Chemical shift and coupling constant analysis of dibenzyloxy disulfides

Article abstract of DOI:10.1016/j.saa.2014.10.109

Dialkoxy disulfides have found applications in the realm of organic synthesis as an S₂ or alkoxy donor, under thermal and photolytic decompositions conditions, respectively. Spectrally, dibenzyloxy disulfides possess an ABq in the ¹H NMR, which can shift by over 1.1 ppm depending on the substituents present on the aromatic ring, as well as the solvent employed. The effect of the said substituents and solvent were analyzed and compared to the center of the ABq, geminal coupling, and the differences in chemical shifts of the individual doublets. Additionally, quantum-chemical calculations demonstrated the intramolecular H-bonding arrangement, found within the dibenzyloxy disulfides.

Full text of DOI:10.1016/j.saa.2014.10.109

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Chemical shift and coupling constant analysis of dibenzyloxy disulfides
Eric G. Stoutenburg, Ganna Gryn’ova, Michelle L. Coote, Ronny Priefer
PII:
S1386-1425(14)01606-0
http://dx.doi.org/10.1016/j.saa.2014.10.109
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Spectrochimica Acta Part A: Molecular and Biomo-
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23 October 2014
Please cite this article as: E.G. Stoutenburg, G. Gryn’ova, M.L. Coote, R. Priefer, Chemical shift and coupling
constant analysis of dibenzyloxy disulfides, Spectrochimica Acta Part A: Molecular and Biomolecular
Spectroscopy (2014), doi: http://dx.doi.org/10.1016/j.saa.2014.10.109
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Chemical shift and coupling constant analysis of dibenzyloxy disulfides
Eric G. Stoutenburg,bGannaGryn’ova,c Michelle L. Coote,cand Ronny Priefera,b*
aCollege of Pharmacy, Western New England University, Springfield, MA 01119, USA
bDepartment of Chemistry, Biochemistry, and Physics, Niagara University, NY 14109, USA
c Research School of Chemistry, Australian National University, Canberra ACT0200, Australia
*Tel: 413-796-2438; Fax: 413-796-2266; email: ronny.priefer@wne.edu
Abstract
Dialkoxy disulfides have found applications in the realm of organic synthesis as an S2 or alkoxy
donor, under thermal and photolytic decompositions conditions, respectively. Spectrally,
1
dibenzyloxy disulfides possess an ABq in the H-NMR, which can shift by over 1.1 ppm
depending on the substituents present on the aromatic ring, as well as the solvent employed. The
effect of the said substituents and solvent were analyzed and compared to the center of the ABq,
geminal coupling, and the differencesin chemical shifts of the individual doublets. Additionally,
quantum-chemical calculations demonstrated the intramolecular H-bonding arrangement, found
within the dibenzyloxy disulfides.
Introduction
Dialkoxy disulfides were first synthesized in the late 19th century by Lengfeld [1],
however they lay in relative obscurity until the 1990’s when Harpp and others began to examine
this novel structural moiety [2-15]. Although examples of the isomeric form, thionosulfite (–
OS(=S)O–) have been reported, however only in cyclic structures [3,12], the predominate form is
believed to be the linear arrangement, (–OSSO–). It was revealed that dialkoxy disulfidescould
act as an S2 donating group in pseudo-Diels Alder reactions [8,11]. Subsequently, Lunazzi and
Placucci utilized this functionality as a photolytic source of alkoxy radicals [5]. We have also
explored this class of compounds, specifically the dibenzyloxy disulfides [16-19]. Recently, we
have reported on their photolytic [16] and thermolytic properties [17,18], as well as their unique
interaction with gold nanoparticles and their subsequent interaction with the Alzheimer’s
association Aβ oligomers [19].

Through some of our aforementioned studies we observed spectral differences in the 1H-
NMR of the dibenzyloxy disulfides depending on what functionality was placed in the para-
position ofthe aromatic ring; specifically, the downfield/upfieldchemical shift of the center of the
characteristic ABq, the geminal coupling constant, and the spectral frequency difference between
the two diastereotopicprotons.The diastereotopic nature of this linear molecule is due to the
geometry around the disulfide bond. Dialkoxy disulfides have a dihedral angle around the –O–S–
S–O– bond of ~90o [2,8]. This has been attributed to the conjugation of a lone pair on a sulfur
atom with theσ* orbital of the adjacent –O–S– bond [13]. It has been postulated that this
provides double bond character and a decrease in bond length of the –S–S– bond to 1.95 Å [2]
from a typical 2.05Å [19-21] for simple disulfides. In addition, there is an elevation in the
rotational barrier energy around the disulfide bond from ~8 kcal/mol [19-21] to ~18 kcal/mol [8].
By augmenting the electronic nature of the substituents on the aromatic ring, we predict that the
placement and coupling of the characteristic ABq would be altered. In addition, we also wanted
to explore the role of the solvent on the spectral profile of the benzylic protons.
Previous studies have investigated the changes in the 1H-NMR chemical shift of protons
and observed that a number of variables can influence proton resonance, including any
substituents and the solvent used within the system. Both of these impact the electron density
surrounding the proton, which alters resonance frequency. Protons that experience a deshielding
of electron density, such as those adjacent to an electron withdrawing substituent, give signals at
a higher resonance frequency.
Substitution of an aromatic ring has a large effect on the pi-electron density, affecting the
aromatic proton shift. Yonemoto and his colleagues have looked at substituted anilines to study
the influence various electron withdrawing/donating groups have on proton resonance, as well as

the effect of the amine group. They found a correlation between Hammett’s constant of a para-
substituent and the degree of proton shift within the aromatic ring [23]. As Hammett’s constant
becomes more positive for a given substituent, indicating an electron-withdrawing group, total
pi-electron density is reduced and proton resonance is shifted downfield. In addition, electron-
withdrawing groups cause the N-H bond to become more polarized. Polarization leads to an
increase in intermolecular hydrogen bonding as well as hydrogen bonding between the solute
and solvent. The degree of solute-solvent interaction is increased for solvents such as DMSO and
acetone, as they are hydrogen bond acceptors. Hydrogen bonds act to deshield the protons,
shifting their resonance downfield [23-26].
1
This work investigates para-substituted dibenzyloxy disulfide proton shift using H-
NMR. We are interested in the hydrogens adjacent to the –O–S–S–O– bond, as they are distinct
from a typical disulfide system, in addition to the aromatic protons. By evaluating various
electron donating and withdrawing groups, we can investigate how these substituents change the
electron density of the molecule, thus shifting proton resonance. Moreover, this information will
give insight into how these groups influence the solute-solvent interactions.
Experimental
Materials, preparation and characterization of compounds
All chemicals were reagent grade with the exception of 4-phenoxybenzyl alcohol which
was synthesized according to published procedure [27].1H NMR (400 MHz) and 13C NMR (100
MHz) spectra were recorded on a Varian instrument with tetramethylsilane (TMS) as an internal
standard. Chemical shifts (δ) are given in ppm, coupling constants (J) in Hz, and spin
multiplicities as s (singlet), d (doublet), ABq (AB quartet) and m (multiplet).

Representative synthesis of a dibenzyloxy disulfide[18]
Bis(4-Nitrobenzyloxy) disulfide
p-Nitrobenzyl alcohol (0.25g, 1.63mmol) was dissolved in anhydrous CH2Cl2 under N2.
Triethylamine (0.227mL, 1.63mmol) was added and the resulting solution was cooled to 0 °C.
S2Cl2 (65.3µL, 0.82mmol) was added dropwise over twenty minutes. The solution was stirred at
0 °C for two hours before being allowed to equilibrate to room temperature for three hours. The
reaction was quenched with dH2O, washed with 2 x 20mL aliquots of brine. The aqueous phase
was extracted with CH2Cl2 (2 x 10 mL), and the combined organic phase was dried over MgSO4,
filtered, and concentrated under reduced pressure. Column chromatography with a 2.5:1 ratio
ofhexanes:ethyl acetate afforded the below compounds. [Note: Bis(p-nitrobenzyloxy) disulfide,
bis(4-methoxybenzyloxy) disulfide, bis(4-tertbutylbenzyloxy) disulfide, and bis(4-benzyloxy)
disulfide have been previously synthesized in another laboratory with reported spectra in Ref 13.
With the exception of bis(4-benzyloxy) disulfide, all spectra reported was almost identical to
those reported below. For bis(4-benzyloxy) disulfide, Ref 13 incorrectly assigned the aromatic
signals as δ 7.39 (m, 15H) instead of our δ 7.17 (m, 10H). In addition, bis(p-nitrobenzyloxy)
disulfide, bis(4-methoxybenzyloxy) disulfide, bis(4-methylbenzyloxy) disulfide, bis(4-
benzyloxy) disulfide, and bis(4-chlorobenzyloxy) disulfide were also reported in Ref 4. The
mp.and NMR matched our samples. Bis(4-phenylbenzyloxy) disulfide was first synthesized and
fully characterized in our laboratory in Ref 16. Bis(4-phenoxybenzyloxy) disulfide, bis(4-
cyanobenzyloxy) disulfide, and bis(4-cyanobenzyloxy) disulfide all were previously synthesized
and fully characterized from our laboratory and reported in Ref 18.]

1
Bis(4-nitrobenzyloxy) disulfide (0.23g, 93%) as an off white solid mp. 93-95°C. H NMR
(400MHz, CDCl3): δ 4.89, 5.01 (ABq, J = 12.6 Hz, 4H), 7.49 (d J = 8.8 Hz, 4H), 8.22 (d, J = 8.8
Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 75.1, 123.8, 128.7, 143.6, 147.9.
Bis(4-Phenylbenzyloxy) disulfide (0.23g, 90%) as white solid. mp.105-107°C.1H NMR
(400MHz, CDCl3): δ 4.85, 4.96 (ABq, J = 11.4 Hz, 4H), 7.35 (t, J = 7.6 Hz, 2H), 7.43 (d, J = 8.0
Hz, 4H), 7.59 (m, 12H). 13C NMR (100 MHz, CDCl3) δ 76.5, 127.1, 127.3, 127.5, 128.8, 129.2,
135.5, 140.6, 141.4.
1
Bis(4-Chlorobenzyloxy) disulfide (0.23g, 92%) as off white solid mp. 45-46°C. H NMR
(400MHz, CDCl3): δ 4.75, 4.86 (ABq, J = 11.4 Hz, 4H), 7.30 (d, J = 7.2 Hz, 4H), 7.33 (d, J = 7.2
Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 75.8, 128.8, 130.0, 134.4, 134.9.
Bis(4-Methoxybenzyloxy) disulfide (0.19g, 76%) as a white low melting solid. mp. 20-22°C.1H
NMR (400MHz, CDCl3): δ 3.81 (s, 6H),4.73, 4.84 (ABq, J = 11.0 Hz, 4H), 6.88 (d, J = 8.4 Hz,
13
4H), 7.24 (d, J = 8.4 Hz, 4H). C NMR (100 MHz, CDCl3) δ 55.3, 76.5, 113.9, 128.8, 130.5,
159.8.
Bis(4-Methylbenzyloxy) disulfide (0.21g, 84%) as an off white low melting solid mp. 25-27°C.
1H NMR (400MHz, CDCl3): δ 2.35 (s, 6H), 4.76, 4.87 (ABq, J = 11.2 Hz, 4H), 7.17 (d, J = 8.0
Hz, 4H), 7.24 (d, J=8.0 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 21.3, 77.2, 128.8, 129.2, 133.6,
138.2.
Bis(4-Benzyloxy) disulfide (0.20g, 80%) as an off white solid mp. 47-49°C. 1H NMR (400MHz,
13
CDCl3): δ 4.80, 4.92 (ABq, J = 11.4 Hz, 4H), 7.17 (m, 10H). C NMR (100 MHz, CDCl3) δ
76.8, 128.4, 128.5, 128.6, 136.6.

1
Bis(4-Tertbutylbenzyloxy) disulfide (0.19g, 72%) as clear liquid. H NMR (400MHz, CDCl3):
δ 1.32 (s, 18H), 4.77, 4.89 (ABq, J = 11.2 Hz, 4H), 7.29 (d, J = 8.0 Hz, 4H), 7.38 (d, J = 8.0 Hz,
4H). 13C NMR (100 MHz, CDCl3) δ 31.3, 34.6, 76.7, 125.5, 128.6, 133.6, 151.6.
1
Bis(4-Trifluorobenzyloxy) disulfide (0.17g, 68%) as clear liquid. H NMR (400MHz, CDCl3):
δ 4.85, 4.96 (ABq, J = 12.0 Hz, 4H), 7.44 (d, J = 7.2 Hz, 4H) 7.62 (d, J = 7.2 Hz, 4H). 13C NMR
(100 MHz, CDCl3) δ 75.7, 124.0 (J = 272.1 Hz), 125.5 (J = 3.8 Hz), 128.4, 130.6 (J = 32.2)
140.4.
Bis(4-Cyanobenzyloxy) disulfide (0.12g, 67%) as a white-yellow low melting solid mp. 27-
29°C. 1H NMR (400MHz, CDCl3): δ 4.84, 4.96 (ABq, J = 12.6 Hz, 4H), 7.44 (d, J = 7.6 Hz, 4H)
7.44 (d, J = 7.2 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 75.4, 112.0, 118.6, 128.6, 132.4, 141.6.
Bis(4-Phenoxybenzyloxy) disulfide (0.65g, 88%) as an off white low melting solid mp. 24-
1
26°C. H NMR (400MHz, CDCl3): δ 4.77, 4.88 (ABq, J = 11.4 Hz, 4H), 6.98 (d, J = 8.4 Hz,
4H), 7.01 (d, J = 7.6 Hz, 4H), 7.13 (t, J = 7.2 Hz, 2H), 7.33 (m, 8H). 13C NMR (100 MHz,
CDCl3) δ 76.3, 118.6, 119.1, 123.5, 129.8, 130.5, 131.3, 156.8, 157.7.
Computational Procedures
Standard ab initio and density functional theory calculations were performed using Gaussian
09 [28] and Molpro 2009.1 [29] software packages. For non-substituted dibenzyloxy disulfide, a
full conformational search at 120° resolution was performed in the gas phase at the M06-2X/6-
31+G(d) level of theory. Three distinctly different conformations were identified and considered
further for the various substituted dibenzyloxy disulfides. Accurate geometries, frequencies
(scaled by the recommended scaling factors [30]) and electronic energies were obtained using

the M06-2X/6-31+G(d) method. For non-substituted dibenzyloxy disulfide, the M06-2X/6-
31+G(d) relative energies of the three conformers were additionally benchmarked at higher
levels – M06-2X/aug-cc-pVTZ and the composite ab initio G3(MP2)-RAD(+) [31] method
(Supplemental Material). Gas-phase entropies and thermal corrections at 25 °C were calculated
using the standard textbook formulae [32] for the statistical thermodynamics of an ideal gas
under the harmonic oscillator approximation in conjunction with the optimized geometries and
scaled frequencies. Free energies of solvation in DMSO and benzene were calculated using
UAKS-CPCM/B3LYP/6-31+G(d) method in conjunction with relaxed solution-phase geometries
[33]. Relative Boltzmann average concentrations of the each of the three considered conformers
were evaluated according to the equation:
ꢆꢇ
ꢈ
ꢉꢊ
ꢄꢅ
ꢀꢁꢂꢀꢃ =
ꢆꢇ
ꢈ
ꢉꢊ
ꢃ ꢄꢅ
ꢋ
where∆Gi is the relative free energy of the i-th conformer, R is the universal gas constant and T is
the absolute temperature.
Results and discussion
Synthesis
Synthesis of the library was performed as previously described [4, 13, 16-18]. In short,
two equivalents of a desired commercially available benzyl alcohol (with the exception of 4-
phenoxybenzyl alcohol, which was synthesized from its corresponding acid following published
procedure [27]) with two equivalents of Et3N and one equivalent of S2Cl2 were reacted in
CH2Cl2 for 2 h at 0oC than 3 h at room temperature (Scheme 1). Compounds were purified via
column chromatography and stored in a freezer until use. Even when stored cold, slight

decomposition was occasionally observed, and these particular dibenzyloxy disulfides were re-
purified prior to any NMR studies. We next ran 1H-NMR on all ten dibenzyloxy disulfides in six
different aprotic deuterated solvents (i.e. CDCl3, d6-DMSO, d6-Acetone, d3-Acetonitrile, C6D6,
and d8-Toluene), as solvents such as D2O and CD3OD cause rapid decomposition of the
compounds.
Scheme 1: Synthesis of dibenzyloxy disulfides
NMR spectra chemical shift
We began by examining the placement of the center of the ABq (Figure 1) versus the
electronic nature of the para-substituent. [For convenience, the chemical shifts, center of the
ABq, geminal coupling, and the ∆ of center of doublets in Hz of the ten dibenzyloxy disulfides in
the six solvents are presented in Tables 1-6]. Unsurprisingly, there is a linear correlation with
Hammett’s constant [33] due to the fact that we were analyzing the benzylic protons (Figure 2).
Interestingly, with CDCl3, d6-DMSO, d6-Acetone, and d3-Acetonitrile, the expected downfield
shift is observed as the ring substituent’s electron withdrawing ability increases (i.e. higher
Hammett’s constant values) (Figure 2); however with C6D6, and d8-Toluene a completely
opposite trend was observed (Figure 2). For example, in d6-Acetone, 4-nitrodibenzyloxy
disulfide’s benzylic protons were centered at 5.103ppm, whereas in C6D6, these protons were at
3.91 ppm. Conversely, in d6-Acetone, 4-methoxydibenzyloxy disulfide’s methylene protons were
centered at 4.82 ppm, whereas in C6D6, these protons were at 4.29 ppm. Indeed, in both cases,
the protons were further downfield compared tod6-Acetone (vide infra); however, it was the fact
that the shifts were near the extremes and in opposite directions that caught our interest. The

reversal of downfield shift in the presence of aromatic solvents has been previously observed
[26]. It has been hypothesized that this is due to the H-bonding ability of the benzylic protons.
As the electron withdrawing nature of the para-substituent increases (i.e. higher Hammett’s
constant values) the benzylic protons become more positively charged and will participate as a
H-bond donor with the lone-pairs of the deuterated solvents (Figure 3a). The same phenomena
exists in an aromatic solvent, however instead of lone pairs H-bonding with the benzylic protons,
it is believed that the cloud of π electrons of C6D6 or d8-Toluene is responsible (Figure 3b).
When this occurs, the proton would fall not in an anisotropic region of the local magnetic field of
the aromatic solvent, but instead in the shielded region. Thus, as the electron withdrawing nature
of the para-substituent increases, enhanced H-bonding with the solvent causes the benzylic
protons to shift further upfield.
(a)
(b)
F
F
C
B
C
B
E
A
E
D
A
D
G
G
1
Figure 1: Expanded H-NMR of ABq for 4-nitrodibenzyloxy disulfide in (a) CDCl3 and (b)
benzene. A-D represents signal placement in ppm; E represents center of ABq in ppm: F
represents coupling constant in Hz; and G represents ∆of center of doublets in Hz.
Table 1:1H-NMR values of dibenzyloxy disulfides inCDCl3

4-X
Nitro
A (ppm) B (ppm) C (ppm) D (ppm) E (ppm) F (Hz)
G (Hz)
49.0
5.03
4.97
4.88
4.86
4.88
4.93
4.91
4.97
4.98
4.90
5.00
4.94
4.85
4.83
4.85
4.90
4.88
4.95
4.95
4.87
4.91
4.86
4.77
4.75
4.77
4.82
4.79
4.86
4.86
4.79
4.88
4.83
4.74
4.72
4.75
4.79
4.76
4.83
4.83
4.76
4.95
4.90
4.81
4.79
4.81
4.86
4.83
4.91
4.90
4.83
12.6
11.4
11.4
11.0
11.2
11.4
11.2
12.0
12.6
11.4
Biphenyl
Chloro
Methoxy
Methyl
Hydrogen
Tert-butyl
CF3
44.2
43.0
41.8
43.2
43.0
46.8
44.0
48.6
43.8
Cyano
Phenoxy
Table 2: 1H-NMR values of dibenzyloxy disulfides ind6-DMSO
4-X
Nitro
A (ppm) B (ppm) C (ppm) D (ppm) E (ppm) F (Hz)
G (Hz)
5.10
5.00
4.93
4.85
4.88
4.94
4.89
5.05
5.04
4.91
5.07
4.97
4.90
4.82
4.85
4.91
4.86
5.02
5.01
4.88
5.01
4.92
4.84
4.76
4.79
4.85
4.80
4.97
4.95
4.82
4.98
4.89
4.82
4.73
4.76
4.82
4.77
4.94
4.92
4.80
5.04
4.94
4.87
4.79
4.82
4.88
4.83
4.99
4.98
4.85
12.2
11.4
11.2
11.0
11.6
11.2
11.2
12.0
12.6
11.2
35.0
33.0
33.6
33.8
34.8
34.8
35.6
32.4
34.2
34.0
Biphenyl
Chloro
Methoxy
Methyl
Hydrogen
Tert-butyl
CF3
Cyano
Phenoxy
Table 3: 1H-NMR values of dibenzyloxy disulfides ind6-Acetone
4-X
Nitro
A (ppm) B (ppm) C (ppm) D (ppm) E (ppm) F (Hz)
G (Hz)
5.17
5.02
4.97
4.89
4.92
4.98
4.94
5.11
5.10
4.96
5.14
5.00
4.94
4.86
4.89
4.95
4.91
5.08
5.07
4.93
5.07
4.93
4.88
4.79
4.82
4.88
4.84
5.01
5.00
4.86
5.04
4.90
4.85
4.76
4.79
4.85
4.81
4.98
4.97
4.84
5.10
4.96
4.91
4.82
4.86
4.92
4.87
5.04
5.04
4.90
12.2
11.6
11.6
11.2
11.4
11.4
11.2
12.2
12.6
11.2
40.2
37.2
37.6
36.8
38.2
38.2
39.6
38.6
39.8
37.6
Biphenyl
Chloro
Methoxy
Methyl
Hydrogen
Tert-butyl
CF3
Cyano
Phenoxy
Table 4: 1H-NMR values of dibenzyloxy disulfides ind4-Acetonitrile
4-X
Nitro
Biphenyl
Chloro
Methoxy
Methyl
A (ppm) B (ppm) C (ppm) D (ppm) E (ppm) F (Hz)
G (Hz)
5.06
5.00
4.91
4.85
4.88
5.02
4.97
4.88
4.83
4.85
4.96
4.90
4.81
4.76
4.78
4.92
4.87
4.78
4.73
4.76
4.99
4.93
4.84
4.79
4.82
12.6
11.4
11.6
11.2
11.2
40.2
37.8
38.4
37.6
38.4

Hydrogen
Tert-butyl
CF3
Cyano
Phenoxy
4.94
4.90
5.02
5.00
4.90
4.91
4.87
4.99
4.97
4.87
4.84
4.80
4.92
4.90
4.81
4.81
4.77
4.89
4.87
4.78
4.88
4.84
4.95
4.93
4.84
11.6
11.4
12.2
12.4
11.2
38.8
38.2
38.2
39.2
37.2
Table 5: 1H-NMR values of dibenzyloxy disulfides ind6-Benzene
4-X
Nitro
A (ppm) B (ppm) C (ppm) D (ppm) E (ppm) F (Hz)
G (Hz)
3.99
4.33
4.06
4.36
4.37
4.32
4.42
4.11
3.97
4.28
3.96
4.30
4.04
4.33
4.34
4.29
4.39
4.08
3.93
4.25
3.85
4.20
3.94
4.24
4.24
4.20
4.30
3.98
3.83
4.16
3.82
4.17
3.91
4.21
4.21
4.17
4.27
3.95
3.80
4.13
3.91
4.25
3.99
4.29
4.29
4.24
4.35
4.03
3.88
4.20
12.4
11.8
11.6
11.0
11.4
11.4
11.4
12.0
12.2
11.2
56.8
51.8
48.8
46.6
49.4
48.2
51.0
52.4
55.4
49.2
Biphenyl
Chloro
Methoxy
Methyl
Hydrogen
Tert-butyl
CF3
Cyano
Phenoxy
Table 6: 1H-NMR values of dibenzyloxy disulfides ind8-Toluene
4-X
Nitro
A (ppm) B (ppm) C (ppm) D (ppm) E (ppm) F (Hz)
G (Hz)
4.41
4.78
4.49
4.72
4.72
4.69
4.77
4.51
4.38
4.66
4.38
4.75
4.46
4.69
4.69
4.65
4.75
4.48
4.34
4.63
4.27
4.65
4.36
4.60
4.60
4.56
4.65
4.37
4.23
4.54
4.24
4.62
4.33
4.57
4.57
4.53
4.62
4.34
4.20
4.51
4.33
4.70
4.41
4.64
4.65
4.61
4.70
4.43
4.29
4.59
12.6
11.2
11.6
10.8
11.0
11.4
11.2
11.8
12.2
11.2
57.8
52.4
49.6
47.2
49.8
48.6
51.6
54.2
57.0
49.6
Biphenyl
Chloro
Methoxy
Methyl
Hydrogen
Tert-butyl
CF3
Cyano
Phenoxy

5.5
5.25
5
y = 0.225x + 4.904
4.75
4.5
4.25
4
d6-Acetone
d6-Benzene
y = -0.418x + 4.210
3.75
3.5
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
Hammett's Constants
Figure 2:1H-NMR chemical shift of the center of the ABq for the library of dibenzyloxy
disulfides in d6-Acetone and d6-Benzene compared to Hammett’s Constants.Line-of-best-fit is a
guideto the eye.
Figure3: H-bonding interaction of the benzylic protons with (a) the lone pair of electrons on
polar aprotic solvents and (b) pi-cloud of aromatic solvents.

Theoretical Calculations
Typical measures of the H-bond strength are: (1) the distances C–H and H–Y in H-bonded
complex C–H…Y (where Y is an electronegative proton acceptor); (2) energy difference
between the H-bonded complex and infinitely separated components (for intermolecular H-
bonds) or between H-bonded and non-H-bonded conformers (for intramolecular H-bonds); (3)
the red shift of the C–H stretch. These are the characteristics we have focused on in order to
probe for the intramolecular H-bonding in the studied set of dibenzyloxy disulfides. This has
been done for the three key conformers we have identified for non-substituted dibenzyloxy
disulfide (Figure 4) – as well as their variously substituted derivatives in gas and solution
phases. The three conformers are denoted ddh1 (highest in energy), ddh2 and ddh3 (lowest in
energy).
All three conformers appear to involve interactions that potentially discriminate between the
two hydrogens of thebenzylic CH2 group. Conformer ddh1 affords an overlap between the lone
pairs on the sulfur atoms and the S–Oσ* (see Figure 1 of the Supplementary Material) at a
distance of approx. 3 Å (Table 7). However, this conformer is not the lowest energy conformer
as there are two distinctly different conformations that are more stable (see Table 1 in the
Supplementary Information). Conformer ddh2 involves interaction between the hydrogen of CH2
group with the π-density of the phenyl ring; this interaction is stronger in the presence of
electron-donating substituents (such as OCH3, allowing for a ca. 2.5 Å H-bonding to the ring,
seeFigure 5a), and is reduced by the electron-withdrawing substituents that promote π-stacking
of two phenyl rings instead (e.g. NO2, correspondingly longer H-bonding of ca. 3.5 Å, see
Figure 5b). This is also demonstrated by the H-bond lengths in Table 7. Finally, conformer
ddh3 involves a 6-membered cycle comprising intramolecular H-bond to the oxygen atom,

approx. 2.8-3.0 Å long. This conformer is universally the global minimum for all derivatives in
the gas phase. We note that there are no appreciable differences in the lengths of C–H bonds
between the different conformers and substituents.
As noted above, substituents with greater Hammett’s constants (stronger electron acceptors)
promote π-π stacking of the two rings over the competitive H-π interaction. The π-π stacking
affords greater energetic benefit than the H-bonding, and hence the relative energy of conformer
ddh2 with electron-withdrawing substituents X is lower than with the electron-donating groups
(see Figure 2 of the Supplementary Information). In other words, the protons are deshielded as
the π-density is involved in a competing interaction.
Solvation tends to disrupt the intramolecular H-bonding, as has been noted earlier. π-
Stacking and interaction of H with the aromatic electron density in conformer ddh2 disappears in
both benzene and DMSO. Nonetheless, in the solvent-phase analogue of the conformer ddh2
benzylic protons are still in the shielded region of the opposite aromatic rings. Moreover, relative
weight of this conformer increases upon solvation compared to that of ddh3 (Table 7). Finally,
the disrupted H-bonds are formally less elongated upon solvation in less polar benzene compared
to DMSO. In summary, these observations are consistent with the fact that in less polar solvents
the protons are interacting with the π-density to a greater extent, i.e. are shielded and hence their
signals are shifted upfield.

gas
DMSO
Benzene
Figure 4:Optimized geometries of the three conformers in the gas and solution phases, X=H. H-
bonds of interest are denoted with purple dash lines.

Figure 5: Gas-phase M06-2X/6-31+G(d) optimized geometries of dibenzyloxy disulfides with
X=OCH3 (a) and X=NO2 (b), shown in two projections.
Table 7:M06-2X/6-31+G(d) free energies at 25 °C (in kJ mol-1), H-bond lengths (in Å) and
relative Boltzmann concentrations (in %) of the three conformers for a series of substituted
dibenzyloxy disulfides.
gas
DMSO
benzene
ddh
#
X
H-
bond
H-
bond
H-
bond
∆G
%
∆G
%
∆G
%
3.0
12.6
1
1
3.2
6.0
4.4
0.0
0.0
3.8
0.4
8.0
1.0
0.0
7
14
79
48
11
41
2
3.2
6.9
5.1
0.0
1.3
5.3
0.0
7.2
0.2
0.0
5
11
84
35
7
H
1
2
3
1
2
3
1
2
3
2.7
2.9
3.0
2.5
2.9
2.9
3.4
2.9
11.3
0.0
5.1
9.5
0.0
11.6
5.6
0.0
5.9
3.4
3.3
5.7
3.5
3.3
5.8
3.5
5.7
3.2
3.2
5.6
3.4
3.2
5.7
3.3
98
11
2
Cl
87
01
10
90
58
3
CN
39
59
47
50

3.0
3.6
2.8
2.9
3.6
2.8
3.0
2.6
2.9
3.0
2.7
2.9
3.0
2.5
2.9
3.0
2.6
3.0
3.0
2.5
2.8
9.6
3.2
2
21
77
1
3.2
5.6
3.4
3.2
5.8
3.4
3.2
5.7
3.4
3.2
5.7
3.6
3.3
5.7
3.4
3.2
5.9
3.6
3.3
5.8
3.5
9.1
0.0
0.7
6.6
2.2
0.0
4.3
2.7
0.0
3.6
6.8
0.0
4.2
8.7
0.0
7.4
7.8
0.0
11.6
15.4
0.0
1
56
43
5
3.2
5.8
3.4
3.2
5.7
3.2
3.2
5.7
3.2
3.2
5.7
3.3
3.3
5.6
3.4
3.1
5.5
3.3
3.2
5.6
3.5
8.2
0.1
0.0
8.1
4.4
0.0
2.5
1.0
0.0
2.6
5.6
0.0
4.7
9.3
0.0
5.6
6.8
0.0
10.3
14.3
0.0
2
49
49
3
NO2
CF3
CH3
tBu
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
0.0
12.0
8.4
3
27
68
12
22
66
18
45
77
15
3
14
83
18
33
49
24
7
96
3
0.0
8.5
6.9
6
91
4
0.0
7.7
10.6
0.0
1
95
3
69
13
2
9.1
OCH3
13.4
0.0
0
97
1
82
5
85
9
11.2
12.0
0.0
Ph
1
4
6
98
0
91
1
85
2
14.5
18.5
0.0
OPh
0
0
0
100
99
98
NMR spectrageminal coupling and proton separation
We also used theory to study the geminal coupling constants for our ten dibenzyloxy
disulfides. Regardless of the solvent employed, there was a linear correlation observed with
Hammett’s constants. As the electron withdrawing ability increased (i.e. higher Hammett’s

constant value) the coupling value increases to a high of 12.6 Hz for nitro substituents to a low of
10.8 Hz for methoxy. Very minor fluctuations were observed between the various solvents.
In addition, we examined how similar the two benzylic protons are by comparing the
difference (in Hz) of the center of their corresponding doublets. Regardless of which solvent was
used, all were logarithmically related to the solvents dielectric constant and polarity index. The
more polar the solvent, the more similar the benzylic protons are spectrally. On the contrary, the
less polar solvents show greater differences between the benzylic protons. This trend can be
attributed to the fact the lower polarity solvents will prevent free rotation in the molecule, as
reflected in the H-bonding distances (Table 7). In virtually every case, whether in the ddh1,
ddh2, or ddh3 conformation, the intramolecular H-bonding length was shorter in benzene
compared to DMSO. This suggests a more compact solution structure of the dibenzyloxy
disulfides in less polar solvents.In addition, from Table 7, the surface area minimizing
conformation, ddh3, was the global minimum for all ten dibenzyloxy disulfides in benzene.
However, in DMSO this was not the case universally, in particular with para-Cl and para-NO2,
where conformations ddh1 and ddh2 were the minima, respectively.
Finally, we analyzed the difference between the two benzylic protons as a function of the
actual substituent on the para-position. By graphing with either Hammett’s Constant [34] or
Swain and Lupton’s R-value [35], no visible trends were observed. However, when graphing with
Swain and Lupton’s F-value [35], we observed a parabolic relationship (Figure 6and 7). This
was unsurprising; we have observed this parabolic phenomenon with Swain and Lupton’s F-
value in previous studies, particularly with the analogous dibenzylicdialkoxy disulfides which
underwent both photolytic [16] and thermolytic [17] decomposition at rates that parabolically
correlated to F-values, in addition to a bis(benzyl) sulfites photolytic decomposition study [36].It

can be rationalized that a substituent with a high F-value, such as nitro, withdraws the electron
cloud towards it and away from the benzylic protons, hence allowing for the proton, that is
participating with intramolecular H-bonding, to do so at a greater extent. As the magnitude of the
F-value decreases, this polarization difference decreases, “bottoming-out” with methoxy [37] at
an F-value of 0.29. Substituents with F-values lower than methoxy, such as t-Bu, Me, etc.,
donates its electron density towards the ring or the oxygen which causes it to participate in H-
bonding, as an acceptor, to a greater extent. In both of these extremes the benzylic protons are
situated in the shielded region of the aromatic ring and thus increasing it electronic environment
more so than its geminal hydrogen neighbor.
1
Figure 6: H-NMR chemical shift separation of the two doublets of the library of dibenzyloxy
disulfides in CDCl3 compared to Swain and Lupton’s F-value.Line-of-best-fit is a guideto the
eye.

1
Figure 7: H-NMR chemical shift separation of the two doublets of the library of dibenzyloxy
disulfides in d6-Acetone compared to Swain and Lupton’s F-value.Line-of-best-fit is a guideto
the eye.
Conclusion
The effect of electron donating and withdrawing groups attached to the dibenzyloxy disulfide has
been shown to not only affect the chemical shift of the benzylic protons, but also the
geminalcoupling. We also observed that there is a linear relationship with Hammett’s constants
with all solvents used, and that the trend is in the opposite direction if the solvent involves
aromatic fragments. In addition, as the polarity of the solvent decreases the downfield chemical
shift of the benzylic protons also decreases. These findings were rationalized via quantum-
chemical modeling on the basis of the competition between several conformations of the
dibenzyloxy disulfides, differing in the H-bonding modes, and affected variously by both the
nature of the para-substituent and the solvent polarity. Finally, we observed that the difference
between the two benzylic protons as a function of the substituent on the para-position is
parabolically related to Swain and Lupton’s F-value.

Acknowledgments.ESand RP would like to thank the Niagara UniversityAcademic Center for
Integrated Sciences, as well as the RochesterAcademy of Science for financial support. RP
would also like tothank Western New England University, College of Pharmacy forgenerous
financial support.MLC gratefully acknowledges generous allocations of supercomputing time on
the National Facility of the Australian National Computational Infrastructure and an Australian
Research Council Future Fellowship
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Chemical shift and coupling constant analysis of dibenzyloxy disulfides
Eric G. Stoutenburg,bGannaGryn’ova,c Michelle L. Coote,cand Ronny Priefera,b*
a College of Pharmacy, Western New England University, Springfield, MA 01119, USA
bDepartment of Chemistry, Biochemistry, and Physics, Niagara University, NY 14109, USA
c Research School of Chemistry, Australian National University, Canberra ACT0200, Australia
*Tel: 413-796-2438; Fax: 413-796-2266; email: ronny.priefer@wne.edu
Graphical Abstract
F
C
B
E
A
D
G

Chemical shift and coupling constant analysis of dibenzyloxy disulfides
Eric G. Stoutenburg,bGannaGryn’ova,c Michelle L. Coote,cand Ronny Priefera,b*
a College of Pharmacy, Western New England University, Springfield, MA 01119, USA
bDepartment of Chemistry, Biochemistry, and Physics, Niagara University, NY 14109, USA
c Research School of Chemistry, Australian National University, Canberra ACT0200, Australia
*Tel: 413-796-2438; Fax: 413-796-2266; email: ronny.priefer@wne.edu
Highlights
- The chemical shift and coupling of a library of dibenzyloxy disulfides were analyzed
- A linear relationship with Hammett’s constants in all solvents was observed
- The benzylic protons are parabolically related to Swain and Lupton’s F-value.