ing on the orientation of OH group at the anomeric carbonC1. Thus, for instance, 1pyr-1C4-b refers to a pyranose conformer

of ribose with the 1C4 chair conformation, the b anomer; ‘1’ in frontof this designation tells the pyranose conformer number. Thedeoxyribose pyranoses are denoted similarly.

Furanose (fur) ring can exist in either envelope (E) or twist (T)conformations.38 Envelope conformations have one atom aboveor below the plane of the ring formed by the four other ring atoms

Table 1The relative energies, DH(0 K), Gibbs free energy differences, DG(298 K) (kJ/mol) and equilibrium rotational constants A–C (MHz) of the thirty eight most stable conformers of D-ribose and of the lowest-lying open-chain structurecalculated at the two geometry optimization levelsa

Conformer M06-2X/6-311++G(d,p) (kJ/mol) MP2/6-311++G(d,p) (kJ/mol) Rotational constantsb (MHz)

DH (0 K) DG (298 K) DH (0 K) DG (298 K) A B C

1pyr-1C4-b 0.00 0.00 0.00 0.62 1850.5 [1844.98735 (18)] 1312.7 [1305.135870 (74)] 1094.5 [1087.84195 (10]2pyr-1C4-b 0.89 0.81 1.25 1.79 1863.4 [1853.13790 (95)] 1305.7 [1301.195100 (89)] [1089.4 1081.87037 (10)]3pyr-1C4-a 1.03 0.65 1.11 1.34 1966.2 [1954.0129 (30)] 1269.9 [1267.42042 (25)] 1005.7 [1000.48929 (28)]4pyr-4C1-b 1.60 0.44 0.55 0.00 2060.4 [2048.18674 (41)] 1179.4 [1176.32050 (22)] 848.9 [845.23676 (21)]5pyr-1C4-a 2.10 1.90 3.25 3.67 1969.2 [1960.29176 (39)] 1279.5 [1272.44554 (21)] 995.9 [994.58926 (20)]6pyr-4C1-a 2.10 2.07 3.19 3.78 1886.1 [1886.47378 (71)] 1287.9 [1280.03450 (25)] 1000.5 [995.20684 (25)]7pyr-1C4-a 2.65 2.85 2.73 3.54 1967.0 [1960.29176 (39)] 1279.0 [1272.44554 (21)] 998.5 [994.58926 (20)]8pyr-4C1-b 4.93 3.86 4.52 4.06 2059.4 1173.8 848.49pyr-1C4-b 5.02 4.45 5.11 5.15 1824.6 1308.2 1103.610pyr-4C1-a 6.25 6.04 7.79 8.20 1939.5 1272.3 992.711pyr-1C4-b 6.38 5.60 6.70 6.54 1836.9 1297.5 1100.212pyr-1C4-a 6.39 6.15 6.34 6.72 1939.8 1276.6 1007.713pyr-4C1-a 10.16 9.10 10.27 9.82 1935.1 1270.1 966.414pyr-1C4-b 12.96 11.93 11.28 10.86 1834.1 1301.4 1110.415pyr-1C4-a 13.11 12.57 12.57 12.64 1958.7 1280.9 988.61fur-2T1-a 14.56 11.53 11.15 8.74 2059.2 1065.6 997.616pyr-1C4-a 16.13 15.50 15.71 15.71 1977.3 1272.0 995.62fur-2T1-a 16.20 12.99 11.87 9.27 2017.8 1068.2 998.017pyr-4C1-a 16.87 15.53 17.20 16.47 1891.2 1286.4 997.218pyr-1C4-b 17.39 17.07 18.62 18.91 1852.5 1299.7 1080.819pyr-4C1-a 17.84 16.66 17.02 16.46 1911.1 1277.1 976.53fur-3T4-a 18.10 13.16 13.68 9.35 1931.4 1152.7 823.620pyr-1C4-b 18.44 17.95 20.12 20.24 1866.9 1292.1 1077.64fur-2E-a 18.88 15.44 15.04 12.22 2039.2 1083.1 1019.25fur-E1-a 18.92 14.25 14.71 10.66 2041.8 1066.7 933.86fur-2E-a 19.03 15.72 15.83 13.14 2303.5 960.5 856.17fur-2T1-a 20.01 16.43 15.68 12.70 2270.4 956.2 857.38fur-E2-b 21.08 15.91 14.91 10.35 1691.2 1295.2 923.621pyr-1C4-a 20.23 18.97 20.03 19.39 1932.0 1277.2 999.522pyr-4C1-a 20.67 20.04 21.10 21.09 1878.7 1287.2 992.523pyr-4C1-b 21.05 19.17 18.33 17.06 2053.1 1175.9 852.09fur-3T4-b 20.16 15.50 16.11 12.07 2210.8 1064.2 799.610fur-3T2-b 21.42 16.86 15.20 11.26 1843.8 1169.0 873.411fur-3T4-a 21.46 15.54 16.56 11.26 1830.2 1119.9 787.412fur-3E-a 21.61 16.42 16.47 11.90 1913.9 1157.5 824.013fur-2T1-a 21.77 17.67 16.92 13.44 1999.1 1086.5 1016.414fur-4T3-b 22.62 18.56 19.74 16.30 1721.1 1309.1 1004.624pyr-4C1-b 22.66 21.10 20.39 19.44 2077.0 1164.8 851.31open 39.29 30.13 28.77 20.23 2535.8 778.3 616.7

a The DH(0 K) values include the harmonic zero-point energy (ZPE) corrections calculated at the M06-2X/6-311++G(d,p) level. The free energy differences (at T = 298 K and p = 1 atm), DG(298 K), were obtained by calculating theZPE, thermal and entropic contributions with the help of the M06-2X/6-311++G(d,p) vibrational frequencies. In Table S1 (Supplementary data) the relative energies DH(0 K) and free energy differences DG(298 K) of the remainingconformers of D-ribose investigated, given in the order of increasing relative energies, can be found.

b The MP2/6-311++G(d,p) results; the values in square brackets are the experimental rotational constants from Ref. 9.

26M

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36

1pyr-1C4-b2pyr-1C4-b3pyr-1C4-a4pyr-4C1-b5pyr-1C4-a6pyr-4C1-a7pyr-1C4-a8pyr-4C1-b9pyr-1C4-b

10pyr-4C1-a11pyr-1C4-b12pyr-1C4-a13pyr-4C1-a14pyr-1C4-b15pyr-1C4-a

1fur-2T1-a16pyr-1C4-a

2fur-2T1-a17pyr-4C1-a18pyr-1C4-b19pyr-4C1-a

3fur-3T4-a20pyr-1C4-b

4fur-2E-a5fur-E1-a6fur-2E-a

7fur-2T1-a8fur-E2-b

21pyr-1C4-a22pyr-4C1-a23pyr-4C1-b

9fur-3T4-b10fur-3T2-b11fur-3T4-a12fur-3E-a

13fur-2T1-a14fur-4T3-b

24pyr-4C1-b15fur-E4-a

16fur-3T2-b17fur-OT1-a25pyr-4C1-b

18fur-2E-a26pyr-1C4-b27pyr-4C1-b

19fur-4E-b20fur-1T2-b28pyr-1C4-a

21fur-E2-b22fur-1T2-b23fur-2T1-a24fur-3E-a

25fur-2T1-a26fur-1T2-b27fur-E2-b28fur-E2-b

29fur-3T4-a30fur-E4-a

29pyr-1C4-b31fur-2E-a

32fur-3T4-a30pyr-4C1-a

33fur-E4-a34fur-2E-b

35fur-2T1-a36fur-2T1-a37fur-3T2-b38fur-4E-b39fur-4E-b40fur-E2-b41fur-2E-b

1open2open

42fur-E2-b43fur-3E-a

3open4open

Open

Furanose

ΔG(298K) [kJ/mol]

Figure 3. Relative Gibbs free energy DG(298 K) results for the seventy seven distinct D-ribose structures calculated at the M06-2X/6-311++G(d,p) level (ranked in order ofincreasing DH(0 K) relative energy). Arrows indicate the most stable furanose and open-chain structures found.


(Scheme 3). Twist conformations have one atom displaced aboveand one atom displaced below the plane of the ring formed bythe three other ring atoms (Scheme 4). Schemes 3 and 4 illustrateten possible E and 10 possible T furanose ring conformations,respectively, along with the corresponding notation. For instance,the term 2E (E2) denotes the envelope conformation with atomC2 above (below) the ring plane, whereas the term 4T3 (3T4)denotes the twist conformation with C4(C3) atom above andC3(C4) atom below the ring plane, etc.38,39

To describe a furanose ring conformation or puckering mathe-matically we have adopted the model of Altona and Sundaralingam(AS)39 which utilizes two parameters: pseudorotational phase an-gle, P, and puckering amplitude, Um. In the AS method,38,39 P valuesbeing odd multiples of 18� (P = 18�, 54�, 90�, etc.) correspond to(symmetrical) E conformations, whereas P values being even mul-tiples of 18� (P = 0�, 36�, 72�, etc.) correspond to (symmetrical) Tconformations—a graphical representation of the dependence ofthe furanose ring conformation on the full range of P values

Table 2The relative energies, DH(0 K) and Gibbs free energy differences, DG(298 K) (kJ/mol)of the seven most stable D-ribopyranoses along with those of the lowest-lying D-ribofuranose and the lowest-lying open-chain structure of D-ribose calculated at theMP2/aug-cc-pVTZ and G4 levels

Conformer G4 (kJ/mol) MP2/aug-cc-pVTZ (kJ/mol)

DH(0 K) DG(298 K) DH(0 K) DG(298 K)

1pyr-1C4-b 0.00 0.88 0.00 0.002pyr-1C4-b 1.21 1.92 1.30 1.213pyr-1C4-a 2.55 3.05 3.18 2.804pyr-4C1-b 0.63 0.00 2.34 1.175pyr-1C4-a 3.55 4.23 3.05 2.856pyr-4C1-a 1.88 2.43 0.79 3.057pyr-1C4-a 2.55 3.68 1.80 1.921fur-2T1-a 12.22 10.42 11.97 8.911open 33.9 25.68 39.08 29.87


(0� 6 P 6 360�) constitutes a ‘pseudorotational wheel’38,39 (seeScheme S2 in Supplementary data). In the AS model, parameterUm describes the extent of the puckering from the four-atom-ring-or three-atom-ring-plane (Schemes 3 and 4). The parameter P canbe determined from five endocyclic torsion angles, U0–U4 (definedin Scheme S2) via Eq. 1, whereas the parameter Um can be deter-mined via Eq. 2:

tan P ¼ ðU2 þU4Þ � ðU1 þU3Þðsin 36� þ sin 72�Þ ð1Þ

Um ¼U0

cos Pð2Þ

Each furanose structure can be again either the a (a) or b (b)anomer, depending on the orientation of OH at C1 (Scheme 1).Combining the anomer type with the furanose ring conformationdescription affords the furanose conformer notation employedhere. For instance, 1fur-2T1-a refers to a first furanose twist con-former with C2 above the plane and C1 below the plane, the a-anomer.

In the vast majority of the quantum mechanical structure opti-mizations performed in this work, the MP2 and M06-2X methodsprovided the same conformer/structure type, especially for thefuranoses, thus their common labeling in the figures presented be-low is justified. The few qualitatively different MP2 optimizedstructures (compared to the M06-2X ones), concerning the higherenergy isomers, are marked with asterisk in the figures.

4. Results and discussion

4.1. D-Ribose conformers

In Figures 1 and 2, the M06-2X/6-311++G(d,p) and MP2/6-311++G(d,p) calculated structures of the most stable pyranosesand furanoses of D-ribose are presented, with those of the remain-ing cyclic as well as open-chain isomers, lying higher in energy,shown in Supplementary data (Figs. S1–S3). The relative energies,DH(0 K), and free energy differences, DG(298 K) of thirty eightmost stable D-ribose conformers and those of the lowest lyingopen-chain isomer are compiled in Table 1 (wherein they areranked in order of increasing M06-2X relative energy). The MP2/6-311++G(d,p) calculated equilibrium rotational constants (A–C)along with those available from experiment9 are also included inTable 1. The DH(0 K) and DG(298 K) values for the remaining thirtynine D-ribose isomers of higher energy can be found in Table S1 ofSupplementary data. In order to make a meaningful comparisonwith the results of the MW study,9 the relative stabilities of D-ri-bose isomers are discussed in terms of Gibbs free energy differ-ences. Figure 3 summarizes graphically the DG(298 K) results ofall the D-ribose structures calculated here.

Table 1 indicates that at least twelve most stable gas phase ri-bose structures are the pyranoses, seven of which are within arange of less than 4 kJ/mol. Specifically, they lie within a range of2.85 kJ/mol and 3.54 kJ/mol of the global minimum in terms ofDG at the M06-2X/6-311++G(d,p) and MP2/6-311++G(d,p) levels,respectively. These four a- and three b-anomers assume eitherthe 1C4 or 4C1 ring chair conformations and are suggested to com-prise intramolecular hydrogen-bonded interactions (this issue isdiscussed in more detail in Section 4.4).

Among the seven low-lying ribopyranoses, we have identifiedsix isomers which were reported to be detected using MW spec-troscopy by Cocinero et al., whose authors’ structure assignmentwas made employing the quantum mechanically calculated rota-tional parameters.9 The following correspondence exists betweenour lowest energy structures (Fig. 1) and the MW detected ones(the Ref. 9 isomer designations are given within parentheses):1pyr-1C4-b (A), 2pyr-1C4-b (C), 3pyr-1C4-a (D), 4pyr-4C1-b (B),6pyr-4C1-a (F) and 7pyr-1C4-a (E). It should be stressed here thatall the lowest-energy ribose isomers we have arrived at are theoutcome of our independent systematic conformational searchstrategy detailed above.

Both our M06-2X/6-311++G(d,p) and MP2/6-311++G(d,p) cal-culations have predicted that the two b-pyranoses, 1pyr-1C4-band 4pyr-4C1-b (Fig. 1) with the 1C4 and 4C1 ring chair conforma-tions, respectively, compete for the lowest energy gas phase riboseisomer (Table 1). This is in agreement with the MW investigation,9

where the two conformers were established to be essentially iso-energetic based on the DG values evaluated from the relativeintensities of the observed rotational transitions. In more detail,the 1pyr-1C4-b structure presents a cyclic counter-clockwise hydro-gen-bonded (HB) chain OH4ðaxÞ ! OH3ðeqÞ ! OH2ðaxÞ (discussedin more detail in 4.4). Our result concerning the lowest energyribose isomers is also in accord with the early B3LYP density func-tional calculations of Guler et al.14 who found the (1C4) b-pyranoseto be its most stable gas phase structure. It is noted that two low-energy a-anomers given in Figure 1, 5pyr-1C4-a and 7pyr-1C4-adiffer mostly by the rotation of the OH groups at C2, C3, and C4,with the former structure being apparently neither reported earliercomputationally14 in that energy range nor observed.9

The comparison between the MP2/6-311++G(d,p) calculated andexperimental9 values of the rotational constants in Table 1 leads to arelatively easy ‘conformational assignment’. Recall that six of theseconformers were MW spectroscopically detected/assigned in Ref. 9with the help of the ab initio determined rotational parameters.Actually, for the 5pyr-1C4-a and 7pyr-1C4-a pyranose conformer pair,where the latter species was assigned9 as the structure ‘E’, Table 1shows that an alternative assignment to 5pyr-1C4-a is likely (usingthe rotational constants alone). From an additional comparison ofthe M06-2X/6-311++G(d,p) calculated rotational constants (givenin Supplementary data) with the experimental values, a somewhatworse agreement arises than with the MP2/6-311++G(d,p)constants. This suggests that our MP2 structural parameters of theribose conformers are expected to be of higher accuracy comparedto the M06-2X ones, at least for the pyranoses.

Table 1 further reveals that the lowest-lying ribofuranose is thea-anomer with the twist 2T1 conformation, 1fur-2T1-a, put 11.53 kJ/mol at M06-2X/6-311++G(d,p) and 8.74 kJ/mol at MP2/6-311++G(d,p) higher in free energy than the most stable ribopyra-nose calculated at these respective levels. This energetically mostfavoured ribofuranose appears to be more stable than the optimalgas phase ribofuranose reported from the earlier MP2/6-31G(d,p)calculations by Jalbout et al.40 which corresponds to the 8fur-E2-bconformer in Figure 2. According to Table 1, the latter species ispredicted to be 3.76 kJ/mol higher in energy (DH(0 K)) than1fur-2T1-a at our MP2/6-311++G(d,p) level (we note that only b-furanose isomers were considered for ribose by the latter authors).


1C4-b


4C1-a

7pyr-1C4-b 8pyr-4C1-b 9pyr-

4C1-b


4C1-b

Figure 4. Structures of the twenty four most stable pyranose conformers of 2-deoxy-D-ribose optimized at the M06-2X/6-311++G(d,p) and MP2/6-311++G(d,p) levels withthe indicated H� � �O distances of the possible HB interactions (in Å, the MP2 values are in parentheses).


Because the seven lowest energy ribopyranoses lie within only4 kJ/mol, the additional more accurate calculations on their rela-tive stabilities have been performed at the MP2/aug-cc-pVTZ andG4 levels of theory. Table 2 presents these results along with those

for the most favoured ribofuranose, 1fur-2T1-a, and most favouredopen-chain ribose, 1open (the latter is given in Fig. S3). It is seenfrom Table 2 that the energetic preference of the two b-pyranoses1pyr-1C4-b and 4pyr-4C1-b is maintained with the corresponding


1C4-a


1C4-a

19pyr-1C4-b 20pyr-skewed-a 21pyr-1C4-a

22pyr-1C4-a 23pyr-4C1-a 24pyr-

1C4-b

Fig. 4 (continued)


minuscule DG of 1.17 kJ/mol (MP2/aug-cc-pVTZ) and 0.88 kJ/mol(G4), where the former (latter) conformer is the global minimumat the MP2/aug-cc-pVTZ (G4) level. With this refined energetics,the most favoured furanose molecule 1fur-2T1-a is predicted as8.91 kJ/mol and 10.42 kJ/mol higher in free energy than the globalminimum structure at these respective levels.

Unlike the pyranose–furanose energy differences, those be-tween the cyclic and open-chain isomers are more strongly meth-

od dependent (Tables 1 and 2). The cyclic-open chain energydifferences correspond to the energies of the reactions of the ringopening and can be calculated accurately with ab initio methodsincluding dynamic correlation. Our MP2/aug-cc-pVTZ and G4 ener-getics (Table 2) yields the free energy difference between the moststable pyranose (1pyr-1C4-b) and open-chain (1open) structures ofribose at 29.87 and 25.68 kJ/mol, respectively. Note that therespective M06-2X/6-311++G(d,p) value of 30.13 kJ (Table 1)

1fur-2T1-a 2fur-2T1-a 3fur-

2E-a

4fur- 4E-b 5fur-4E-b 6fur-2T1-a

7fur-4E-b 8fur-E2-b 9fur-2E-a

10fur-2 1T2E-a 11fur- -b *11fur-3T2-b

12fur-E2-b

Figure 5. Structures of the twelve most stable furanose conformers of 2-deoxy-D-ribose optimized at the M06-2X/6-311++G(d,p) and MP2/6-311++G(d,p) levels with theindicated H� � �O distances of the possible HB interactions (in Å, the MP2 values are in parentheses). The MP2 structure marked with asterisk is qualitatively different from theM06-2X one.


Table 3The relative energies, DH(0 K), Gibbs free energy differences, DG(298 K) (kJ/mol) and equilibrium rotational constants A–C (MHz) of the thirty seven most stable conformers of2-deoxy-D-ribose and of the lowest-lying open-chain structure calculated at the two geometry optimization levelsa

Conformer M06-2X/6-311++G(d,p) (kJ/mol) MP2/6-311++G(d,p) (kJ/mol) Rotational constantsb (MHz)

DH(0 K) DG(298 K) DH(0 K) DG(298 K) A B C

1pyr-4C1-a 0.00 0.00 0.00 0.00 2485.4 1529.5 1246.72pyr-1C4-b 5.60 4.54 4.30 3.25 2441.3 1523.3 1154.83pyr-1C4-b 9.74 8.23 6.67 5.17 2457.3 1519.8 1146.74pyr-1C4-a 9.84 8.59 8.06 6.82 2497.3 1392.3 1074.25pyr-1C4-b 10.63 8.76 8.67 6.80 2449.2 1518.5 1151.06pyr-4C1-a 11.39 10.95 11.28 10.84 2505.4 1516.3 1246.37pyr-1C4-b 11.55 10.06 8.44 6.95 2441.0 1524.3 1147.41fur-2T1-a 12.25 9.00 6.19 2.95 2519.5 1375.9 1151.48pyr-4C1-b 12.89 11.08 10.54 8.73 2948.6 1276.2 1027.49pyr-4C1-b 13.27 11.50 11.36 9.59 2941.2 1270.0 1025.410pyr-4C1-b 13.98 12.08 11.49 9.60 2940.1 1275.9 1026.211pyr-1C4-a 14.30 12.81 12.98 11.49 2506.0 1376.9 1065.42fur-2T1-a 15.55 11.78 9.43 5.67 2618.5 1258.7 1032.112pyr-4C1-b 16.72 14.96 14.86 13.10 2954.8 1268.4 1025.513pyr-4C1-b 16.94 14.92 15.68 13.66 2948.4 1261.3 1023.914pyr-1C4-a 17.68 14.60 15.53 12.46 2524.1 1373.8 1061.015pyr-1C4-a 17.72 15.79 14.28 12.36 2541.2 1375.9 1053.616pyr-4C1-b 17.85 15.72 15.96 13.82 2946.0 1268.1 1024.53fur-2E-a 17.88 14.09 11.22 7.43 2569.0 1367.3 1168.517pyr-1C4-a 18.67 16.64 16.12 14.10 2543.0 1362.7 1051.718pyr-1C4-a 19.05 16.61 17.32 14.88 2525.5 1361.4 1057.419pyr-1C4-b 19.14 17.44 19.55 17.85 2442.5 1506.8 1144.64fur-4E-b 19.64 16.95 15.25 12.56 2126.1 1623.0 1241.620pyr-skewed-a 20.36 19.61 21.09 20.34 2379.7 1480.9 1359.921pyr-1C4-a 20.50 18.43 17.17 15.11 2517.9 1381.4 1053.95fur-4E-b 20.53 17.28 16.51 13.26 2109.6 1635.0 1237.76fur-2T1-a 20.58 16.96 14.46 10.85 2569.3 1359.0 1146.422pyr-1C4-a 20.90 18.65 18.35 16.09 2518.8 1368.7 1051.87fur-4E-b 21.02 17.80 16.92 13.70 2101.4 1638.4 1236.423pyr-4C1-a 21.84 20.94 20.72 19.82 2484.3 1517.0 1227.724pyr-1C4-b 22.18 20.51 19.67 18.00 2384.9 1539.1 1151.88fur-E2-b 22.20 16.10 16.45 10.36 1879.4 1685.8 1131.59fur-2E-a 23.24 19.33 17.14 13.23 2675.1 1245.8 1029.525pyr-skewed-b 23.25 21.74 22.74 21.23 2853.2 1351.4 1144.910fur-2E-a 23.33 18.94 16.34 11.96 2819.6 1227.6 1028.211fur-1T2-b 23.52 18.00 16.92 11.40 1879.4 1685.8 1131.512fur-E2-b 24.07 19.05 17.18 12.17 2408.9 1352.6 1035.61open 33.83 25.00 22.33 13.50 3823.2 816.1 711.3

a The DH(0 K) values include the harmonic zero-point energy (ZPE) corrections calculated at the M06-2X/6-311++G(d,p) level. The free energy differences (at T = 298 K andp = 1 atm), DG(298 K), were obtained by calculating the ZPE, thermal and entropic contributions with the help of the M06-2X/6-311++G(d,p) vibrational frequencies. InTable S2 (Supplementary data) the relative energies DH(0 K) and free energy differences DG(298 K) of the remaining conformers of 2-deoxy-D-ribose investigated, given inthe order of increasing relative energies, can be found.

b The MP2/6-311++G(d,p) results.


compares well with these two estimates. In the recent conforma-tional analysis of the gas phase hexoses,30 the open-chain formswere also found significantly less stable than the ring structures.

4.2. 2-Deoxy-D-ribose conformers

Figures 4 and 5 show the M06-2X/6-311++G(d,p) and MP2/6-311++G(d,p) calculated structures of the most stable pyranoses andfuranoses of 2-deoxy-D-ribose, with those of the remaining cyclic aswell as open-chain isomers which lie higher in energy included inSupplementary data (Figs. S4–S6). The relative energies, DH(0 K), freeenergy differences, DG(298 K) of thirty seven most stable conformersof 2-deoxy-D-ribose and those of the lowest lying open-chain isomeras predicted using the two methods are summarized in Table 3(wherein they are ordered by their M06-2X relative energies). TheMP2/6-311++G(d,p) calculated equilibrium rotational constants (A–C) are also included in Table 3. The DH(0 K) and DG(298 K) resultsfor the remaining sixty five isomers of deoxyribose can be found inTable S2. As for ribose, the relative stabilities of the deoxyribose iso-mers will be discussed in terms of Gibbs free energy differences. Fig-ure 6 summarizes graphically the DG(298 K) values of all the 2-deoxy-D-ribose structures calculated in this work.

Table 3 first shows that compared to D-ribose, the seven deoxy-ribose conformers of top stability are contained in a wider energyrange of 10.9 kJ/mol. Second, the most favoured furanose of deoxy-ribose lies relatively low in energy at the correlated MP2 level.These observations reflect an important difference between theconformational energy landscapes of ribose and deoxyribosecaused by the presence of the OH group at C2 in the former andthe absence of this group in the latter sugar. Both the M06-2X/6-311++G(d,p) and MP2/6-311++G(d,p) calculations have found (Ta-ble 3) that the lowest energy conformer of 2-deoxy-D-ribose is thea-pyranose with the 4C1 ring chair, 1pyr-4C1-a. It is hoped that thecalculated rotational constants in Table 3, especially those corre-sponding to the most stable isomers, may facilitate their futuredetection in the gas phase using MW spectroscopy.

With Table 3, the lowest-lying 2-deoxy-D-ribofuranose is the a-anomer having the twist 2T1 ring conformation, 1fur-2T1-a (Fig. 5),similar to the lowest energy D-ribofuranose species. Figure 5 alsoshows that the second most stable furanose of deoxyribose, 2fur-2T1-a, differs from 1fur-2T1-a mostly by the rotation of the extracyclicCH2OH group. It is also of relevance to note that the most stablegas phase 2-deoxy-D-ribofuranose reported by Vannier et al.41 hasthe envelope ring conformation (E2) and corresponds to our higher

33f

101

12131116

1119

20pyr2

2

224

25pyr

1

1

126pyr

2

2

2222

28pyr3fur-C4

2

3

3

4

4

5

5

5

55

5

6

1pyr-42pyr-13pyr-14pyr-15pyr-16pyr-47pyr-11fur-2

8pyr-49pyr-4

10pyr-411pyr-1

2fur-212pyr-413pyr-414pyr-115pyr-116pyr-4

3fur17pyr-118pyr-119pyr-1

4furyr-skew21pyr-1

5fur6fur-2

22pyr-17fur

23pyr-424pyr-1

8fur9fur

yr-skew10fur

11fur-112fur13fur

14fur-215fur16fur

17fur-1yr-skew

18fur19fur

20fur-121fur

27pyr-122fur23fur24fur25fur

26fur-127fur-228fur-129fur-230fur31fur32fur

yr-skew4-endo29pyr-1

34fur35fur36fur

37fur-338fur39fur40fur

1o2o

41fur3o

42fur4o

30pyr-143fur44fur45fur

46fur-15o

47fur-348fur49fur

50fur-351fur

52fur-153fur

54fur-36o7o

55fur-56fur-257fur-O

58fur59fur-O

60fur8o

61fur62fur-2

9o10o11o

4C1-a1C4-b1C4-b1C4-a1C4-b4C1-a1C4-b2T1-a4C1-b4C1-b4C1-b1C4-a2T1-a4C1-b4C1-b1C4-a1C4-a4C1-b

ur-2E-a1C4-a1C4-a1C4-b

ur-4E-bewed-a

1C4-aur-4E-b

2T1-a1C4-a

ur-4E-b4C1-a1C4-b

ur-E2-bur-2E-aewed-bur-2E-a

1T2-bur-E2-bur-2E-a

2T1-aur-E2-bur-2E-a

1T2-bewed-aur-4E-bur-E4-a

1T2-bur-E2-b

1C4-aur-E2-bur-2E-aur-4E-bur-E4-a

1T2-b2T1-a1T2-b2T1-a

ur-4E-bur-E4-aur-4E-bewed-bo-4E-b1C4-a

ur-4E-bur-E4-aur-E2-b

3T2-bur-4E-bur-E4-aur-3E-b1open2open

ur-E3-a3open

ur-4E-a4open1C4-a

ur-4E-bur-4E-bur-2E-b

1T2-b5open3T2-b

ur-E2-bur-E4-a

3T4-aur-3E-b

1T2-bur-2E-a

3T4-a6open7open-EO-b2T1-aOT4-a

ur-4E-bOT4-a

ur-E4-a8open

ur-E4-a2T3-b

9open10open11open

F

ΔGG (29(298K8K) [k) [kJ/mJ/molol]

O en

Furauranosose

Open

Figure 6. Relative Gibbs free energy DG(298 K) results for one hundred and three distinct structures of 2-deoxy-D-ribose calculated at the M06-2X/6-311++G(d,p) level(ranked in order of increasing DH(0 K) relative energy). Arrows indicate the most stable furanose and open-chain structures found.


energy furanose 15fur-E2-b (Fig. S5, Table S2), lying 15.73 kJ/molabove 1fur-2T1-a in terms of DH(0 K) at MP2/6-311++G(d,p).

Table 4 presents the DH(0 K) and DG(298 K) results of higheraccuracy, at MP2/aug-cc-pVTZ and G4, for the eleven lowest energy

Table 6Natural bond orbital analysis of the endo- and exo-anomeric effects in the lowestenergy pyranoses of 2-deoxy-D-ribose

Conformera Orbitalhyperconjugation

jDEð2Þnr�jb (kcal/

mol)

r⁄ occupancy(e)c

1pyr-4C1-a (ax) n(O5)?r⁄(C1–O1)n(O1)?r⁄(C1–O5)

16.1411.79

0.0560.051

2pyr-1C4-b (ax) n(O5)?r⁄(C1–O1)n(O1)?r⁄(C1–O5)

13.6615.23

0.0480.058


15.6413.67

0.0530.053

4pyr-1C4-a (eq) n(O1)?r⁄(C1–O5)n(O5)?r⁄(C1–O1)

14.054.51

0.0580.029

1fur-2T1-a (ax) n(O4)?r⁄(C1–O1)n(O1)?r⁄(C1–O4)

17.6612.33

0.0580.051

a ‘ax’/‘eq’ indicates that the OH group at the anomeric C1 is oriented axially/equatorially.

b jDEð2Þnr�j is the stabilization energy corresponding to hyperconjugation assessedwith the second-order perturbation theory.

c Electron occupancy of antibonding orbital.

Table 5Natural bond orbital analysis of the endo- and exo-anomeric effects in the lowestenergy pyranoses of D-ribose

Conformera Orbitalhyperconjugation

jDEð2Þnr�jb (kcal/

mol)

r⁄ occupancy(e)c


14.3215.33

0.0480.055


14.3914.93

0.0450.055


9.704.97

0.0480.031

4pyr-4C1-b (eq) n(O1)?r⁄(C1–O5)n(O5)?r⁄(C1–O1)

14.234.51

0.0510.031


18.194.34

0.0610.026

6pyr-4C1-a (ax) n(O5)?r⁄(C1–O1)n(O1)?r⁄(C1–O5)

15.7313.85

0.0540.050


18.604.35

0.0610.027

1fur-2T1-a (ax) n(O4)?r⁄(C1–O1)n(O1)?r⁄(C1–O4)

17.7114.24

0.0540.050

a ‘ax’/‘eq’ indicates that the OH group at the anomeric C1 is oriented axially/equatorially.

b jDEð2Þnr�j is the stabilization energy corresponding to hyperconjugation assessedwith the second-order perturbation theory.

c Electron occupancy of antibonding orbital.

Table 4The relative energies, DH(0 K), and Gibbs free energy differences, DG(298 K) (kJ/mol)of the eleven most stable 2-deoxy-D-ribopyranoses along with those of the threelowest-lying 2-deoxy-D-ribofuranoses and the lowest-lying open-chain structure of 2-deoxy-D-ribose calculated at the MP2/aug-cc-pVTZ and G4 levels

Conformer G4 (kJ/mol) MP2/aug-cc-pVTZ (kJ/mol)

DH(0 K) DG(298 K) DH(0 K) DG(298 K)

1pyr-4C1-a 0.00 0.00 0.00 0.002pyr-1C4-b 4.43 3.39 5.40 3.013pyr-1C4-b 7.91 6.44 9.75 6.904pyr-1C4-a 7.85 6.56 8.87 6.905pyr-1C4-b 8.93 6.93 11.21 8.036pyr-4C1-a 10.75 10.38 12.43 10.677pyr-1C4-b 9.50 8.30 10.50 7.708pyr-4C1-b 10.75 8.91 12.51 9.419pyr-4C1-b 11.25 9.29 13.51 10.4210pyr-4C1-b 12.17 10.54 13.14 9.9211pyr-1C4-a 11.96 10.50 13.18 10.38

1fur-2T1-a 9.46 6.22 10.88 6.322fur-2T1-a 12.26 8.72 13.64 8.583fur-2E-a 13.92 10.11 15.61 10.461open 29.41 20.21 34.43 24.27


pyranoses of deoxyribose along with those for its lowest-lyingfuranoses and open-chain structure. As seen, the a-pyranose1pyr-4C1-a is retained the global minimum deoxyribose structure,now put 3.01 kJ/mol (MP2/aug-cc-pVTZ) and 3.39 kJ/mol (G4) low-er in DG than the second most stable b-pyranose 2pyr-1C4-b. Inter-estingly, Table 4 also indicates that the furanose 1fur-2T1-a is nowpredicted to be only 6.22 kJ/mol (MP2/aug-cc-pVTZ) and 6.32 kJ/mol (G4) higher in free energy than the global minimum structure,becoming actually the third most stable isomer of 2-deoxy-D-ri-bose in terms of DG. This pyranose–furanose energy separation isapparently reduced compared to the free ribose counterpart of8.91 and 10.42 kJ/mol, respectively (Table 2).

Our calculated pyranose–furanose energy separation of 2-deoxy-D-ribose is significantly smaller than the value of 33.10 kJ/mol (7.9 kcal/mol) reported recently by Ghosh et al.15 based onthe density functional xB97x/cc-pVTZ calculations (note that therelative energy of Ghosh et al. should be directly compared withour DH(0 K) results for 1fur-2T1 of 9.46 and 10.88 kJ/mol in Table 4).However, in Ref. 15, only a limited search of the conformational en-ergy surface was done as the study focused primarily on the deter-

mination of the ionization energy of deoxyribose. Table 4 alsoshows that, similar to the ribose case, the most favoured open-chain isomer of deoxyribose (1open, Fig. S6) is not thermodynam-ically competitive with its low-lying cyclic forms, being 24.27 kJ/mol (MP2/aug-cc-pVTZ) and 20.21 kJ/mol (G4) higher in free en-ergy than the global minimum 1pyr-4C1-a structure.

4.3. Natural bond orbital analysis of the anomeric effect

The anomeric effect refers to a stabilization of a pyranose sugarwith a chair conformation having an electronegative substituent X(like OH group) at the anomeric C1 position.42,43 The endo-anomer-ic effect involves interaction of the endocyclic O5 oxygen atomwith the substituent X, whereas the exo-anomeric effect involvesinteraction of the exo-cyclic X substituent with O5. Currently,one observes an ongoing discussion concerning the main originof the anomeric effect, with no general consensus achieved yet.44

The reported explanations of this origin include hyperconjuga-tion45 nO?r⁄CX, electrostatic/steric interactions46,47 andexchange48 effects. Combining infra-red spectroscopy and theoret-ical natural bond orbital (NBO) analysis,49 Cocinero et al.43 pro-vided recently the evidence that hyperconjugation is responsiblefor the exo-anomeric effect in methyl D-galactopyranoside in thegas phase. Also, the recent computational study by Freitas44 hasdemonstrated that hyperconjugation depends on the kind of sub-stituent X at C1 and on the medium. In the following, we analyzewith NBO the anomeric effects in the most stable gas phase pyra-nose structures of ribose and deoxyribose.

In this perturbation theory (PT) analysis of Fock matrix in NBObasis, the second-order energy corrections jDEð2Þij j (stabilizationenergies) are calculated for possible NBO i?j delocalizations.49 Ta-bles 5 and 6 summarize the relevant jDEð2Þij j values with the corre-sponding charge transfer qi?j values calculated at the M06-2X/6-311++G(d,p) level for the selected pyranose conformers of D-riboseand 2-deoxy-D-ribose. The ‘ax’ and ‘eq’ in Tables 5 and 6 refer to thestructures with the OH group occupying the axial and equatorialpositions, respectively. In these tables, the endo-anomeric effectcorresponds to the n(O5)?r⁄(C1–O1) hyperconjugative interac-tion, whereas the exo-anomeric effect is related to the n(O1)?r⁄(C1–O5) hyperconjugation.

Table 5 shows that for the three ribopyranoses with the axiallyoriented OH, including the global minimum structure 1pyr-1C4-b,the operating endo- and exo-anomeric effects are strong and ofcomparable magnitude in terms of the jDEð2Þnr�j stabilization energyand the electronic orbital occupancy for the r⁄(C1–O1)/r⁄(C1–O5)orbitals. By contrast, for the four ribopyranoses with the equatori-

Table 7Natural bond orbital analysis of the intramolecular HB interactions in the lowestenergy pyranoses of D-ribosea

Conformerb Orbital interaction jDEð2Þnr�jc

(kcal/mol)

r⁄ occupancy(e)d

1pyr-1C4-b (ax) n(O2)?r⁄(O3–H3)n(O3)?r⁄(O4–H4)n(O4)?r⁄(O2–H2)

1.770.642.48

0.0130.0090.015

2pyr-1C4-b (ax) n(O2)?r⁄(O4–H4)n(O3)?r⁄(O2–H2)n(O4)?r⁄(O3–H3)

1.920.621.98

0.0140.0090.013

3pyr-1C4-a (eq) n(O2)e?r⁄(O4–H4)n(O2)f?r⁄(O4–H4)n(O4)?r⁄(O3–H3)n(O1)?r⁄(O2–H2)

1.302.760.78[


exhibit two and one HB interactions, respectively, as supported bythe NBO results in Table 8. Interestingly, second-order perturbativeanalysis in this table shows the involvement of the O5 ring lonepair in the formation of the HB in the 2pyr-1C4-b and 4pyr-1C4-apyranose structures (not shown explicitly in Fig. 4). However, theH-bonding comprising the ring oxygen O4 in the deoxyribofura-nose 1fur-2T1-a associated with the n(O4)-r⁄(O5–H5) interactionis not confirmed.

5. Conclusions

Using computational methods, we have probed the conforma-tional space of two pentoses of biological and potential astrobiolog-ical importance, D-ribose and 2-deoxy-D-ribose, including a- andb-pyranoses, a- and b-furanoses and open-chain structures. Ourstudy revealed a multitude of existing minima structures. Numerousfuranose conformers found are described with the Altona and Sun-daralingam pseudorotation parameters. In agreement with the re-cent gas-phase MW investigation of Cocinero et al.,9 the two moststable free ribose isomers predicted here are the b-pyranoses withthe 1C4 and 4C1 ring chair conformations. Both b-pyranoses lie within0.9 kJ/mol in terms of DG(298 K), thus challenge the computationalmethods used to predict the free ribose global minimum. At the G4level, the seven lowest energy ribopyranoses are within 4.2 kJ/mol ofthe global minimum. The predicted most favorable ribofuranose isthe a-anomer with the twist 2T1 ring conformation, being 10.4 kJ/mol higher in free energy than the global minimum.

By contrast with D-ribose, the calculated most stable isomer offree 2-deoxy-D-ribose is the a-pyranose, whose most favouredfuranose structure (the a-anomer) is only 6.2 kJ/mol less stable(in DG). Additionally, we have reported the equilibrium rotationalconstants for the lowest energy structures of the two sugars, whichcan be useful for their future spectroscopic detection in the gasphase, especially deoxyribose species. For the two pentoses, theopen-chain isomers lie significantly higher in energy than thelow-lying cyclic species. A good overall agreement is observed be-tween the M06-2X/6-311++G(d,p) and MP2/6-311++G(d,p) resultsin terms of both the existing low-energy minima structures andintramolecular H-bonding geometrical parameters. The naturalorbital analysis confirms the occurence of the endo- and exo-ano-meric effects and maximization of intramolecular H-bonding inthe lowest-lying pyranoses and furanoses of both sugars.

In summary, the furanose forms of D-ribose and 2-deoxy-D-riboseare known to be constituents of many compounds that are essentialfor life such as DNA, RNA, ATP etc. In the gas phase, however, thepyranose forms are energetically more favoured for both sugars.

Note added in the proof

After accepting our work for publication, the paper by Peñaet al.51 appeared. By using Fourier-transform microwave spectros-copy and laser ablation methods combined with quantum-mechan-ical calculations, these authors identified two a- and four b-pyranose conformers of 2-deoxy-D-ribose. Among these conform-ers there are five low-energy structures which have been reportedin our work as inferred by comparing both the geometrical struc-tures (Figure 4) and the MP2 rotational constants (Table 3) withthose provided by Peña et al.51 The following correspondence existsbetween our predicted 2-deoxy-D-ribose structures and the MWdetected ones (the Ref.51 designations are given within the paren-theses): 1pyr-4C1-a (Rotamer V), 2pyr-1C4-b (Rotamer I), 3pyr-1C4-b(Rotamer II), 8pyr-4C1-b (Rotamer III), 9pyr-4C1-b (Rotamer IV).Based on the MP2 rotational constants alone, our 6pyr-4C1-amatches Rotamer VI in Ref.51, but the latter was assigned by Peñaet al. to the other (4C1) b-pyranose form.

Acknowledgements

Both reviewers are thanked for their helpful suggestions and re-marks. The authors acknowledge a generous support of computertime at the Wroclaw Center for Networking and Supercomputing,WCSS.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.carres.2013.10.013.

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Conformational studies of gas-phase ribose and 2-deoxyribose by density functional, second order PT and multi-level method calculations: the pyranoses, furanoses, and open-chain structures1 Introduction2 Computational methods3 Labeling of conformers4 Results and discussion4.1 d-Ribose conformers4.2 2-Deoxy-d-ribose conformers4.3 Natural bond orbital analysis of the anomeric effect4.4 Natural bond orbital analysis of the intramolecular HB interactions

5 ConclusionsNote added in the proofAcknowledgementsSupplementary dataReferences

conformational studies of gas-phase ribose and 2 ...szolcsanyi/education/files/chemia%20...above,...

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