Solvent Mol. Wt.

Density BP MP
Methylene Chloride 84.83 1.325 40
Chloroform 119.38 1.492 61
Carbon Tetrachloride 153.82 1.594 77 23

Methanol 32.04 0.791 65

Ethanol 46.07 0.789 78 130
Isopropanol 60.1 0.785 82 90
t-Butanol 74.12 0.803 83 25
Ethylene Glycol 62.07 1.113 197

Diethyl Ether 74.12 0.706 35

Tetrahydrofuran 72.11 0.886 67 108
Dimethoxyethane 90.12 0.867 85 58
p-Dioxane 88.11 1.034 101 45

Pentane 72.15 0.626 35

Hexane 86.18 0.659 69
Heptane 100.21 0.684 98 91

Benzene 78.11 0.874 80 5

Toluene 92.14 0.867 111 93

Dimethylformamide 73.1 0.944 153 61

Dimethylacetmide 87.12 0.937 158 20
Hexamethylphosphoramide 179.2 1.03 231

Dimethylsulfoxide 78.13 1.101 189 18

Triethylamine 101.19 0.726 89

Diisopropylamine 101.19 0.722 84
Pyridine 79.1 0.978 115
Tetramethylenediamine 116.21 0.77 121
2,6-Lutadine 107.16 0.92 144
OR: http://www.sigmaaldrich.com/sigma-aldrich/areas-of-interest/chemistry/solvents/learning-center/nomo-assets.html
Cooling Bath Compositions

from "The Chemist's Companion," Gordon, A. J.; Ford, R. A.; Wiley: New York, 1972

-25

TC % o-xyl % p-xyl
-35
-30 83 17
-35 75 25
-45
-40 66 34
TC

-45 58 42
-55 -50 50 50
-55 42 58

-65
-60 33 67
-65 25 75
-70 17 83
-75
0.0 0.2 0.4 0.6 0.8 1.0
volume fraction of o-xylene

Figure 1. Cooling bath temperatures for mixtures of o- and p-xylene and dry ice
(from Phipps & Hume, J. Chem. Educ. 1968, 45, 664)
 Alan M. Phipps
Boston College
Chestnut Hill, Massachusetts
General Purpose Low Temperature
and David N. Hume
Massachusetts Institute of Technoloqv
Dry-Ice Baths
Cambridge, Massachusetts 62139
- I
A great many methods have been de- is not useful since it forms a thick sludge at its melting
scribed for thc preparation and maintenance of low point ( - 2 6 T ) but mixtures of o- and m-xylene give low
temperature baths, and the field has been extensively viscosity baths with an approximately linear tempera-
reviewed recently.' Among the simpler techniques, the ture dependence on composition (see figure). Analyti-
liquid nitrogen-organic solvent slush bath has become cal grade acetonitrile gives a useful bath a t -4ZC,
increasingly popular and a compilation of 86 such baths while temperatures between -4ZC and -51C are
has been published by R ~ n d e a u . ~ obtainable with acetonitrile containing 0-3% acrylo-
We have found it convenient to employ an even nitrile. Technical grade acetouitrile was found to give
simpler bath composed of solid carbon dioxide and a reproducible bath at -46'C. Some mixtures do not
organic solvents or solvent mixtures having a freezing give baths in which the temperature varies normally
point above -7SC. Solid lumps of dry ice in a with composition. Mixtures of 3-hept,anone or cyclo-
Dewar flask containing one of several solvent systems hexanone with acetone act as if they were acetone-dry
afford a bath of rcasonahly uniform temperature and ice baths containing the solidified higher-melting ketone.
low viscosity. Such a bath is not, of course, a system a t A similar result ensues for mixtures of n-octane and
equilibrium; a layer of solid solvent appears to form iso-octane.
over the dry ice and a steady state is obtained with Because of the simplicity of the technique, the easy
slow evolution of gaseous CO1. The baths are generally availability of dry ice and its low cost, and the readiness
reproducible to + 1C if they are agitated intermittantly with which a desired temperature may be obtained, the
and if only a small excess of dry ice is used (e.g., 2 4 cc use of dry ice baths is worth consideration even where
per 200 ml in a standard 265 ml (one pint) Dewar flask). equipment for handling liquid nitrogen is available.
Many of the solvents cited by Rondeau may be em- This work was supported in part through funds pro-
ployed, although the bath temperature is not always vided by the U.S. Atomic Energy Commission under
the melting point of the solvent. Carbon tetrachlo- Contract AT(30-1)-905.
ride (-23"C), 3-hcptanone (-3S0C), cyclohexanone
(-46C) and chloroform (-61C) provide reproducible
low viscosity baths at the temperature indicated.
Many solvents which have appropriate melting
points may be unsatisfactory because they solidify, or
becon~ehighly viscous at low temperatures (c.g., n-
octane, alcohols) or are noxious. Certain solvents,
however, when mixed in the right proportions provide a
considerable range of stable bath temperatures together
with low viscosity. Of especial interest to this labora-
tory has been the attainment of temperatures through-
out the liquid range of ammonia (-78' to -33"C), and
we have fonnd that most of this range can be covered
with mixtures of ovtho and nzeta-xylene. Pure o-xylene

-80
NABSLER, J., "Experimental Techniques for Low Boiling Sol- 0 0.2 0.4 0.6 0.8
vents," Academic Press, New York, N . Y . , 1966, "Vol. I.- Volume Froction of 0-rylene
The Chemistry of Non-Aqueous Solvents," (Editor: J. J. LAG-
OWSKI), p. 213.
RONDBAU, R. E., 3. Chem. and Eng. Data, 11,124 (1966). Stecldy stole temperature of dry-ice--xylene, m-xylem mixtvro~.

664 / Journal o f Chemicol Education

LITERATURE CITED
(1) Butler, W.P., Ryan, R.L., Methods of Analysis, Pub. No.
341 (Rev, 2-60), U.S. Treasury Dept. Internal Revenue
Service, Washington, February 1960.
. , Davis, T.W.C.. Farmilo. C.G., Genest, K., Bull. Narcotics
(2)
U . N.Dept. Sokal Affairs 14, 47, (1962).
(3) Fulton, C.C., Zbid., 5, 27 (9153).
(4) Lerner, M., Anal. Chem. 32,198 (1960).
(5) Small, L.F., Lutz, R.E., Chemistry of theopium Alkaloids,
p. 154, U. S. Treasury Dept., Public Health Service, Wash-
ington, 1932.
RECEIVED
for review July 19, 1965. Accepted October 6, 1965.

Slush Baths

R. E. RONDEAU

Air Force Materials Laboratory, Wright-Patterson AFB, Ohio

The preparation of constant temperature slush baths is described and 86 common slush baths are
tabulated in order of decreasing temperature from 1 3 to -160 C. Some experimental applica-
tions of these cooling agents are also described.

THE
ACCOMPANYING TABLE lists 86 common solvents
and their slush bath temperatures in order of decreasing temper-
ature from 13 to -160 C. A slush bath can be defined as a Table I. Materials for Low Temperature Slush Baths (with
coolant consisting of a low melting liquid which has been parti- Liquid Nitrogen)
ally frozen by mixing with liquid nitrogen. It is prepared by
slowly pouring liquid nitrogen into a Dewar flask containing Solvent Tcmp., C. Solvent Temp., C.
the solvent while continuously stirring the mixture until the
desired consistency is obtained. When properly mixed, the con-
p-Xylene 13 + l o Ethyl acetate -84
p-Dioxane 12 n-Hexyl bromide -85
sistency of the crystallized solvent is that of a fluid slush which Cyclohexane 6 Methyl ethyl ketone -86
will maintain a constant temperature as long as the bath is Benzenc R Acrolein -88
kept slushy by occasionally blending in more liquid nitrogen. Formamide 2 Amyl bromide -88
Rondeau and Harrah (2) made use of an ethyl bromide Aniline -6 +Butanol a - 89
slush bath in measuring the melting point of 3-hexyne. The Diethylene glycol - 15,
5 s-Butanol -89
temperature rise 01 this particular slush was approximately Cy cloheptane - 12 Isopropyl alrohol a -89
0.2 C. per minute when left standing a t room temperature in Methyl benzoate - I2 Nitroethane -90
Benzonitrile -13 Heptane -91
an uncovered 47 X 125 mm. Dewar flask. Benzyl alcohol - 15 %-Propyl acetate -92
With certain solvents, such as diethylene glycol and some of Propargyl alcohol - 17 2-Nitropropane -93
the alcohols, a heavy sirup is formed. Although not a5 conven- 1,2-Dichlorobenzene - 18 Cyclopentane -93
ient t o handle, a viscous bath is still useful for cooling purposes. Tetrachloropthyleue -22 Ethyl benzcne -94
The solvents in Table I that form a highly viscous coolant have Corbon tetrachloride -23 Hexane -94
heen marked with a n asterisk. 1,3-Dichlorobenzene - 25 Toluene -95
The temperatures listed in the table are given to the nearest Xitromcthane -29 Cumene - 97
degree centigrade. Measurements were made with a calibrated o-Xylene - 29 Methanol -98
toluene thermometer for temperatures above -95 C. and Bromobenxene -30 Methyl acetate - 98
with a calibrated pentane thermometer for readings below
Iodobenmie -31 Isobutyl acetate -99
nt-Toluidine - 32 Amyl chloridc -99
-95 C. All of the solvents used were reagent grade chemicals. Thiophene -38 Butyraldehyde - 99
In general, the purer the compound, the narrower its dush .hetonitrile - 11 Propyl iodide -101
bath temperature range; however, the variation in temperature Pyridine -42 Butyl iodide - 103
with purity has not been studied. Benzyl bromide -43 Cyclohexene - 104
Slush baths are especially useful in degassing liquids and Cyclohexyl rhloride -44 s-Butyl amine - 105
fractionating mixtures. Irewton (1) has desigr.ed a low tempera- Chlorobenzenc - 45 Isooctane - 107
ture reflux condenser in which the liquid can he refluxed under m-Xylene -47 1-Nitropropane - 108
vncuum a t a temperature where its vapor preqsure is negligible.
n-Butyl amine - 50 Ethyl iodide - 109
Benzyl acetate - 52 Propyl bromide -110
The method requires the use of a constant temperature cooling n-Octane - 56 Carbon disulfide -110
bath to maintain the desired temperature. The convenience Chloroform - 63 Butyl bromide -112
of a table of slush bath temperatures in using such a technique Methyl iodide - 66 Ethyl alcohol Q - 116
is readily apparent. tert-Butyl amine - 68 Isoamyl alcohol Q -117
Volatile mixtures can be separated in a vacuum system by Trichloroethylene - 73 Ethyl bromide -119
fractional condensation through a series of three traps cooled Isopropyl acetate -73 Propyl chloride - 123
to successively lower temperature. Here again, the judicious o-Cymene - 74 Butyl chloride - 123
selection of the proper slush bath temperature determines the p-Cymene - 74 Acetaldehvde - 124
efficiency of the separation.
Butyl acetate -77 Methyl r&lohcxane - 126
Isoamyl aretate -79 n-Propanol 5 - 127
Acrylonitrile -82 n-Pentane -131
LITERATURE CITED n-Hexyl chloride -88 1,5-Hexadiene - 141
(1) Newton, AB., Anal. Chem. 28, 1214 (1956).
Propyl amine -83 i.w-Pen tane - 160
(2) Rondeau, R.E., Harrah, LA., J. CHEM.ENQ.~ ) A T A 10, 84
(1965). a High viscosity slush.
RECEIVED
for review April 20, 1965. Accepted September 16, 1965. -
194 JOURNAL OF CHEMICAL A N D ENGINEERING D A T A
TLC VISUALIZATION SOLUTIONS

Ultraviolet Light

Commercial TLC plates are impregnated with a fluorophor, which can be quenched by certain
compounds. In this event, the analyte appears as a dark spot (non-fluorescing) against a bright
background when irradiated with short-wavelength UV light (254 nm). Fluorescence can be quenched
by extended systems as well as amines and thiols. However, not all compounds are effective
quenchers; therefore, other means of visualization are sometimes needed.

p-Anisaldehyde Stain 1

This stain is an excellent multipurpose visualization method for examining TLC plates. It is sensitive to
most functional groups, especially those which are strongly and weakly nucleophilic. It tends to be
insensitive to alkenes, alkynes, and aromatic compounds unless other functional groups are present in
the molecules which are being analyzed. It tends to stain the TLC plate itself, upon mild heating, to a
light pink color, while other functional groups tend to vary with respect to coloration. It is recommended
that a record is kept of which functional group stains which color for future reference, although these
types of comparisons may be misleading when attempting to ascertain which functional groups are
present in a molecule (especially in complex molecules). The shelf-life of this stain tends to be quite
long except when exposed to direct light or solvent is allowed to evaporate. It is recommended that the
stain be stored in a 100 mL wide mouth jar wrapped with aluminum foil to ensure a long life time.

Preparation: To 135 mL of absolute ethanol was added 5 mL of concentrated sulfuric acid, 1.5 mL of
glacial acetic acid and 3.7 mL of p-anisaldehyde. The solution is then stirred vigorously to ensure
homogeneity. The resulting staining solution is ideally stored in a 100 mL wide mouth jar covered with
aluminum foil.

p-Anisaldehyde Stain 2

A more specialized stain than the above, used for terpenes, cineoles, withanolides, acronycine, etc.
As above, heating with a heat gun must be employed to effect visualization.

Preparation: Prepare solution as follows: anisaldehyde:HClO4:acetone:water (1:10:20:80)

Bromocresol Green Stain

This stain is excellent for functional groups whose pKa is approximately 5.0 and lower. Thus, this stain
provides an excellent means of selectively visualizing carboxylic acids. These will appear as bright
yellow spots on either a dark or light blue background and typically, it is not necessary to heat the TLC
plate following immersion. This TLC visualization method has a fairly long lifetime (usually weeks)
thus, it is not often necessary to circle such spots following activation by staining.

Preparation: To 100 ml of absolute ethanol is added 0.04 g of bromocresol green. Then a 0.1 M
solution of aqueous NaOH is added dropwise until a blue color just appears in solution (the solution
should be colorless prior to addition). Ideally, these stains may be stored in 100 mL wide mouth jars.
The lifetime of such a solution typically depends upon solvent evaporation. Thus, it would be
advantageous to tightly seal such jars in-between uses.

Ceric Ammonium Sulfate

Specifically developed for vinca alkaloids (aspidospermas).

Preparation: Prepare a 1% solution of of cerium (IV) ammonium sulfate in 50% phosphoric acid.
Cerium Molybdate Stain (Hanessian's Stain)

This stain is a highly sensitive, multipurpose (multifunctional group stain). One word of caution, very
minor constituents may appear as significant impurities by employing this stain. To ensure accurate
results when employing this stain, it is necessary to heat the treated TLC plate vigorously (a heat gun
works well). Thus, this may not be a stain to employ if your sample is somewhat volatile. The TLC
plate itself will appear as either light blue or light green upon treatment, while the color of the spots
may vary (although they usually appear as a dark blue spot). Typically, functional groups will not be
distinguishable based upon the color of their spots; however, it would be worth while to make a list of
potential colors of various functional groups as you experience variations in colors. This may permit
future correlations which may prove beneficial when performing similar chemistry on related
substrates.

Preparation: To 235 mL of distilled water was added 12 g of ammonium molybdate, 0.5 g of ceric
ammonium molybdate, and 15 mL of concentrated sulfuric acid. Storage is possible in a 250 mL wide
mouth jar. This stain has a long shelf-life so long as solvent evaporation is limited. It may also prove
worth while to surround the jar with aluminum foil as the stain may be somewhat photo-sensitive and
exposure to direct light may shorten the shelf-life of this reagent. It is worth while to also mention that it
would be beneficial to circle the observed spots with a dull pencil following heating as this stain will
eventually fade on the TLC plate after a few days.

Cerium Sulfate

General stain, particularly effective for alkaloids.

Preparation: Prepare an aqueous solution of 10% cerium (IV) sulfate and 15% sulfuric acid.

Dinitrophenylhydrazine (DNP)

Developed mainly for aldehydes and ketones; forms the corresponding hydrazones, which are usually
yellow to orange and thus easily visualized.

Preparation: Dissolve 12g of 2,4-dinitrophenylhydrazine, 60mL of conc. sulfuric acid, and 80mL of
water in 200mL of 95% ethanol.

Ferric Chloride

Excellent for phenols.

Preparation: Prepare a solution of 1% ferric (III) chloride in 50% aqueous methanol.

Iodine

The staining of a TLC plate with iodine vapor is among the oldest methods for the visualization of
organic compounds. It is based upon the observation that iodine has a high affinity for both
unsaturated and aromatic compounds.

Preparation: A chamber may be assembled as follows: To 100 mL wide mouth jar (with cap) is added
a piece of filter paper and few crystals of iodine. Iodine has a high vapor pressure for a solid and the
chamber will rapidly become saturated with iodine vapor. Insert your TLC plate and allow it to remain
within the chamber until it develops a light brown color over the entire plate. Commonly, if your
compound has an affinity for iodine, it will appear as a dark brown spot on a lighter brown background.
Carefully remove the TLC plate at this point and gently circle the spots with a dull pencil. The iodine
will not remain on the TLC plate for long periods of time so circling these spots is necessary if one
wishes to refer to these TLC's at a later date.
Morin Hydrate

General stain (morin is a hydroxy flavone), is fluorescently active.

Preparation: Prepare a 0.1% solution of morin hydrate (by weight) in methanol.

Ninhydrin

Excellent for amino acids

Preparation: Dissolve 1.5g ninhydrin in 100mL of n-butanol and then add 3.0mL acetic acid.

Phosphomolybdic Acid (PMA) Stain

Phosphomolybdic acid stain is a good "universal" stain which is fairly sensitive to low concentrated
solutions. It will stain most functional groups, however it does not distinguish between different
functional groups based upon the coloration of the spots on the TLC plate. Most often, TLC's treated
with this stain will appear as a light green color, while compounds of interest will appear as much
darker green spots. It is necessary to heat TLC plates treated with this solution in order to activate the
stain for visualization. The shelf life of these solutions are typically quite long, provided solvent
evaporation is kept to a minimum.

Preparation: Dissolve 10 g of phosphomolybdic acid in 100 mL of absolute ethanol.

Potassium Permanganate

This stain is excellent for functional groups which are sensitive to oxidation. Alkenes and alkynes will
appear readily on a TLC plate following immersion into the stain and will appear as a bright yellow
spot on a bright purple background. Alcohols, amines, sulfides, mercaptans and other oxidizable
functional groups may also be visualized, however it will be necessary to gently heat the TLC plate
following immersion into the stain. These spots will appear as either yellow or light brown on a light
purple or pink background. Again it would be advantageous to circle such spots following visualization
as eventually the TLC will take on a light brown color upon standing for prolonged periods of time.

Preparation: Dissolve 1.5g of KMnO4, 10g K2CO3, and 1.25mL 10% NaOH in 200mL water. A typical
lifetime for this stain is approximately 3 months.

Vanillin

Very good general stain, giving a range of colors for different spots.

Preparation: Prepare a solution of 15g vanillin in 250mL ethanol and 2.5mL conc. sulfuric acid.

from Yutan Getzler, Kenyon College

Notes J . Org. Chem., Vol. 43, No. 14, 1978 2923

(1 1) Potassium ferricyanide has previously been used to convert vic-l,2-di-

carboxylate groups to double bonds. See, for example, L. F. Fieser and
M. J. Haddadin, J. Am. Chem. SOC.,86, 2392 (1964). The oxidative dide-
carboxylation of 1,2dicarboxyiic acids is, of course, a well-known process.
See inter alia (a) C. A. Grob, M. Ohta, and A. Weiss, Helv. Chirn. Acta, 41,
191 1 [ 1958); and (b) E. N. Cain, R. Vukov, and S. Masamune, J. Chern. SOC.
D, 98 (1969).

1 I I L
<40 26- 40- 63-
40 63 200
Rapid Chromatographic Technique for Preparative Figure 2. Silica gel particle size6 (pm):( 0 )r h : ( 0 )r / ( w / 2 ) .
Separations w i t h Moderate Resolution
W. Clark Still,* M i c h a e l K a h n , a n d Abhijit M i t r a

Departm(7nt o/ Chemistry, Columbia Uniuersity,

1Veu York, Neu; York 10027

ReceiLied January 26, 1978

We wish to describe a simple absorption chromatography

technique for the routine purification of organic compounds. 0 1.0 20 3.0 4.0
Large scale preparative separations are traditionally carried Figure 3. E l u a n t flow rate (in./min).
out by tedious long column chromatography. Although the
results are sometimes satisfactory, the technique is always
time consuming and frequently gives poor recovery due to
band tailing. These problems are especially acute when sam-

Psz24
ples of greater than 1 or 2 g must be separated. In recent years 41
several preparative systems have evolved which reduce sep-
aration times to 1-3 h and allow the resolution of components
having Al?f 1 0.05 on analytical TLC. Of these, medium
I
pressure Chromatography' and short column chromatogra-
phy2 have been the most successful in our laboratory. We have 0 100 200 300 400
recently developed a substantially faster technique for the
Figure 4. Sample size (mg).
routine purification of reaction products which we call flash
chromatography. Although its resolution is only moderate
( L R f L 0.15), the system is extremely inexpensive to set up
and operate and allows separations of samples weighing
0.01-10.0 g3 in 10-15 m ~ n . ~
Flash chromatography is basically an air pressure driven
hybrid of medium pressure and short column chromatography
which has been optimized for particularly rapid separations.
Optimization studies were carried out under a set of standard
conditions5 using samples of benzyl alcohol on a 20 mm X 5
in. column of silica gel 60 and monitoring the column output
with a Tracor 970 ultraviolet detector. Resolution is measured
in terms of the ratio of retention time ( r )to peak width ( w , w / 2 )
(Figure l),and the results are diagrammed in Figures 2-4 for
r
Air
variations in silica gel particle size, eluant flow rate, and
sample size.
A number of interesting facts emerge from these data. First,
we find that one of the most popular grades of silica gel 60,
70-230 mesh (63-200 pm),gives the poorest resolution of any
gel studied under our standard conditions. Second, particle
sizes less than 40 pm offer no improvement in resolution with
our method of packing.' Column performance is quite sensi- Flow Controller
tive to the rate of elution m d is best with relatively high eluant V A
flow rates. The solvent head above the adsorbent bed should
drop 2.0 f 0.1 in./min for optimum resolution with mixtures
of ethyl acetate/petroleum ether (30-60 "C).EFinally, the peak
width shows the expected increase with the sample size.
Sample recovery was 295%.
Figure 5.

The apparatus required for this technique consists of a set

of chromatography columns and a flow controller valve
(below). The column is a flattened bottom 18 in. glass tube
fitted with a Teflon stopcock and topped with a 24/40 glass
~ ~~
joint. Columns without fritted glass bed supports are generally
TIME preferred since they have significantly less dead volume than
Figure 1. T y p i c a l chromatogram. the standard fritted round-bottom variety. The flow controller

0022-3263/78/1943-2923$01.00/0 1978 American Chemical Society

2924 J . Org. Chem., Vol. 43, No. 14, 1978
I,"? . . a . . . c. . . . . . .
RI I 2 Y
e -
5
-am-
7 1 q IO
*
II
?CRUDE FRACTIONS
SAMPLE
Figure 6.
valve is a simple variable bleed device for precise regulation
of the elution rate and is constructed from a gladTeflon
needle valve (Ace Glass Co. No. 8193-04 or equivalent) and
a standard 24/40 joint.
A detailed procedure is presented in the experimental
section and is summarized as follows: (1)A solvent is chosen
which gives good separation and moves the desired component
to R f = 0.35 on analytical TLC (E. Merck No. 5765).9 (2) A
column of the appropriate diameter (see Table I) is selected
and filled with 5-6 in. of dry 40-63 pm silica gel (E. Merck No.
9385).1 (3) The column is filled with solvent and pressure is
used to rapidly push all the air from the silica gel. (4) The
sample is applied and the column is refilled with solvent and
eluted at a flow rate of 2 in./min.
The time required to elute the desired components from the
column is generally so fast (5-10 min) that we have abandoned
automatic fraction collectors in favor of a simple rack holding
forty 20 X 150 mm test tubes. Small fractions are typically
collected early in the elution with larger ones being collected
toward the end of the chromatography. Separated compo-
nents are conveniently detected by spotting -5 pL of each
fraction along the long side of 7 cm X 2.5 cm TLC plate and
then by developing the plate sideways. Heavier spotting may
be required for small samples or highly retentive components.
A typical separation is shown in Figure 6.
Over the past year we have run many hundreds of these
columns. In every case we have been able to effect clean sep-
aration of compounds having ARf 2 0.15 in less than 15 min
and in many cases separations a t ARf 0.10 were possible.
The amount of sample used on a given column is proportional
to its cross-sectional area and Table I can serve as a guide to
column selection.
The sample size may increase substantially if less resolution
is required; we have used a 50-mm column for the purification
of up to 10 g of compound having impurities a t ARf 2 0.4.
Resolution is maintained even with large diameter columns.
For example the epimeric alcohols 1 and 2 have an R f of 0.34
Bu3Sn' Qk Bu3s"+Q,,oH
OH Bu
I 2
and 0.25, respectively, in 5% ethyl acetate/petroleum ether.
A 1.0-g mixture of 1 and 2 (ARf = 0.09) easily separated with
only a 65-mg mixed fraction in 7 min on a 40-mm diameter
column (500 mL of 5% EtOAc/petroleum ether).
If the components to be separated are closer o n TLC than
ARf 0.15, increased resolution may be achieved by using a
longer (e.g., 10 in.) column of gel alternatively a less polar
solvent can be used. Such a solvent can be selected to move
the desired components on TLC to R f = 0.25 without in-
creasing the elution times too drastically. In either case, the
column should be only lightly loaded with sample and a2rapid
flow rate of 2 in./min should be maintained. Sloweir flows
clearly give poorer resolution with ethyl acetate/petroleum
ether mixtures.
Notes
Table I
12
T
I
column
diameter,
mm
10
20
vol of
eluant,"
mL
100
200
sample:
typical loading (mg)
ARf 2 0.2 I R f 2 0 . 1
100
400
40
160
typical
fraction
size,
mL
5
10
30 400 900 360 20
40 600 1600 600 30
50 1000 2500 1000 50
0 Typical volume of eluant required for packing and elution.
In conclusion, flash chromatography provides a rapid and
inexpensive general method for the preparative separation
of mixtures requiring only moderate resolution. Even in cases
where high resolution is required, preliminary purification by
the flash technique allows simplified high-resolution sepa-
rations without contamination of expensive HPLC columns.
Finally, we would like to stress the facts that use of the 40-63
pm silica gel and a pressure- (and not vacuum-) driven flow
rate of 2.0 in./min are crucial for successful separations by this
method.
Experimental Section
Chromatography columns and the flow controller valve were as-
sembled as described in the text. The silica gel used was 40-63 pm
(400-230 mesh) silica gel 60 (E. Merck No. 9385).1 Solvents were
distilled prior to use. Thin layer chromatograms (TLC) were run on
glass supported silica gel 60 plates (0.25-mm layer, F-254) (E. Merck
No. 5765).
Flash Chromatography. General Procedure. First a low vis-
cosity solvent system (e.g., ethyl acetateh0-60 "C petroleum etherla
is found which separates the mixture and moves the desired compo-
nent on analytical TLC to an Rf of 0.35.9If several compounds are to
be separated which run very close on TLC, adjust the solvent to put
the midpoint between the components a t R f = 0.35. If the compounds
are widely separated, adjust the R, of the less mobile component to
0.35. Having chosen the solvent, a column of the appropriate diameter
(see text, Table I) is selected and a small plug of glass wool is placed
in the tube connecting the stopcock to the column body (A in the di-
agram above). Two telescoping lengths of glass tubing (6and 8 mm
0.d.) make placement of the glass wool plug easy. Next a smooth '/a
in. layer of 50-100 mesh sand is added to cover the bottom of the
column and dry 40-63 pm silica gel is poured into the column in a
single portion to give a depth of 5.5-6 in. With the stopcock open, the
column is gently tapped vertically on the bench top to pack the gel.
Next a l/a in. layer of sand is carefully placed on the flat top of the dry
gel bed and the column is clamped for pressure packing and elution.
The solvent chosen above is then poured carefully over the sand to
fill the column completely. The needle valve (B) of the flow controller
is opened all the way and the flow controller is fitted tightly to the top
of the column and secured with strong rubber bands. The main air
line valve leading to the flow controller is opened slightly and a finger
is placed fairly tightly over the bleed port (C). This will cause the
pressure above the adsorbent bed to climb rapidly and compress the
silica gel as solvent is rapidly forced through the column. It is im-
portant to maintain the pressure until all the air is expelled and the
lower part of the column is cool; otherwise, the column will fragment
and should be repacked unless the separation desired is a trivial one.
Particular care is necessary with large diameter columns. The pressure
is then released and excess eluant is forced out of the column above
the adsorbent bed by partially blocking the bleed port (C). The top
of the silica gel should not be allowed t o run dry. Next the sample is
applied by pipette as a 20-250% solution in the eluant to the top of the
adsorbent bed and the flow controller is briefly placed on top of the
column to push all of the sample into the silica gel." The solvent used
to pack the column is ordinarily reused to elute the column. The walls
of the column are washed down with a few milliliters of fresh eluant,
the washings are pushed into the gel as before, and the column is
carefully filled with eluant so as not to disturb the adsorbent bed. The
flow controller is finally secured to the column and adjusted to cause
the surface of the solvent in the column to fall 2.0 in./min. This seems
to be an optimum value of the flow rate for most low viscosity solvents
for any column diameter with the 40-63 km silica gel. Fractions are
Notes J . Org. Chenz., Vol. 43, No. 14, 1978 2925

collected until all the solvent has been used (see Table I to estimate
the amount of solvent and fraction size). It is best not to let the column
run dry since further elution is occasionally necessary. Purified
components are identified as described in the text by TLC. If the
foregoing instructions are followed exactly, there is little opportunity
for the separation to fail.
Although we generally pack fresh columns for each separation,the
expense of large-scale separations makes it advantageous to reuse
large diameter columns. Column recycling is effected by first flushing 1 2
(rate = 2 in./min) the column with approximately 5 in. of the more Tr = trityl
polar component in the eluant (generally ethyl acetate or acetone)
and then with 5 in. of the desired eluant. If the eluant is relatively
nonpolar (e.g., 110% EtOAc/petroleum ether), it may be more ad-
visable to use a flushing solvent (e.g., 2 0 4 0 % EtOAc/petroleum ether)
which is somewhat less polar than the pure high polarity compo-
nent.
Registry No.-l,66417-28-5; 2,66417-27-4.
References and Notes
(1) Such units have been described and used extensively by J. M. McCali. R .
E. TenBrinkt, and C. H. Lin at the Upjohn Company and A. I. Meyers at
Colorado State University
(2) B. J. Hunt and W.Rigby, Chern. Ind. (London), 1868 (1967). 4
(3) This is not a limitation but is merely the scale range which we have
used. 3
(4) This is the total time required for column packing, sample application, and a, R = NH,
complete elution.
Standard conditions: 5 in. high bed of 40-63 p m silica gel 60 in a 20 mm b, R = CH,
diameter column packed as described in text, 2.0 in. of solvent flow/min, c, R = SH
200 mg of benzyl alcohol. 25% ethyl acetate/petroleum ether eluant. d , R = phenyl
These gels are manufactured by E. Merck and are the following grades: e,R=H
<40 p m (silica gel H,No. 7736), 25-40 p m (LiChroPrep Si60, No. 9390),
40-63 pm (silica gel 60, No. 9385), 63-200 p m (silica gel 60, No.
10180\. occur at 6 25.66 and 27.54, within the range strongly indicative
of a p configuration (25.5 f 0.2 and 27.5 f 0.2).7,s
(7) Slurry packing, incremental dry packing, or single portion dry packing gave
identical results with the 40-63 p m gel. Since the last technique was the
It has been shown that the a-anomer of 1is more stable than
simplest, it was employed in ail our studies.
the p,4 and recently a rationalization for this seemingly un-
(8) This is a particularly good general solvent system. For extremely polar
compounds, acetone/petroleum ether or acetone/methylene chloride usual behavior has been p r e ~ e n t e d On
. ~ this basis it seems
mixtures are often useful. Significantly higher viscosity solvents will require
slower optimum resolution flow rates. likely that the a anomer of 2 is also more stable than the @.The
conditions involved in the preparation of 2 (low-temperature,
(9) If this R, is given by a solvent having <2% of the polar component, a slightly
less polar eluant is desirable. Thus if 1 % ethyl acetate/petroleum ether
aprotic solvent) probably do not allow equilibration, though
gives a compound an R, of 0.35 on TLC, the column is run with 0.5% ethyl
acetate. there is some leakage to the a-anomer. Further support for
these postulates is provided by the finding that p-2 is isom-
(10) 40-63 p m gel is also used for medium pressure chromatography' and is
available from MCB in 1 kg ($45/kg) or 25 kg ($16/kg) lots.
erized readily under basic conditions to an alp mixture which
(11) if the sample is only partially soluble in the eluant, just enough of the more
is predominantly a.
polar component is added to give complete dissolution. Large quantities
of very polar impurities are best removed prior to chromatography so that
Condensation of 2 with guanidine, acetamidine, thiourea,
excessive quantities of solvent or large increases in solvent polarity will
be unnecessary for sample application. and benzamidine under basic conditions afforded the pro-
tected nucleosides 3a-d as anomeric mixtures (ca. 3:1, alp)
which were chromatographically inseparable. That the major
anomers after condensation are all a is also indicated by the
chemical shifts of the isopropylidene methyls. For example,
Homo- C-nucleosides. The Synthesis of Certain the shifts of the methyls in 3a are at 6 25.09 and 26.33, clearly
6-Substituted 4-Pyrimidinonesl in the a range (24.9 f 0.3 and 26.3 f 0.2).7,SIn view of the
John A. Secrist 111 ready isomerization of 8-2 to a mixture of anomers containing
predominantly a-2, it seems likely that equilibration is oc-
Department oJ Chemistry, T h e Ohio S t a t e University, curring prior to cyclization, and that the anomeric composition
Columbus, Ohio 43210 of 2 after equilibration dictates the ratio of a - and @-homo-
Receioed February I , 1978 C-nucleosides. Desulfurization of 3c with Raney Nickel in
refluxing 95% ethanol provided the hydrogen-substituted
The chemistry of C-nucleosides has received considerable compound 3e. Interestingly, while both urea and formamidine
attention recently due to the biological activities of naturally reacted with 2, neither led to the formation of cyclized mate-
occurring compounds such as showdomycin, formycin, and rial under a variety of conditions. The free nucleosides 4a-e
oxazinomycin.2 Though synthetic methodology has evolved were obtained by treatment of 3a-e with either methanolic
for the preparation of a number of C-nucleoside analogues,2 hydrogen chloride or aqueous trifluoroacetic acid for several
only one investigation has dealt with the synthesis of homo- hours. These acidic conditions, even over longer periods of
C- nucleoside^,^ compounds with a methylene unit between time (2 days), caused no change in the alp ratio of the nucle-
a carbon of the nitrogen base and the standard D-ribose osides. Chromatographic separation of the free nucleoside
moiety. This note describes the facile synthesis of a series of anomers was once again not possible. 4e was also available by
6-substituted 4-pyrimidinone homo-C-nucleosides from the desulfurization of 4c.
ester 1, which is available in three steps from D - r i b o ~ e . ~ , ~ The 13C NMR spectra of the free nucleosides contained
Treatment of 1 with lithio-tert-butyl acetate6 in toluene characteristic signals for the five compounds, and all values
a t 0 OC for several hours affords an anomeric mixture (ca. 3:1, are reported in the Experimental Section. Salient 1H NMR
@la)of the p-keto ester 2 in 75% yield. The assignment of /3 to values are the methyl singlet of 4b at 6 2.28 and the pyrimidine
the major anomer was made on the basis of l3C NMR data. In C2H singlet of 4e at 6 8.92, as well as the pyrimidine C5 signal
particular, the isopropylidene methyls of the major anomer of all five nucleosides in the neighborhood of d 6.0.

0022-326317811943-2925$01.00/0 0 1978 American Chemical Society

7512 J. Org. Chem. 1997, 62, 7512-7515
NMR Chemical Shifts of Common
Laboratory Solvents as Trace Impurities
Hugo E. Gottlieb,* Vadim Kotlyar, and
Abraham Nudelman*
Department of Chemistry, Bar-Ilan University,
Ramat-Gan 52900, Israel
Received June 27, 1997
In the course of the routine use of NMR as an aid for
organic chemistry, a day-to-day problem is the identifica-
tion of signals deriving from common contaminants
(water, solvents, stabilizers, oils) in less-than-analyti-
cally-pure samples. This data may be available in the
literature, but the time involved in searching for it may
be considerable. Another issue is the concentration
dependence of chemical shifts (especially 1H); results
obtained two or three decades ago usually refer to much
more concentrated samples, and run at lower magnetic
fields, than todays practice.
We therefore decided to collect 1H and 13C chemical
shifts of what are, in our experience, the most popular
extra peaks in a variety of commonly used NMR
solvents, in the hope that this will be of assistance to
the practicing chemist.
Experimental Section
NMR spectra were taken in a Bruker DPX-300 instrument
(300.1 and 75.5 MHz for 1H and 13C, respectively). Unless
otherwise indicated, all were run at room temperature (24 ( 1
C). For the experiments in the last section of this paper, probe
temperatures were measured with a calibrated Eurotherm 840/T
digital thermometer, connected to a thermocouple which was
introduced into an NMR tube filled with mineral oil to ap-
proximately the same level as a typical sample. At each
temperature, the D2O samples were left to equilibrate for at least
10 min before the data were collected.
In order to avoid having to obtain hundreds of spectra, we
prepared seven stock solutions containing approximately equal
amounts of several of our entries, chosen in such a way as to
prevent intermolecular interactions and possible ambiguities in
assignment. Solution 1: acetone, tert-butyl methyl ether, di-
methylformamide, ethanol, toluene. Solution 2: benzene, di-
methyl sulfoxide, ethyl acetate, methanol. Solution 3: acetic
acid, chloroform, diethyl ether, 2-propanol, tetrahydrofuran.
Solution 4: acetonitrile, dichloromethane, dioxane, n-hexane,
HMPA. Solution 5: 1,2-dichloroethane, ethyl methyl ketone,
n-pentane, pyridine. Solution 6: tert-butyl alcohol, BHT, cyclo-
hexane, 1,2-dimethoxyethane, nitromethane, silicone grease,
triethylamine. Solution 7: diglyme, dimethylacetamide, ethyl-
ene glycol, grease (engine oil). For D2O. Solution 1: acetone,
tert-butyl methyl ether, dimethylformamide, ethanol, 2-propanol.
Solution 2: dimethyl sulfoxide, ethyl acetate, ethylene glycol,
methanol. Solution 3: acetonitrile, diglyme, dioxane, HMPA,
pyridine. Solution 4: 1,2-dimethoxyethane, dimethylacetamide,
ethyl methyl ketone, triethylamine. Solution 5: acetic acid, tert-
butyl alcohol, diethyl ether, tetrahydrofuran. In D2O and
CD3OD nitromethane was run separately, as the protons
exchanged with deuterium in presence of triethylamine.
Results
Proton Spectra (Table 1). A sample of 0.6 mL of the
solvent, containing 1 L of TMS,1 was first run on its
own. From this spectrum we determined the chemical
shifts of the solvent residual peak2 and the water peak.
It should be noted that the latter is quite temperature-
(1) For recommendations on the publication of NMR data, see:
IUPAC Commission on Molecular Structure and Spectroscopy. Pure
Appl. Chem. 1972, 29, 627; 1976, 45, 217.
S0022-3263(97)01176-6 CCC: $14.00
Figure 1. Chemical shift of HDO as a function of tempera-
ture.
dependent (vide infra). Also, any potential hydrogen-
bond acceptor will tend to shift the water signal down-
field; this is particularly true for nonpolar solvents. In
contrast, in e.g. DMSO the water is already strongly
hydrogen-bonded to the solvent, and solutes have only a
negligible effect on its chemical shift. This is also true
for D2O; the chemical shift of the residual HDO is very
temperature-dependent (vide infra) but, maybe counter-
intuitively, remarkably solute (and pH) independent.
We then added 3 L of one of our stock solutions to
the NMR tube. The chemical shifts were read and are
presented in Table 1. Except where indicated, the
coupling constants, and therefore the peak shapes, are
essentially solvent-independent and are presented only
once.
For D2O as a solvent, the accepted reference peak (
) 0) is the methyl signal of the sodium salt of 3-(trimeth-
ylsilyl)propanesulfonic acid; one crystal of this was added
to each NMR tube. This material has several disadvan-
tages, however: it is not volatile, so it cannot be readily
eliminated if the sample has to be recovered. In addition,
unless one purchases it in the relatively expensive
deuterated form, it adds three more signals to the
spectrum (methylenes 1, 2, and 3 appear at 2.91, 1.76,
and 0.63 ppm, respectively). We suggest that the re-
sidual HDO peak be used as a secondary reference; we
find that if the effects of temperature are taken into
account (vide infra), this is very reproducible. For D2O,
we used a different set of stock solutions, since many of
the less polar substrates are not significantly water-
soluble (see Table 1). We also ran sodium acetate and
sodium formate (chemical shifts: 1.90 and 8.44 ppm,
respectively).
Carbon Spectra (Table 2). To each tube, 50 L of
the stock solution and 3 L of TMS1 were added. The
solvent chemical shifts3 were obtained from the spectra
containing the solutes, and the ranges of chemical shifts
(2) I.e., the signal of the proton for the isotopomer with one less
deuterium than the perdeuterated material, e.g., CHCl3 in CDCl3 or
C6D5H in C6D6. Except for CHCl3, the splitting due to JHD is typically
observed (to a good approximation, it is 1/6.5 of the value of the
corresponding JHH). For CHD2 groups (deuterated acetone, DMSO,
acetonitrile), this signal is a 1:2:3:2:1 quintet with a splitting of ca. 2
Hz.
(3) In contrast to what was said in note 2, in the 13C spectra the
solvent signal is due to the perdeuterated isotopomer, and the one-
bond couplings to deuterium are always observable (ca. 20-30 Hz).
1997 American Chemical Society
Notes J. Org. Chem., Vol. 62, No. 21, 1997 7513

Table 1. 1H NMR Data

proton mult CDCl3 (CD3)2CO (CD3)2SO C6D6 CD3CN CD3OD D2O
solvent residual peak 7.26 2.05 2.50 7.16 1.94 3.31 4.79
H2O s 1.56 2.84a 3.33a 0.40 2.13 4.87
acetic acid CH3 s 2.10 1.96 1.91 1.55 1.96 1.99 2.08
acetone CH3 s 2.17 2.09 2.09 1.55 2.08 2.15 2.22
acetonitrile CH3 s 2.10 2.05 2.07 1.55 1.96 2.03 2.06
benzene CH s 7.36 7.36 7.37 7.15 7.37 7.33
tert-butyl alcohol CH3 s 1.28 1.18 1.11 1.05 1.16 1.40 1.24
OHc s 4.19 1.55 2.18
tert-butyl methyl ether CCH3 s 1.19 1.13 1.11 1.07 1.14 1.15 1.21
OCH3 s 3.22 3.13 3.08 3.04 3.13 3.20 3.22
BHTb ArH s 6.98 6.96 6.87 7.05 6.97 6.92
OHc s 5.01 6.65 4.79 5.20
ArCH3 s 2.27 2.22 2.18 2.24 2.22 2.21
ArC(CH3)3 s 1.43 1.41 1.36 1.38 1.39 1.40
chloroform CH s 7.26 8.02 8.32 6.15 7.58 7.90
cyclohexane CH2 s 1.43 1.43 1.40 1.40 1.44 1.45
1,2-dichloroethane CH2 s 3.73 3.87 3.90 2.90 3.81 3.78
dichloromethane CH2 s 5.30 5.63 5.76 4.27 5.44 5.49
diethyl ether CH3 t, 7 1.21 1.11 1.09 1.11 1.12 1.18 1.17
CH2 q, 7 3.48 3.41 3.38 3.26 3.42 3.49 3.56
diglyme CH2 m 3.65 3.56 3.51 3.46 3.53 3.61 3.67
CH2 m 3.57 3.47 3.38 3.34 3.45 3.58 3.61
OCH3 s 3.39 3.28 3.24 3.11 3.29 3.35 3.37
1,2-dimethoxyethane CH3 s 3.40 3.28 3.24 3.12 3.28 3.35 3.37
CH2 s 3.55 3.46 3.43 3.33 3.45 3.52 3.60
dimethylacetamide CH3CO s 2.09 1.97 1.96 1.60 1.97 2.07 2.08
NCH3 s 3.02 3.00 2.94 2.57 2.96 3.31 3.06
NCH3 s 2.94 2.83 2.78 2.05 2.83 2.92 2.90
dimethylformamide CH s 8.02 7.96 7.95 7.63 7.92 7.97 7.92
CH3 s 2.96 2.94 2.89 2.36 2.89 2.99 3.01
CH3 s 2.88 2.78 2.73 1.86 2.77 2.86 2.85
dimethyl sulfoxide CH3 s 2.62 2.52 2.54 1.68 2.50 2.65 2.71
dioxane CH2 s 3.71 3.59 3.57 3.35 3.60 3.66 3.75
ethanol CH3 t, 7 1.25 1.12 1.06 0.96 1.12 1.19 1.17
CH2 q, 7d 3.72 3.57 3.44 3.34 3.54 3.60 3.65
OH sc,d 1.32 3.39 4.63 2.47
ethyl acetate CH3CO s 2.05 1.97 1.99 1.65 1.97 2.01 2.07
CH2CH3 q, 7 4.12 4.05 4.03 3.89 4.06 4.09 4.14
CH2CH3 t, 7 1.26 1.20 1.17 0.92 1.20 1.24 1.24
ethyl methyl ketone CH3CO s 2.14 2.07 2.07 1.58 2.06 2.12 2.19
CH2CH3 q, 7 2.46 2.45 2.43 1.81 2.43 2.50 3.18
CH2CH3 t, 7 1.06 0.96 0.91 0.85 0.96 1.01 1.26
ethylene glycol CH se 3.76 3.28 3.34 3.41 3.51 3.59 3.65
grease f CH3 m 0.86 0.87 0.92 0.86 0.88
CH2 br s 1.26 1.29 1.36 1.27 1.29
n-hexane CH3 t 0.88 0.88 0.86 0.89 0.89 0.90
CH2 m 1.26 1.28 1.25 1.24 1.28 1.29
HMPAg CH3 d, 9.5 2.65 2.59 2.53 2.40 2.57 2.64 2.61
methanol CH3 sh 3.49 3.31 3.16 3.07 3.28 3.34 3.34
OH sc,h 1.09 3.12 4.01 2.16
nitromethane CH3 s 4.33 4.43 4.42 2.94 4.31 4.34 4.40
n-pentane CH3 t, 7 0.88 0.88 0.86 0.87 0.89 0.90
CH2 m 1.27 1.27 1.27 1.23 1.29 1.29
2-propanol CH3 d, 6 1.22 1.10 1.04 0.95 1.09 1.50 1.17
CH sep, 6 4.04 3.90 3.78 3.67 3.87 3.92 4.02
pyridine CH(2) m 8.62 8.58 8.58 8.53 8.57 8.53 8.52
CH(3) m 7.29 7.35 7.39 6.66 7.33 7.44 7.45
CH(4) m 7.68 7.76 7.79 6.98 7.73 7.85 7.87
silicone greasei CH3 s 0.07 0.13 0.29 0.08 0.10
tetrahydrofuran CH2 m 1.85 1.79 1.76 1.40 1.80 1.87 1.88
CH2O m 3.76 3.63 3.60 3.57 3.64 3.71 3.74
toluene CH3 s 2.36 2.32 2.30 2.11 2.33 2.32
CH(o/p) m 7.17 7.1-7.2 7.18 7.02 7.1-7.3 7.16
CH(m) m 7.25 7.1-7.2 7.25 7.13 7.1-7.3 7.16
triethylamine CH3 t,7 1.03 0.96 0.93 0.96 0.96 1.05 0.99
CH2 q, 7 2.53 2.45 2.43 2.40 2.45 2.58 2.57
a In these solvents the intermolecular rate of exchange is slow enough that a peak due to HDO is usually also observed; it appears at

2.81 and 3.30 ppm in acetone and DMSO, respectively. In the former solvent, it is often seen as a 1:1:1 triplet, with 2JH,D ) 1 Hz.
b 2,6-Dimethyl-4-tert-butylphenol. c The signals from exchangeable protons were not always identified. d In some cases (see note a), the

coupling interaction between the CH2 and the OH protons may be observed (J ) 5 Hz). e In CD3CN, the OH proton was seen as a multiplet
at 2.69, and extra coupling was also apparent on the methylene peak. f Long-chain, linear aliphatic hydrocarbons. Their solubility in
DMSO was too low to give visible peaks. g Hexamethylphosphoramide. h In some cases (see notes a, d), the coupling interaction between
the CH3 and the OH protons may be observed (J ) 5.5 Hz). i Poly(dimethylsiloxane). Its solubility in DMSO was too low to give visible
peaks.

show their degree of variability. Occasionally, in order ambiguous, a further 1-2 L of a specific substrate were
to distinguish between peaks whose assignment was added and the spectra run again.
7514 J. Org. Chem., Vol. 62, No. 21, 1997 Notes

Table 2. 13C NMR Dataa

CDCl3 (CD3)2CO (CD3)2SO C6D6 CD3CN CD3OD D2O
solvent signals 77.16 ( 0.06 29.84 ( 0.01 39.52 ( 0.06 128.06 ( 0.02 1.32 ( 0.02 49.00(0.01
206.26 ( 0.13 118.26 ( 0.02
acetic acid CO 175.99 172.31 171.93 175.82 173.21 175.11 177.21
CH3 20.81 20.51 20.95 20.37 20.73 20.56 21.03
acetone CO 207.07 205.87 206.31 204.43 207.43 209.67 215.94
CH3 30.92 30.60 30.56 30.14 30.91 30.67 30.89
acetonitrile CN 116.43 117.60 117.91 116.02 118.26 118.06 119.68
CH3 1.89 1.12 1.03 0.20 1.79 0.85 1.47
benzene CH 128.37 129.15 128.30 128.62 129.32 129.34
tert-butyl alcohol C 69.15 68.13 66.88 68.19 68.74 69.40 70.36
CH3 31.25 30.72 30.38 30.47 30.68 30.91 30.29
tert-butyl methyl ether OCH3 49.45 49.35 48.70 49.19 49.52 49.66 49.37
C 72.87 72.81 72.04 72.40 73.17 74.32 75.62
CCH3 26.99 27.24 26.79 27.09 27.28 27.22 26.60
BHT C(1) 151.55 152.51 151.47 152.05 152.42 152.85
C(2) 135.87 138.19 139.12 136.08 138.13 139.09
CH(3) 125.55 129.05 127.97 128.52 129.61 129.49
C(4) 128.27 126.03 124.85 125.83 126.38 126.11
CH3Ar 21.20 21.31 20.97 21.40 21.23 21.38
CH3C 30.33 31.61 31.25 31.34 31.50 31.15
C 34.25 35.00 34.33 34.35 35.05 35.36
chloroform CH 77.36 79.19 79.16 77.79 79.17 79.44
cyclohexane CH2 26.94 27.51 26.33 27.23 27.63 27.96
1,2-dichloroethane CH2 43.50 45.25 45.02 43.59 45.54 45.11
dichloromethane CH2 53.52 54.95 54.84 53.46 55.32 54.78
diethyl ether CH3 15.20 15.78 15.12 15.46 15.63 15.46 14.77
CH2 65.91 66.12 62.05 65.94 66.32 66.88 66.42
diglyme CH3 59.01 58.77 57.98 58.66 58.90 59.06 58.67
CH2 70.51 71.03 69.54 70.87 70.99 71.33 70.05
CH2 71.90 72.63 71.25 72.35 72.63 72.92 71.63
1,2-dimethoxyethane CH3 59.08 58.45 58.01 58.68 58.89 59.06 58.67
CH2 71.84 72.47 17.07 72.21 72.47 72.72 71.49
dimethylacetamide CH3 21.53 21.51 21.29 21.16 21.76 21.32 21.09
CO 171.07 170.61 169.54 169.95 171.31 173.32 174.57
NCH3 35.28 34.89 37.38 34.67 35.17 35.50 35.03
NCH3 38.13 37.92 34.42 37.03 38.26 38.43 38.76
dimethylformamide CH 162.62 162.79 162.29 162.13 163.31 164.73 165.53
CH3 36.50 36.15 35.73 35.25 36.57 36.89 37.54
CH3 31.45 31.03 30.73 30.72 31.32 31.61 32.03
dimethyl sulfoxide CH3 40.76 41.23 40.45 40.03 41.31 40.45 39.39
dioxane CH2 67.14 67.60 66.36 67.16 67.72 68.11 67.19
ethanol CH3 18.41 18.89 18.51 18.72 18.80 18.40 17.47
CH2 58.28 57.72 56.07 57.86 57.96 58.26 58.05
ethyl acetate CH3CO 21.04 20.83 20.68 20.56 21.16 20.88 21.15
CO 171.36 170.96 170.31 170.44 171.68 172.89 175.26
CH2 60.49 60.56 59.74 60.21 60.98 61.50 62.32
CH3 14.19 14.50 14.40 14.19 14.54 14.49 13.92
ethyl methyl ketone CH3CO 29.49 29.30 29.26 28.56 29.60 29.39 29.49
CO 209.56 208.30 208.72 206.55 209.88 212.16 218.43
CH2CH3 36.89 36.75 35.83 36.36 37.09 37.34 37.27
CH2CH3 7.86 8.03 7.61 7.91 8.14 8.09 7.87
ethylene glycol CH2 63.79 64.26 62.76 64.34 64.22 64.30 63.17
grease CH2 29.76 30.73 29.20 30.21 30.86 31.29
n-hexane CH3 14.14 14.34 13.88 14.32 14.43 14.45
CH2(2) 22.70 23.28 22.05 23.04 23.40 23.68
CH2(3) 31.64 32.30 30.95 31.96 32.36 32.73
HMPAb CH3 36.87 37.04 36.42 36.88 37.10 37.00 36.46
methanol CH3 50.41 49.77 48.59 49.97 49.90 49.86 49.50c
nitromethane CH3 62.50 63.21 63.28 61.16 63.66 63.08 63.22
n-pentane CH3 14.08 14.29 13.28 14.25 14.37 14.39
CH2(2) 22.38 22.98 21.70 22.72 23.08 23.38
CH2(3) 34.16 34.83 33.48 34.45 34.89 35.30
2-propanol CH3 25.14 25.67 25.43 25.18 25.55 25.27 24.38
CH 64.50 63.85 64.92 64.23 64.30 64.71 64.88
pyridine CH(2) 149.90 150.67 149.58 150.27 150.76 150.07 149.18
CH(3) 123.75 124.57 123.84 123.58 127.76 125.53 125.12
CH(4) 135.96 136.56 136.05 135.28 136.89 138.35 138.27
silicone grease CH3 1.04 1.40 1.38 2.10
tetrahydrofuran CH2 25.62 26.15 25.14 25.72 26.27 26.48 25.67
CH2O 67.97 68.07 67.03 67.80 68.33 68.83 68.68
toluene CH3 21.46 21.46 20.99 21.10 21.50 21.50
C(i) 137.89 138.48 137.35 137.91 138.90 138.85
CH(o) 129.07 129.76 128.88 129.33 129.94 129.91
CH(m) 128.26 129.03 128.18 128.56 129.23 129.20
CH(p) 125.33 126.12 125.29 125.68 126.28 126.29
triethylamine CH3 11.61 12.49 11.74 12.35 12.38 11.09 9.07
CH2 46.25 47.07 45.74 46.77 47.10 46.96 47.19
a See footnotes for Table 1. b 2J ) 3 Hz. c Reference material; see text.
PC
Notes
For D2O solutions there is no accepted reference for
carbon chemical shifts. We suggest the addition of a drop
of methanol, and the position of its signal to be defined
as 49.50 ppm; on this basis, the entries in Table 2 were
recorded. The chemical shifts thus obtained are, on the
whole, very similar to those for the other solvents.
Alternatively, we suggest the use of dioxane when the
methanol peak is expected to fall in a crowded area of
the spectrum. We also report the chemical shifts of
sodium formate (171.67 ppm), sodium acetate (182.02 and
23.97 ppm), sodium carbonate (168.88 ppm), sodium
bicarbonate (161.08 ppm), and sodium 3-(trimethylsilyl)-
propanesulfonate [54.90, 19.66, 15.56 (methylenes 1, 2,
and 3, respectively), and -2.04 ppm (methyls)], in D2O.
Temperature Dependence of HDO Chemical
Shifts. We recorded the 1H spectrum of a sample of D2O,
containing a crystal of sodium 3-(trimethylsilyl)propane-
sulfonate as reference, as a function of temperature. The
J. Org. Chem., Vol. 62, No. 21, 1997 7515
data are shown in Figure 1. The solid line connecting
the experimental points corresponds to the equation
) 5.060 - 0.0122T + (2.11 10-5)T2 (1)
which reproduces the measured values to better than 1
ppb. For the 0 - 50oC range, the simpler
) 5.051 - 0.0111T (2)
gives values correct to 10 ppb. For both equations, T is
the temperature in C.
Acknowledgment. Generous support for this work
by the Minerva Foundation and the Otto Mayerhoff
Center for the Study of Drug-Receptor Interactions at
Bar-Ilan University is gratefully acknowledged.
JO971176V
4096 J. O r g . C h e m . 1994,59, 4096-4103

A Practical Guide to First-OrderMultiplet Analysis in lH NMR

Spectroscopy
Thomas R. Hoye,*Paul R. Hanson,la and James R. Vyvyanlb
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455

Received March 9, 1994*

The ability to deduce the proper set of coupling constant (J)values from a complex first-order
multiplet in a IH NMR spectrum is an extremely important asset. This is particularly valuable to
the task of assigning relative configurations among two or more stereocenters in a molecule. Most
books and treatises that deal with coupling constant analysis address the less usefid operation of
generating splitting trees to create the line pattern from a given set of J values. Presented here
are general and systematic protocols for the converse, Le., for deducing the complete set of J values
from the multiplet. Two analytical methods (A, systematic analysis of line spacings, and B,
construction of what can be called inverted splitting trees) are presented first. A reasonably
thorough and systematic set of graphical representations of common doublet of doublets (dd's),
ddd's, and dddd's are then presented. These constitute a complementarymethod for identification
of Js through visual pattern recognition. These approaches are effective strategies for extraction
of coupling constant values from even the most complex first-order multiplets.

Introduction general method for assigning relative configurations of

Proton NMR spectroscopy is, arguably, the most pow-
erful tool for structure assignment in most classes of
organic molecules. Increased access to spectral data
acquired on higher-field NMR spectrometers means that
more and more of the resonances in routine spectra are
first-order. While it is true that most modern spectrom-
eters (as well as an increasing number of desktop
personal computers) have software routines capable of
performing rapid simulation of multispin systems, this
approach to the analysis of complex first-order multiplets
is often cumbersome, time consuming, or less than
convenient. Simulation of a given multiplet is largely
an empirical process that requires an initial determina-
tion or estimate of several of the individual coupling
constants. Thus, the use of these computer-aided algo-
rithms for the generation of simple first-order multiplets
is less attractive than the ability to deduce a correct set
of coupling constants upon simple visual inspection of any
of the typically encountered line patterns. Graphical
representations of common multiplet patterns are, in
principle, quite useful for comparative analysis of actual
data, but nearly all the published work has focused on
non-first-order multiplets.2 The general application of
such representations is somewhat limited for two rea-
sons: second-order multiplets are less frequently en-
countered at higher fields, and if one's spin system does
not have the precise AvlJ value of the calculated spec-
trum, the multiplet in question may look significantly
different from the published representation.
The emergence of routine multidimensional NMR
spectroscopy has been accompanied by a decline in the
learning, teaching, and practice of the important skill of
assigning first-order multiplets by inspection. Determi-
nation of coupling constants is still the most valuable
@ Abstract published in Advance ACS Abstracts, June 15, 1994.
(1) (a) University of Minnesota Graduate School Fellow, 1991-92.
(b) Hercules Fellow, 1993-94.
(Z)(a) Jackman, L. M., Sternhell, S. In International Series of
Monographs in Organic Chemistry;Barton, D. H. R., Doering, W., Eds.;
Oxford: Pergamon Press, 1969; Vol. 5: Applications of Nuclear
Magnetic Resonance Spectroscopy in Organic Chemistry, Chapters 2
and 4 and references therein. (b) Wiberg, K. B., Nist, B. J. The
Interpretation of NMR Spectra; W. A. Benjamin: New York, 1962. (c)
Becker, E.D. High Resolution NMR: Theory and Chemical Applica-
tions, Academic Press: New York, 1980 and references therein.
stereogenic centers in molecules. While the power of
various routine two-dimensional NMR experiments is
unarguable, it comes with a price. Data collection for
2-D experimentsis always more time-consuming than for
the simpler 1-D experiment, and in most settings access
to magnet time is finite. Since 1-D and 2-D methods
often provide complementary structural information, it
is important that chemists maintain expertise with both.
This paper describes two related methods (A and B)
that allow one to identify individual coupling constants
within even the most complex first-order multiplets likely
to be encountered in lH NMR spectra. It also provides a
set of graphical representations (Cand Tables 1-11) for
assisting in empirical, visual pattern recognition.
A first-order multiplet arises when no two of the spins
within an interacting multispin system have 6vIJ 5 -6,
and it always contains a symmetrical distribution of line
positions about the midpoint of the multiplet (i.e., the
chemical ~ h i f t ) .In
~ first-order multiplets the distance
between the outermost pair of peaks is the sum of each
of the coupling constants (Zl's), a fact that we frequently
find useful in assigning or verifying, for example, the last
J value for an incompletely resolved complex m ~ l t i p l e t . ~
Often "special relationships" exist among the sets of
coupling constants. We define these as cases where one
of the coupling constants is equal to some combination
of sums and/or differences among the remaining coupling
constants. So defined, these special relationships always
serve to reduce the number of lines in the multiplet and
simplify (or complicate, depending on one's experience
and point of view) the observed pattern. Finally, note
that it is often, but by no means always, possible to
determine a given coupling constant from either of a pair
of spin-coupled resonances.
Methods for Deducing Coupling Constant Values
A. Systematic Analysis of Line Spacings. The
task of extracting the actual values of coupling constanta
(3) Caution must be exercised, however, because many second-order
patterns (e.g.,AB,AA'BB', AAXX', and ABX) are also symmetrical.
(4) Often the sum of the S s for non-first-order multiplets is also
the distance between the outside lines of the multiplet, but this
relationship deteriorates by the appearance of additional lines as AvlJ
becomes smaller and smaller.

0022-326319411959-4096$04.50/00 1994 American Chemical Society

First-Order Multiplet Analysis in HNMR Spectroscopy J. Org. Chem., Vol. 59, No. 15,1994 4097
Chart 1. Assocation between Coupling Constants and Line SpacingeO within dds and ddds

Association Line Spacing Description

for dds JL { 1 to 3)a (= {2 to 4)) larger J
Js { 1 to 2) (= (3 to 4)) smaller J
ZJS = JL + J s 11 t04) sum of Js
JL- Js (2 to 31 difference of Js

for ddds JL (lto5)(={2to6)={3to7)={4to8)) largestJ

where JM { l t03) (= (2 to4) = {5 to 7) = (6to 8)) medium J
JL 2 Ju + Js JS { l to 2) (= {3 to 4) = (5 to 6 }= {7 to 8)) smallest J
ZJS = JL + JM + Js {1 to81 sum of Js
JM + Js { l t04) (= {5 to 8)) sum of smaller two Js
JM - Js {2 to 3) (I { 6 to 7)) differenceof smallertwo Js
JL + JM {lto7)(={2t08}) sum of larger two Js
J L - JM (3 to 5) (= {4 to 6)) differenceof larger two Js
JL+ Js { 1 to 6) (= (3 to 8)) sum of largest and smallest Js
JL- Js (2 to 5 }(= {4 to 7)) differenceof largest and smallest Js

for ddds JL { I to4) (= {2to6} = {3 to7) = (5 tog)) largest J

where JM { 1 to3) (= (2 to5) = (4 to 7) = ( 6 to 8)) mediumJ
JL 5 JM + Js Js ( 1 to 2) (= {3 to 5) = {4 to 6 } = {7 to 8)) smallest J
ZJS = JL + JM + J s 11 to81 sum of Js
JM + Js ( 1 to 5) (= {4 to 8)) sum of smaller two Js
JM - Js {2 to 3) (= {6 to 7)) differenceof smaller two Js
JL + JM ( 1 to7)(={2to8)) sum of larger two Js
JL - JM {3 to 4) (= {S to 6)) difference of larger two Js
JL + Js { 1 to 6) (= (3 to 8)) sum of largest and smallest Js
JL - Js (2 to 4) (= (5 to 7)) diffennce of largest and smallest Js

a {i to JI = the separation in hertz between lines i and j .

7 Hz distance between lines i and j is denoted as (i to j )

II
-
A J = 7,4, and 2 Hz throughout the discussion.
f 4Hz (rel. int. = It is important to recognize that even though various
2 Hz
1
I 1:1:1:1:1:1:1:1) sets of lines can have the same spacing, not all of those
sets represent a coupling constant; some are coincidental.
11 12 13 14 s 1 6 1 1
7 1
a This is often a point of confusion. For example the
distances between lines 1to 2,2 to 3, and 3 to 4 in entry
b in Table 1 are all identical even though only (1 to 2)
and (3 to 4) represent an actual J; (2 to 3) is the
4 HZ difference between the two S s (and (1 to 4) is the sum
of the two Ss).
J = 4 , 4 , and 2 Hz
The situation for doublet of doublet of doublets (ddds,
2 Hz bottom portion of Chart 1)is somewhat more complex,
- 1 1 but still readily decipherable. For this treatment it is
useful to define the S s as Js,Jm,and J1 to correspond to
the smallest, medium, and largest S s of the ddd, respec-
tively. Again, the lines are numbered sequentially from
Figure 1. Examples of ddds where JI2 J, + J, (case i) and left to right. The relative line intensities are important.
where Jl s J, + J, (case ii).
In the absence of special relationships, all lines are of
equal intensity, and for a ddd there is a total of eight
from within a given multiplet is most obvious for simple lines [cf. the example in case i) in Figure 11. One
doublet of doublets (dds). If the lines of the multiplet frequently encounters multiplets that contain line su-
are numbered sequentially from, say, left to right (cf. perposition, which is always accompanied by differential
entry a in Table 11,two (of the six) pairs of line spacings relative line intensities and a reduction in the total
are associated with the smaller J value. As also sum- number of lines [cf. the example in case ii) in Figure 11.
marized in the top portion of Chart 1,two more pairs of Under any circumstances the sum of the relative line
line spacings are associated with the larger J, and the intensities will always equal 8 for a ddd (4 for a dd, 16
remaining two pairs represent, respectively, the sum of for a dddd, etc.). Lines of relative intensity greater than
and difference between the large and small S s . The one are assigned more than one line number [e.g., the
4098 J. Org. Chem., Vol. 59, No. 15, 1994 Hoye et al.
sequence 1-(2/3/4)-(5/6/7)-8 for a 1:3:3:1 apparent Chart 2. Protocol for Generating an Inverted
quartet (ddd with three equivalent J's) or the example Splitting Tree: Identification of Individual
in case ii)]. Be aware that "leaning" within a given Coupling Constants as Applied to the dddd from
multiplet, arising from intermediate AvlJ values for Entry e of Table 9
which first-orderedness still holds, will distort the rela-
tive intensities from perfect integer ratios.
For doublet of doublet of doublets two situations can
arise: case i where J1 IJ, +
J , and case ii where J1 5
+
J,,, J,. A typical example for each case is shown in
Figure 1.6 With the lines now numbered as described
above and with reference to the bottom portion of Chart
1, one can assign the values of Js, Jm, and J1 in each of
these multiplets by measuring the appropriate line
spacings. The distance between lines 1 and 2 (i.e., (1 to
2)) always corresponds to the smallest coupling constant
(J,) and { 1 to 3) always corresponds to the next smallest
coupling constant (J,). However, JIcorresponds to (1
t o 5) for case i but to (1 to 4) for case ii. The task of
identifying J 1 from within dddd's (or higher multiplets)
by this strategy is considerably more difficult. However, -
I
JS
I d Ill1 1
removing the smallest coupling (J,)from a dddd, thereby
creating a simplified ddd, permits application of the above
strategy. On the other hand, this simplification is the ii)
first step in creating what we call here an inverted
splitting tree, a process that is generalized next. iii)
B. Inverted Splitting Tree Generation. The pro-
cess of deconvoluting a first-order multiplet more complex
than a ddd by the method described in A is not straight-
forward. We now describe a systematic approach that
is applicable to even the most complex first-order mul-
tiplets. This strategy amounts to generation of an
inverted splitting tree. Many readers are familiar with
iv) c, w LJ
the process of generating the appearance of a first-order
multiplet from a given set of J values, and many texts
present the creation of splitting trees from a single line
by sequential branching (most easily done proceeding
from the largest J to the smallest). However, the ability
to do the converse, to deduce the proper individual J's
uu
from a given complex multiplet, is the more valuable yet
more difficult skill to attain.
The total number of lines and the relative line intensi-
ties within a given multiplet are important parameters.
Recall that dd's, ddd's, and dddd's with no special
relationships will consist of 4, 8, and 16 lines, respec-
tively, all of equivalent intensity and that the presence cult step in the process. A dddd will contain eight such
of special relationships among the coupling constants pairs. Each pair will have a partner pair symmetrically
both reduces the total number of lines and alters the arranged by reflection through the midpoint of the
relative line intensities. The sum of the line intensities, multiplet. Those pairs associated with lines of intensities
appropriately normalized, will be identical for every > 1 will be partially or totally coincident with other pairs.
multiplet of a given class (Le., 4 for dd's, 8 for ddd's, and Thus, the total number of pairs associated with any
16 for dddd's). single line is equal to the relative intensity of that line.
A general protocol for deducing the individual J's for As seen in panel ii), this is manifested in the number of
a given multiplet (illustrated in Chart 2 specifically for times the ends of interconnecting arcs intersect a given
the ten-line 1:2:1:1:3:3:1:1:2:1dddd corresponding to line position (or vertical tick). That is, lines of intensities
entry e of Table 9) consists of the following: 1, 2, and 3 in the multiplet in Chart 2 have the ends of
Step i: As discussed earlier, the distance between lines one, two, or three arcs, respectively, terminating at that
1 and 2 (or the, say, left-hand-most pair) always repre- line position [ef. panel ii)].
sents the smallest J value of the multiplet [cf.,J,in panel Step iii: Identify the centers of each of the pairs
i) of Chart 21. If their relative intensity is 1:1, then the created in step ii, which collectively represent a new,
smallest J is unique; if it is 1:2 (or 1:3, etc.), then there simplified pattern (a ddd) as indicated by the dots in
are two (or three, etc.) identical smallest S s . panel iii) as well as the tick marks in panel iv) in Chart
Step ii: Identify the full set of pairs of lines separated 2. Notice that this submultiplet (in this instance a seven-
by this smallest J value. This is perhaps the most diffi- line 1:1:1:2:1:1:1ddd) is the residual pattern that would
remain after selective decoupling of the spin responsible
( 5 ) Notice that the examples chosen to illustrate cases i and ii were for the smallest J in the original multiplet. The spacing
somewhat arbitrarily chosen. Examples could easily have been selected
in which the case i and case ii multiplets contained fewer than and between the first (or last) pair of dots in this simplified
exactly eight total lines, respectively, rather than the converse. multiplet represents the next smallest J of the original
First-Order Multiplet Analysis in lH NMR Spectroscopy J. Org. Chem., Vol. 59, No. 15, 1994 4099
Table 1. dd's Table 2. ddd's Where J, = J, (app dt's)

ntry Multlplet Appearance -

nl

a D 4 4 20

b I2 4 4 20

C 9 4-4 17

d 8 4-4 16 Jir-Jir+J

0 7 4-4 15

f 6 4-4 14

II 5 4-4 13

h 4 44 12 J i r - J i ~

1B
1 I
z4
I 3 4-4 11

a"' -
I 2 44 IO

r
25 1 4-4 9

@ 6 = 0.61; dd; J 8.3.3.8 Hz; entry b

H'
''*e/\\ -
6 - 0.44;d d J 3.8,3.8 Hr; entry e
I 0 4-4 8

-
11
b
h3.72, ddd, J I 11.3, 11.3,2.5 Hi
mw k
&D 15 ID 6 D -S -ID -15 Ik

J, decreases until the two halves are superimposed in

multiplet [i.e.,Jdmdium in panel iv); incidentally note
that J, = J,, for the example in Chart 21.
Step iv: The centers of each of these new pairs
[diamonds in panel iv)] collectively represent a new,
further simplified, four-line pattern (a dd). The distance
between the first (or last) pair of diamonds in panel iv)
as well as the tick marks in panel v) represents the third
smallest Coupling Constant, Jamedium large).
Step v: Repeat as necessary until all S s have been
established. One simple check for internal consistency
is to verify that the sum of the determined coupling
constants ( V s )is equal to the distance between the two
outermost lines of the multiplet.
C. Graphical Representations (Tables 1-11). An
alternative strategy for analysis of first-order multiplets
is through visual pattern recognition. Many will find this
approach complementary or preferable to the more
analytical methods discussed above. We have generated
a series of tables that shows systematic sets of first-order
multiplets for the most commonly encountered spin
systems. Representations of dd's and ddd's as well as of
the more complex doublet of doublet of doublet of doublets
(5 spins, dddd's) are included. Within any one table a
single coupling constant, arbitrarily named J,, is varied
from large to small (usually to 0 Hz)values; the remain-
ing coupling constants (J,,Jx,J,) are invariant through-
out any one table. As a consequence, within any one
table, entry a consists of relatively widely spaced, identi-
cal halves of the multiplet that converge as the variable
the limit where the J, = 0. Intermediate entries cor-
respond to partially merged situations in which the two
halves have undergone one or more sequential crossings
of the innermost lines.
For some of the Table entries, special relationships
(vide supra) exist among the Ss. These relationships,
along with the magnitudes of J,, Jx,Jy,JL,and the U s ,
are listed in the right-hand columns of each table.
Note that although a specific (but arbitrary) set of J
values has been chosen for illustrating the trends within
any one table, those trends hold, of course, for any set
of Js having similar relative magnitudes and special rela-
tionships.
For any given table the specific line numbers that
correspond to the generic J,, Jx, Jy, and J, are noted
below the generic column heading. These line number-
ings change from table to table. For example, J, in Table
1 is J13 (i.e., 11 to 30 while J, in Table 2 is J14.
Note that the line numberings used in Tables 1-11
do not follow the rigorous convention used in sections A
and B. Instead, the multiplet in entry a is simply
numbered from left to right disregarding relative line
intensities. Thus, each line has a single number at the
outset (entry a), the crossing phenomena just mentioned
are more easily tracked, identification of Ss within a
visually matched multiplet is facilitated, and, impor-
tantly, the 1ine.spacingscorresponding to every coupling
constant, including the variable J,, remain the same for
all entries in the table.
4100 J.Org. Chem., Vol. 59, No. 15, 1994 Hoye et al.
Table 3. ddd's Where J, = J, Table 4. ddd'e Where J, = 25%

-
ni
-en1

a 9 4 3 1 6 a 10 4 2 16

b 8 4 3 1 5 b 8 4 2 1 4
m
C 7 4 3 14Jf,=Je+Jlz 7 4 2 1 3
" C

d 6 4 3 1 3
ci 6 4 2 12Jls=Jfa+Jj;

0 5 4 3 1 2 e 5 4 2 1 1

f 4 4 3 11 Jl,-Jlj f 4 4 2 10 Je-Jfj

Q 3 4 3 10 Ji5-Jj~ 0 3 4 2 9

h 2 4 3 9 h 2 4 2 8 Jf5~Ja

i i t!!tfl,!t 1 1 4 2 7

I
-

~ @ b2.58.ddd,J-18.2.9.6.8.4HZ
88 II *I I 8 4 -1s -15 w
mry C

Included in each table is one (or two) representative Table 1. ddd's Where J, JI
multiplet(s) arising from the circled (or boxed) proton(s)
taken from 'H NMR spectra of known molecules.6 Al-
though many of these presentations are simulations' of
tabulated J values (since they are taken from 'pre-
Lentry Multiplet Appearance
Jz Jy
J u J'r Jfr J'e

9 8 1 1 6
Jr ' Relation-
8hlPS

electronic storage" spectra), we have confirmed that this

is an accurate representation of the actual spectrum by 8 6 1 1 5

simulating multiplets for which the actual spectra were 7 6 1 14 Jls=J~j+Jfz

available. The examples in Tables 1, 4, 5, 9(e), and 10
(g) are taken from "real" rather than simulated spectra. 6 6 1 13 Jfs=Jfa
The examples in all of the tables were selected to
illustrate cases where special relationships exist among 5 6 1 12 Ja-Jta-Js
the Js. These are particularly instructive since first-
4 6 1 1 1
order multiplets with no special relationships give a full
complement of 4,8,16, ... lines of identical intensity that 3 6 1 1 0
are relatively easy to identify and interpret.
Table 1 and Tables 2-5 contain all the possible h 2 6 1 9
permutations of relative J values for dd's and ddd's,
respectively. In other words, every conceivable first-order 1 6 1 8 Jjs=Jiz
dd and ddd pattern can be approximatelymatched to one 0 8 1 7
of the entries in these tables. On the other hand, only a
somewhat arbitrarily chosen representative set (vide
infra) of all possible dddd's is illustrated in Tables 6-11.
Table 1shows the familiar series of typical doublet of
doublets. Notice that there are several relative line
(6)Spectral data were collected on a variety of spectrometers
ranging from 300 to 500 MHz. (a) Examples from Tables 1, 5, and 9,
entry e: Vyvyan, J. R. Unpublished results. (b) Examples from Tables
2,6, entry f, 7, and 8: North, J. T. Ph. D. Dissertation, University of
Minnesota, 1990.(c) Examples from Tables 3,9,entry g, and 10,entry
c: Peck, D. R. Ph. D. Dissertation, University of Minnesota, 1984.(d)
Example from Table 4: Koltun, D. O., Vyvyan, J. R. Unpublished
results. (e) Examples from Tables 6, entry c, and 11: Dellaria, J. F.
Ph. D. Dissertation, University of Minnesota, 1982.(0Example from spacings that repeat themselves during the progression
Chart 3: Renner, M. K, Priest, 0. P. Unpublished results. from large to small. For example, entries a and
of Jz(13)
(7) Simulation was performed with the VNMR version 4.1 software
package on a Varian VXR spectrometer using a spectrometer frequency h are each a pair of narrowly spaced outer and a pair of
of 500 MHz and a line width ranging from 0.5 to 0.7 Hz. widely spaced inner lines. Similarly, entries b and g are
First-Order Multiplet Analysis in ' H N M R Spectroscopy J . Org. Chem., Vol. 59, No. 15, 1994 4101
Table 8. dddd's Where JJ = J, (app dtd's)

a @
b
b
C

El d
0
d
t
r 9
h
0
I
I
i
k

@ 62.80, dddd,J -H
12.0.3.0.3.0, 1.0 Hz
entry a

Table 7. dddd's Where J, = J, and Jx = Jw (app tt's)

Ja* Jy J.*Jw Z ~ ~ ~ ~
a !
i ~
f! i
a 12 5 3-3 23
entry Multiplet Apprrrancr JI,= J W Ja=J W J'S Relationships

0-8 2-2 20

6-6 2. 16

65 2-2 14

/ml .12.10
!
% .6'4'.2
! fA!!Ak!
0 2 4 6 8
a
10 12*

@b0.61. -
dddd,J 8.7, 5.3. 3.4,3.4 HZ
nnby 0
?
,

Tables 2-5 show the multiplets associated with dou-

blet of doublet of doublets under circumstances where
each a set of four equally spaced lines; they also have two of the three coupling constants are equal (Jy(12,)=
the same special relationship. Finally, the number of JdI2),Table 21, nearly equal (Jd13)= J d l ~ Table
), 3), related
lines is reduced to three (cf. entry e) in the trivial and by a factor of two (Jd13)= 2Jd12),Table 41, or very different
common case of a dd appearing as an apparent triplet * J ~ I zTable
(Jy(13) ), 5). Table 2 contains the case where
with relative line intensities of 1:2:1. the two invariant coupling constants (Jy(ly)and Jx(12)) of
4102 J . Org. Chem., Vol. 59,No. 15, 1994 Hoye et al.
Table 10. dddd's Where Jy Jx rx Jw Chart 3. Inverted Splitting Tree Analysis for the
x ddq (app tq) from H(3) in One Rotamer of the
Jz Jy Jx Jw
;% ;:\-
-entry Multiplrt Apporrantr
~~~~
J t r JtaJis J'r #hip8 Mosher Amide 1
a I ?I!C L C ?. A,! !!I d
b ! I!! I ! ! ! !A! A! c,
El 4 111 !Id Id! !dB 4
d 1 1 1 1 Al All 1 1 1 1
e 1 1 1 1 llllll 1 1 1 1
t 1 1111111111111 1

9 1 Al 1 1 1 1 1 1 1 1
h 1 Ill 111 Al 1
I 1 llllllllll 1
I 1 1 1 l ~ l ~ l ~ 1l l A
6.5 Hz
k 11 l l l l l l l l 11
I I 111 1 1 1 1
.h , i, . i ' i . 6

-
I . . .
42.10 1 i'b'h'b'ti
- 6.5 Hz

61.83.dddd. J-14.0.7.6,6.5, 5.0Hz

entry c W 9.5 Hz ~ L S

'"'
a
r
Table 11. dddd's Where J y

Multlplrt Appearancr

t t ! ! ! :t A A! a a tf c 12 7 3
* Jx

2
F-Z

24
Jw

JIO-JIS+J~S+JIZ
Me' 0 @i 0

b ! !! ! : it!!!! a b tf t I1 7 3 2 23
'eM
0 Me
Ph"' CF~
!!!!!!1I!A!tA! s 10
10 7 3 2 22 Jio-Jis+Jis Me0
! t ! ! ! !!!! a r, A!' f 9 7 3 2 21 JIO-JIJ+JIZ

lines)]. Table 3 contains the cases where the two invari-

! t! ! $:;!a! a Ct t 8 7 3 2 20 JIO-J~S*JII-JD
ant coupling constants are only slightly different. The
t !f ! A !J ?, a ?a d 7 7 3 2 19 Jio-Jis illustrated example,in which the central two lines of the
I011
ddd coincide and for which the largest J value is the s u m
6 7 3 2 18 JIO-J,I+J~Z.JR
+
of the two smaller Ss (i.e., J2(15)= J ~ l 3 ) Jx(12)cf. entry
5 7 3 2 17 JIO-JIJ+JIZ c), is a commonly encountered one. This relationship and
pattern (a seven-line 1:1:1:2:1:1:1multiplet) are also seen
in the example accompanying Table 4 (entry d). Table 5
illustrates the case where one of the invariant Ss is
always significantly larger than the second (Jd13,>> J~(12)).
0 The multiplet arising from the boxed proton in the
example molecule corresponds to a situation intermediate
between entries c and d and illustrates an important
point. Namely, to find the best fit one must sometimes
envision the continuum of multiplets that arise by sliding
together the two halves of the pattern for entry a (as J ,
decreases) within any one table. There often is not a
perfect correlation between the multiplet under analysis
and a specific table entry.
the ddd are identical so that the multiplets are all Tables 6-11 show doublet of doublet of doublet of
apparent doublets of triplets (6 lines), sometimes with doublets (dddd's) that increase in their complexity as the
additional simplification arising from additional special tables progress. Table 6 illustrates the case where three
relationships [e.g., entries d (5 lines), h (4 lines), and 1(3 of the four S s are equal, resulting in an apparent doublet
First-Order Multiplet Analysis in 'H NMR Spectroscopy
of quartets (i.e., app dq). This type of relationship is
prevalent in rigid ring systems either where a geminal
and two diaxial couplings give three approximately
equivalent S s and the fourth and smallest J arises from
the gauche axial-equatorial arrangement of a pair of
vicinal protons or, as is the case for the example of the
boxed proton (cf. entry c), where a single large geminal
coupling is accompanied by three approximately equiva-
lent and small gauche couplings. The special relationship
where the largest J is twice as large as any of the
equivalent smallest S a is present in the example of the
circled proton (cf. entry f) and results in the greatly
simplified six-line pattern. Table 7 shows multiplets that
contain two pairs of identical S a (i.e., app tt's). The
example in Table 7 (cf. entry e) is commonly encountered
in acyclic molecules where a methine proton is flanked
by two methylene groups that each constitutes a pair of
diastereotopic protons. Table 8 depicts dddd's in which
the two S a of intermediate magnitude are identical (i.e.,
app dtd's). Notice that the smallest J (1 Hz) in the
example multiplet (cf. entry a) arises from four-bond
W-coupling. Table 9 presents multiplets in which the two
smallest S s are identical in magnitude (i.e., app ddt's),
although cases where the value of Jz(mdrops below Jy(13)
are not shown . Another commonly encountered ddt
arises from the methine of a terminal allyl group (i.e.,
CHz=CHCHzR, not shown).
Tables 10 and 11include representative cases of dddd's
t o which no universal special relationship applies (as is
the case for Tables 6-9). Thus, for the first time among
Tables 6-11 some of the entries show multiplets having
the full complement of sixteen lines. The multiplets in
Table 10 contain three and those in Table 11contain two
small S a of nearly equal magnitude.
J. Org. Chem., Vol.59, No.15, 1994 4103
Recognize that there exist other possible combinations
for the relative magnitudes of J's within the family of
dddd's than those shown in Tables 6-11. Recall that all
permutations of J values for the simpler dd's and ddd's
were encompassed by Tables 1 and 2-5, respectively.
When in need, the reader is encouraged to extend the
methods described here to those cases of J value combi-
nations for dddd's not explicitly covered as well as to yet
more complex multiplets like the ddddd's.
We conclude with one example of the latter. Chart 3
shows the multiplet arising from H(3) in the minor
rotamer of the indicated Mosher amide.6f The multiplet
was identified by the inverted splitting tree method as a
ddq with J = 9.5, 9.5, and 6.5 by the sequence of steps
outlined in Chart 3. This set of coupling constants
requires that the molecule exists largely in the conforma-
tion having dihedral angles of -150" and 30" between
H(3)/H(4a) and H(3)/H(4b), respectively. It should be
noted that it was not possible to identify the two vicinal
9.5 Hz Js from the benzylic methylene resonances due
to significant overlap among those resonances for the
amide rotamers, even at 500 MHz.
We have found the complementary approaches of
visual pattern recognition (C) as well as the more
systematic and analytical methods described in A and B
to be effective and powerful tools. These approaches
permit easy access to the rich, intrinsic information that
is universally available via the simplest of N M R experi-
ments.
Acknowledgment. This work was supported by the
DHHS Grants GM 34492 and 39339. We acknowledge
Mr. Zhixiong Ye for enunciating ideas that aided the
development of the systematic analysis of line spacings
and inverted splitting tree generation described here.
4014 J. Org. Chem. 2002, 67, 4014-4016

A Method for Easily Determining Coupling Constant Values: An

Addendum to A Practical Guide to First-Order Multiplet Analysis
in 1H NMR Spectroscopy

Thomas R. Hoye* and Hongyu Zhao

Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455

hoye@chem.umn.edu

Received July 26, 2000 (Revised Manuscript Received March 28, 2002)

A systematic procedure to decipher first-order 1H NMR multiplets is described. This method is a

very practical tool for extracting coupling constant values. It requires only that one (a) learn to
identify each of the 2n (n ) number of spin 1/2 nuclei to which the proton is coupled) units of
intensity of a multiplet and (b) then apply a clearly delineated sequence of iterative steps that
allows the Js to be assigned in order (from smallest to largest). The approach is even easier to use
than one described previously (J. Org. Chem. 1994, 59, 4096-4103).

Introduction

Several years ago, we described a method for decipher-

ing the individual coupling constants from a complex,
first-order multiplet in a 1H NMR spectrum.1 Anecdotal
evidence makes it clear that many have found this
discussion to be very helpful. We now present an alterna-
tive, complementary protocol for obtaining the same
information. The method we describe here makes the
task of extracting the individual J values from complex
multiplets even easier.
In general,2 a first-order multiplet with chemical shift
, having coupling constants arising from interaction
with n spin 1/2 nuclei, will contain a maximum of 2n peaks
that are symmetrically arrayed about the midpoint ().
The actual number of individual peaks is usually reduced
by degeneracies arising from certain relationships among
two or more Js (e.g., two identical J values or cases
where a third J is the sum or difference of two other J
values). Nonetheless, the total units of intensity, here-
after called components, will always sum to 2n regardless
of the presence or absence of line degeneracy. A trivial
example makes the point: a 1:1:1:1 doublet of doublets
(dd) and a 1:2:1 triplet (i.e., a dd with identical Js in
which components number 2 and 3 are superimposed)
both contain a total of four (22) components.3 The increas-
ingly complex set of multiplets shown in Figure 1 Figure 1. Four examples of assignment of all 2n components
reinforce this important point. Recognize that each of the to the individual lines in a first-order multiplet.
2n individual components coincides with one of the
following line positions in the multiplet: (Hz) + 1/2((J1 lines in the multiplet are (Hz) + 1/2(+J1 + J2 + J3 ... +
( J2 ( J3 ... (Jn). The furthest downfield and upfield Jn) and (Hz) + 1/2(-J1 - J2 - J3 ... -Jn), respectively.
It follows that the separation between the outermost
(1) Hoye, T. R.; Hanson, P. R.; Vyvyan, J. R. J. Org. Chem. 1994, peaks of a multiplet is the sum of the individual coupling
59, 4096-4103. constants.4,2
(2) Most of the concepts noted in this introductory paragraph are
well established and accepted truths, the original statements of which In what follows and for the sake of generality, we
are difficult to locate but the existences of which are evidenced in many consider any multiplet arising from interaction with n
of the early treatises in the field: e.g., (a) Jackman, L. M.; Sternhell, protons to be a series of n doublets (e.g., dddd for n ) 4)
S. Applications of Nuclear Magnetic Resonance Spectroscopy in Organic
Chemistry; Pergamon: Oxford, 1959. (b) Bovey, F. A. Nuclear Magnetic regardless of whether any of the protons are chemically
Resonance Spectroscopy; Academic Press: New York, 1969. (c) Becker, and magnetically equivalent. In the case of equivalency,
E. D. High-Resolution NMR.; Theory and Chemical Applications;
Academic Press: New York, 1969.
(3) The outermost peaks in the multiplet are always the smallest (4) I.e., the total width of the multiplet ) (Hz) + 1/2(+J1 + J2 + J3
and should be assigned a relative intensity value of 1. ... + Jn) - [ (Hz) + 1/2(-J1 - J2 - J3 ... -Jn)] ) (J1 + J2 + J3 ... + Jn).

10.1021/jo001139v CCC: $22.00 2002 American Chemical Society

Published on Web 05/14/2002
Determination of Coupling Constant Values J. Org. Chem., Vol. 67, No. 12, 2002 4015

Chart 1. Steps for Identifying J Values in Sequence from Smallest to Largest (J1 to Jn) ({1 to x}
Represents the Distance between the Peak Corresponding to Component 1 to the Peak Corresponding to
Component x)

a {1 to 2} ) (Hz) + 1/ (+J + J + J ... + J ) - [ (Hz) + 1/ (-J + J + J ... + J )] ) J . b {1 to 3} ) (Hz) + 1/ (+J + J + J ...

2 1 2 3 n 2 1 2 3 n 1 2 1 2 3
+ Jn) - [ (Hz) + 1/2(+J1 - J2 + J3 ... + Jn)] ) J2. c Each peak in the multiplet may (and often will) contain more than one component;
each component should be individually removed from consideration or associated with a J value. For a ddd: {1 to 4} (or {1 to 5}) )
d

(Hz) + 1/2(+J1 + J2 + J3 ... + Jn) - [ (Hz) + 1/2(-J1 - J2 + J3 ... + Jn)] ) J1 + J2 and {1 to 5} (or {1 to 4}) ) (Hz) + 1/2(+J1 + J2 +
J3 ... + Jn) - [ (Hz) + 1/2(+J1 + J2 - J3 ... + Jn)] ) J3.

identification of the individual Js (cf. Chart 1 and the

Figure 2. Assignment of J1-J4 for a dddd by applying steps
i-vi from Chart 1.
the multiplets are more commonly referred to, of course,
as triplets, quartets, pentets, etc. (i.e., dd, ddd, dddd, etc.
with identical Js). Recognize then, that the method
presented below for deducing the values of all Js in, e.g.,
a dddd is applicable to all multiplets with 16 compo-
nents: i.e., a pentet (p), a doublet of quartets (dq), a
triplet of triplets (tt), or a doublet of doublet of triplets
(ddt) in addition to a true doublet of doublet of doublet
of doublets (dddd).
The method we now describe for deducing the indi-
vidual J values from any first-order multiplet requires
two principal operations: (i) assignment of each of the
individual 2n components (cf. Figure 1) and (ii) systematic
example in Figure 2).5
For the first operation, assign every peak in the
multiplet one or more component numbers from 1 to 2n
from left to right (arbitrarily) by analogy to the examples
shown in Figure 1. This involves assigning the relative
intensities among all peaks of the multiplet, an operation
that for some complex resonances (cf., Figure 1d) might
require an iterative approach but that is usually straight-
forward for multiplets having 4, 8, 16, and even 32
components.
The second operation requires systematic identification
of the Js by the series of steps outlined in Chart 1. Adopt
the convention that J1 e J2 e J3 e J4 e ... Jn. Appreciate
that for J3 and beyond it is necessary to have first
determined the previous coupling constants (e.g., both
J1 and J2 must be known before J3 can be determined).
In other words, one must deduce the Js in order, from
smallest to largest. Assign individual coupling constant
values starting with step i (Chart 1), where {1 to x} is
the distance in Hz between component 1 (which, neces-
sarily, corresponds to the lefthandmost peak) and com-
ponent x. The task is complete (all Js identified) following
step iv for a ddd, vi for a dddd, and viii for a ddddd. In
practice, for some complex, slightly non-first-order (lean-
ing/distorted), and/or partially overlapped multiplets, it
is advantageous to work synergistically from both ex-
tremities of the multiplet.
Consider the dddd, whose component numbers were
assigned in Figure 1c. In Figure 2, the determination of
(5) The process requires practice at the outset, but it is well worth
learning. Once familiar with the technique, people have deduced the
six individual J values in the multiplet shown in Figure 3e (a dddddd)
in 1-2 min.
4016 J. Org. Chem., Vol. 67, No. 12, 2002 Hoye and Zhao

Figure 3. Examples of experimental multiplets for which the complete set of J values has been determined.

the Js, arrived at by sequential application of steps i-vi,
is shown.
This method has proven to be very practical. Com-
monly encountered first-order multiplets can be quickly
analyzed.6 Some selected multiplets from actual spec-
tra are presented in Figure 3 to further demonstrate
the power of this method. Notice that resolution en-
hancement/line broadening (vertical arrow in Figure
3e) can sometimes make the assignment of the 2n
component numbers more straightforward. Finally, it
should not be overlooked that coupling constant values
are valuable because they convey information about
geometry.7,8
Acknowledgment. This study was supported by a
grant awarded by the DHHS (CA-76497). We thank Mr.
B. M. Eklov for help with rendering the graphics.
JO001139V
(8) For example, the vicinal coupling constants for the two protons
shown in Figure 3d,e suggest that the hydrogen-bonded conformation
1 (with two gauche relationships between Ha and its methine neighbors
and one gauche and two anti arrangements between Hb and its three
neighbors) is a major contributor in CDCl3 to the family of conformers
that define the solution structure of this polyol fragment. This is not
necessarily to be expected because of the steric congestion flanking
the C(4)-C(5) bond and would be a very difficult issue to assess by
any method other than the magnitudes of coupling constants.

(6) Note Added in Proof. For a very recently described, comple-

mentary approach to automated first-order multiplet analysis, see:
Golotvin, S.; Vodopianov, E.; Williams, A. Magn. Reson. Chem. 2002,
40, 331-336.
(7) Karplus, M. J. Chem. Phys. 1959 30, 11-15.

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,2 2)-6('*4 'B6&1),+*M)+ -,,/ ,(/'(7
O3'+ ",6 &(' *&1)*2)'/ 13&1 ",6 3&>' )+056/'/ 0// 13' /&1&
J,( 13&1 ",6 I+,= =3&1 &//)1),+&5 /&1& ",6 )+1'+/ 1, 0,55'01K4
&+/ 3&>' & %5&6*)?5' ,(-&+).&1),+4 -)>' 13' ,615)+' 1, ;'7 S);9
%5" )+/)0&1' =3'(' ;)**)+- /&1& =)55 -,4 3,= ",6 13)+I
J3"%,13'*).'K 13'" =)55 5,,I4 &+/ 3,= ",6 =)55 )+1'(%('1 13';
)2 ",6( 3"%,13'*)* )* 0,(('017 : =)55 1&I' 13)* ,615)+'4 &// ;"
,%)+),+*4 *6--'*1 03&+-'*4 &+/ ('16(+ )1 1, ",67 :1 6*6&55" 1&I'*
2,6( 1, 2)>' )1'(&1),+* J,21'+ =)13 &//)1),+&5 'C%'();'+1*K 1,
&-('' ,+ &+ ,615)+'7 O3'+ =' )0>" &-(''/4 13' /&1& &(' 6*6&59
5" )+ J,( 05,*' 1,K 2)+&5 2,(; J13&1 )*4 13' 1&?5'*4 2)-6('*4 '1074 )+
13' ,615)+' =)55 ?' 13' 1&?5'*4 2)-6('*4777 )+ 13' %&%'(K7
E,6 0&+ 13'+ *1&(1 =()1)+-4 =)13 *,;' &**6(&+0' 13&1 ;603
,2 ",6( %(,*' =)55 ?' 6*'/7
H3' I'" 1, '22)0)'+1 6*' ,2 ",6( &+/ ;" 1);' )* 13&1 =' *1&(1
'C03&+-)+- ,615)+'* &+/ %(,%,*&5* &* '&(5" )+ & %(,<'01 &* %,*9
*)?5'7 ;# 1#+? 51-"$ 01@ 4*$456,+014",? A0*+ 51+*/ +)" 4#//"4+*#1
#3 -0+0 *, B4#6./"+"C D"3#$" ,+0$+*1% +# A$*+" 01 #5+/*1"' Y,
%(,<'01 )* '>'( 0,;%5'1'4 &+/ )1 *&>'* '+,(;,6* '22,(1 &+/
;603 1);' 1, %(,%,*' & %5&6*)?5' %&%'( &+/ ,615)+' &* *,,+ &*
",6 *'' 13' ?&*)0 *1(6016(' ,2 & %(,<'017 \>'+ )2 =' /'0)/' 1,
/, *)-+)2)0&+1 &//)1),+&5 =,(I ?'2,(' *'(),6*5" ,(-&+).)+- &
%&%'(4 13' '22,(1 ,2 =()1)+- &+ ,615)+' =)55 3&>' 3'5%'/ 1,
-6)/' 13' ('*'&(037
:5C5 ="% ;,$<#/%
O3&1 &+ ,615)+' *3,65/ 0,+1&)+N
7' E*+/"
9' F5+)#$,
<' FD,+$04+
Q, 1#+ =()1' &+ &?*1(&017 H3&1 0&+ ?' /,+' =3'+ 13' %&%'(
)* 0,;%5'1'7
G' 81+$#-54+*#1
H3' 2)(*1 %&(&-(&%3 ,( 1=, *3,65/ ?' =()11'+ ,61 0,;%5'1'9
5"7 8&" %&(1)065&( &11'+1),+ 1, 13' ,%'+)+- *'+1'+0'7 :/'&55"4 )1
*3,65/ *1&1' 0,+0)*'5" 13' ,?<'01)>' ,2 13' =,(I4 &+/ )+/)0&1'
=3" 13)* ,?<'01)>' )* );%,(1&+17
:+ -'+'(&54 13' :+1(,/601),+ *3,65/ 3&>' 13'*' '5';'+1*N
! H3' #DH"4+*>", ,2 13' =,(I7
(0./ - .//, 012345678 69:;<) =>?8 @ 7#$ A=<'! 09BCD9B>
,$ %$ -./'(0/"(0_0DB+9*BK9*` =:#(MX 0:B+BC) < H<M9:
! H3' H5,+*3*40+*#1 2,( 13'*' ,?<'01)>'*N O3" )* 13' =,(I );9
%,(1&+1P
! I04J%$#51-N O3, '5*' 3&* /,+' =3&1P R,=P O3&1 3&>'
A" /,+' %('>),6*5"P
! !5*-014" +# +)" $"0-"$N O3&1 *3,65/ 13' ('&/'( =&103 2,(
)+ 13' %&%'(P O3&1 &(' 13' )+1'('*1)+- 3)-3 %,)+1*P O3&1
*1(&1'-" /)/ =' 6*'P
! K5660$@L4#14/5,*#1N O3&1 *3,65/ 13' ('&/'( 'C%'01 &*
0,+056*),+P :+ &/>&+0'/ >'(*),+* ,2 13' ,615)+'4 ",6
*3,65/ &5*, )+056/' &55 13' *'01),+* 13&1 =)55 -, )+ 13'
\C%'();'+1&5 *'01),+ J&1 13' 5'>'5 ,2 %&(&-(&%3 *6?3'&/9
)+-*K &+/ )+/)0&1' =3&1 )+2,(;&1),+ =)55 -, )+ 13' L)0(,9
2)5; *'01),+7
M' :",5/+, 01- ;*,45,,*#1
H3' ('*651* &+/ /)*06**),+ &(' 6*6&55" 0,;?)+'/7 H3)* *'09
1),+ *3,65/ ?' ,(-&+).'/ &00,(/)+- 1, ;&<,( 1,%)0*7 H3' *'%&9
(&1' %&(1* *3,65/ 3&>' *6?3'&/)+-* )+ ?,5/2&0' 1, ;&I' 13)*
,(-&+).&1),+ 05'&(4 &+/ 1, 3'5% 13' ('&/'( *0&+ 13(,6-3 13'
2)+&5 1'C1 1, 2)+/ 13' %&(1* ,2 )+1'('*17 H3' 2,55,=)+- 5)*1
)+056/'* 'C&;%5'* ,2 %3(&*'* 13&1 ;)-31 %5&6*)?5" *'(>' &*
*'01),+ 3'&/)+-*N
! S"+13'*)* ,2 $5I&+' H3),5*
! Z3&(&01'().&1),+ ,2 L,+,5&"'(*
! $?*,561' Z,+2)-6(&1),+ ,2 13' ])0)+&5 Q),5 ^+)1
! R"*1'('*)* Z,(('5&1'* =)13 D,6-3+'** ,2 13' S6(2&0'
! Q'%'+/'+0' ,2 13' D&1' Z,+*1&+1 ,+ H';%'(&16('
! H3' D&1' ,2 S'529\C03&+-' Q'0('&*'* =)13 13' 8,5&()1" ,2
13' S,5>'+1
H(" 1, ;&I' 13'*' *'01),+ 3'&/)+-* &* *%'0)2)0 &+/ )+2,(;&9
1),+9()03 &* %,**)?5'7 [,( 'C&;%5'4 13' %3(&*' @H3' D&1' ,2
S'529\C03&+-' Q'0('&*'* =)13 H3' 8,5&()1" ,2 H3' S,5>'+1A )*
,?>),6*5" 5,+-'( 13&+ @L'&*6(';'+1 ,2 D&1'*A4 ?61 ;603
;,(' 6*'265 1, 13' ('&/'(7 :+ -'+'(&54 1(" 1, 0,>'( 13' ;&<,(
0,;;,+ %,)+1*N
! S"+13'*)* ,2 *1&(1)+- ;&1'()&5*
! Z3&(&01'().&1),+ ,2 %(,/601*
! L'13,/* ,2 03&(&01'().&1),+
! L'13,/* ,2 ;'&*6(';'+1
! D'*651* J(&1' 0,+*1&+1*4 0,+1&01 &+-5'*4 =3&1'>'(K
:+ 13' ,615)+'4 /, +,1 =()1' &+" *)-+)2)0&+1 &;,6+1 ,2 1'C14
?61 -'1 &55 13' /&1& )+ 13')( %(,%'( %5&0'N $+" 1'C1 *3,65/ *);9
%5" )+/)0&1' =3&1 =)55 -, )+ 13&1 *'01),+7
! S'01),+ R'&/)+-*
! [)-6('* JA*+) 0&%1),+*K
! S03';'* J=)13 0&%1),+* &+/ 2,,1+,1'*K
! \B6&1),+*
! H&?5'* J0,(('015" 2,(;&11'/K
D';';?'( 1, 13)+I ,2 & %&%'( &* & 0,55'01),+ ,2 'C%'();'+9
1&5 ('*651*4 *6;;&().'/ &* 05'&(5" &+/ '0,+,;)0&55" &* %,**)?5'
)+ 2)-6('*4 1&?5'*4 'B6&1),+*4 &+/ *03';'*7 H3' 1'C1 )+ 13'
%&%'( *'(>'* <6*1 1, 'C%5&)+ 13' /&1&4 &+/ )* *'0,+/&("7 H3'
;,(' )+2,(;&1),+ 0&+ ?' 0,;%('**'/ )+1, 1&?5'*4 'B6&1),+*4
'1074 13' *3,(1'( &+/ ;,(' ('&/&?5' 13' %&%'( =)55 ?'7
2334'**555)+,6-+3),7 !"#$ %&'()$ !""#! *+! "#$ %&! '()(*+ ,
,$ %$ -./'(0/"(0_0DB+9*BK9*` =:#(MX 0:B+BC) < H<M9:
N' =#14/5,*#1,
:+ 13' ,615)+'4 *6;;&().' 13' 0,+056*),+* ,2 13' %&%'( &* &
5)*1 ,2 *3,(1 %3(&*'* ,( *'+1'+0'*7 Q, +,1 ('%'&1 =3&1 )* )+ 13'
D'*651* *'01),+4 6+5'** *%'0)&5 ';%3&*)* )* +''/'/7 H3' Z,+9
056*),+* *'01),+ *3,65/ ?' <6*1 13&14 &+/ +,1 & *6;;&("7 :1
*3,65/ &// & +'=4 3)-3'( 5'>'5 ,2 &+&5"*)*4 &+/ *3,65/ )+/)0&1'
'C%5)0)15" 13' *)-+)2)0&+0' ,2 13' =,(I7
O' PQ."$*6"1+0/
:+056/'4 )+ 13' 0,(('01 ,(/'( 1, 0,(('*%,+/ 1, 13' ,(/'( )+
13' D'*651* *'01),+4 &55 ,2 13' %&(&-(&%3 *6?3'&/)+-* ,2 13'
\C%'();'+1&5 *'01),+7
:5D5 E/ 6,FF1*G
! S1&(1 =()1)+- %,**)?5' ,615)+'* 2,( %&%'(* "0$/@ )+ & %(,<'017
Q, +,1 =&)1 6+1)5 13' @'+/A7 H3' '+/ ;&" +'>'( 0,;'7
! U(-&+).' 13' ,615)+' &+/ 13' %&%'( &(,6+/ '&*)5" &**);)9
5&1'/ /&1&M1&?5'*4 'B6&1),+*4 2)-6('*4 *03';'*M(&13'(
13&+ &(,6+/ 1'C17
! U(-&+).' )+ ,(/'( ,2 );%,(1&+0'4 +,1 )+ 03(,+,5,-)0&5 ,(9
/'(7 $+ );%,(1&+1 /'1&)5 )+ =()1)+- %&%'(* 0,+0'(+* 13'
=')-31 1, ?' -)>'+ 1, 1,%)0*7 Y',%3"1'* ,21'+ ,(-&+).' &
%&%'( )+ 1'(;* ,2 03(,+,5,-"N 13&1 )*4 13'" -)>' & ('0)1&1),+
,2 13')( 'C%'();'+1&5 %(,-(&;4 *1&(1)+- =)13 13')( 03'(9
)*3'/ )+)1)&5 2&)56('* &+/ 5'&/)+- 6% 1, & 05);&01)0 *600'**9
265 2)+&5'7 E)*, 0..$#04) *, 4#6./"+"/@ A$#1%7 K+0$+ A*+)
+)" 6#,+ *6.#$+01+ $",5/+,4 &+/ %61 13' *'0,+/&(" ('*651*
5&1'(4 )2 &1 &557 H3' ('&/'( 6*6&55" /,'* +,1 0&(' 3,= ",6
&(()>'/ &1 ",6( ?)- ('*651*4 ,+5" =3&1 13'" &('7 S3,(1'(
%&%'(* &(' '&*)'( 1, ('&/ 13&+ 5,+-'( ,+'*7
C5 6+F% 2+#/$& +8 6$G<%
! Q, +,1 6*' +,6+* &* &/<'01)>'*N
R#+N
$H8 2,(;&1),+F ('&01),+ %(,/601
I5+N
2,(;&1),+ ,2 $H8F %(,/601 ,2 13' ('&01),+
cccccccccccccccccccccc
!"#$ %&'()$ !""#! *+! "#$ %&! '()(*+ , 2334'**555)+,6-+3),7
!""#$
! H3' =,(/ @13)*A ;6*1 &5=&"* ?' 2,55,='/ ?" & +,6+4 *,
13&1 )1* ('2'('+0' )* 'C%5)0)17
R#+N
H3)* )* & 2&*1 ('&01),+F H3)* 5'&/* 6* 1, 0,+056/'
I5+N
H3)* ('&01),+ )* 2&*1F H3)* ,?*'(>&1),+ 5'&/* 6* 1, 0,+056/'
! Q'*0()?' 'C%'();'+1&5 ('*651* 6+)2,(;5" )+ 13' %&*1 1'+*'7
R#+N
$//)1),+ ,2 =&1'( %*>", %(,/6017
I5+N
$//)1),+ ,2 =&1'( %0>" %(,/6017
! ^*' 13' &01)>' >,)0' =3'+'>'( %,**)?5'7
R#+N
:1 =&* ,?*'(>'/ 13&1 13' *,561),+ 16(+'/ ('/7
I5+N
H3' *,561),+ 16(+'/ ('/7 #$
O' ,?*'(>'/ 13&1 13' *,561),+ 16(+'/ ('/7
! Z,;%5'1' &55 0,;%&()*,+*7
R#+N
H3' ")'5/ =&* 3)-3'( 6*)+- ?(,;)+'7
I5+N
H3' ")'5/ =&* 3)-3'( 6*)+- ?(,;)+' 13&+ 035,()+'7
! H"%' &55 %&%'(* /,6?5'9*%&0'/ J+,1 *)+-5'9 ,( ,+'9&+/9&9
3&529*%&0'/K4 &+/ 5'&>' 1=, *%&0'* &21'( 0,5,+*4 &+/ &21'(
%'(),/* &1 13' '+/ ,2 *'+1'+0'*7 _'&>' -'+'(,6* ;&(-)+*7
$**6;' 13&1 =' =)55 =()1' &55 %&%'(* 6*)+- 13' *1"5' ,2 13'
$;'()0&+ Z3';)0&5 S,0)'1"7 E,6 0&+ -'1 & -,,/ )/'& ,2 13)*
*1"5' 2(,; 13('' *,6(0'*N
! E)" H#5$10/,7 S);%5" 5,,I &1 &(1)05'* )+ 13' <,6(+&5* &+/
0,%" 13' ,(-&+).&1),+ ",6 *'' 13'('7
! S$">*#5, .0."$, 3$#6 +)" %$#5.7 !" 5,,I)+- &1 %('>),6*
%&%'(*4 ",6 0&+ *'' 'C&015" 3,= & %&%'( *3,65/ @5,,IA7 :2
=3&1 ",6 =(,1' 5,,I* /)22'('+14 )1 %(,?&?5" )* +,1 =3&1 ='
=&+17
! E)" F=K T01-D##J 3#$ F5+)#$,7 ^*'2654 /'1&)5'/4 '*%'9
0)&55" 13' *'01),+ ,+ ('2'('+0'*4 %%7 V`XWaab7
: &5*, *6--'*1 ",6 ('&/ S1(6+I &+/ O3)1'4 E)" P/"6"1+, #3
K+@/" JL&0;)55&+N Y'= E,(I4 Vb`b4 X(/ '/7K 1, -'1 & *'+*' 2,(
6*&-'7 $ +6;?'( ,2 ,13'( ?,,I* ,+ *0)'+1)2)0 =()1)+- &(' )+
13' -(,6% 5)?(&("F 13'*' ?,,I* &55 0,+1&)+ 6*'265 &/>)0'4 ?61
&(' +,1 5)>'5" ('&/)+-7 H3'(' &(' &5*, *'>'(&5 'C0'55'+1 ?,,I*
,+ 13' /'*)-+ ,2 -(&%3* &+/ 2)-6('*7
- .//, 012345678 69:;<) =>?8 @ 7#$ A=<'! 09BCD9B> (0..
 pKa's of Inorganic and Oxo-Acids Chem 206
Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO)
INORGANIC ACIDS CARBOXYLIC ACIDS ALCOHOLS PROTONATED SPECIES
H2O 15.7 (32) O O
HOH 15.7 (31.2)
N+ -12.4
H3O+ -1.7 X OH MeOH 15.5 (27.9) Ph OH
X= CH3 4.76 (12.3) i-PrOH (29.3)
+
OH
H2S 7.00 16.5
CH2NO2 1.68 -7.8
t-BuOH 17.0 (29.4) Ph OH
HBr -9.00 (0.9) CH2F 2.66 +
c-hex3COH OH
HCl -8.0 (1.8) CH2Cl 2.86 24.0
-6.2
CH2Br 2.86 CF3CH2OH 12.5 (23.5) Ph CH3
HF 3.17 (15)
CH2I 3.12 (CF3)2CHOH 9.3 (18.2) H
HOCl 7.5 CHCl2 1.29 O+ -6.5
C6H5OH 9.95 (18.0) Ph Me
HClO4 -10 CCl3 0.65
CF3 -0.25 m-O2NC6H4OH 8.4 H
HCN 9.4 (12.9) O+ -3.8
H 3.77 p-O2NC6H4OH 7.1 (10.8) Me Me
HN3 4.72 (7.9) HO 3.6, 10.3 p-OMeC6H4OH 10.2 (19.1) O+ H -2.05
C6H5 4.2 (11.1)
HSCN 4.00 2-napthol (17.1) H
o-O2NC6H4 2.17 O+ -2.2
H2SO3 1.9, 7.21 m-O2NC6H4 2.45 OXIMES & HYDROXAMIC ACIDS Me
+
H
OH
p-O2NC6H4 3.44 OH
H2SO4 -3.0, 1.99 N S -1.8
o-ClC6H4 2.94 11.3 (20.1) Me Me
H3PO4 2.12, 7.21, Ph Ph
12.32 m-ClC6H4 3.83 O
N+ OH 0.79 (+1.63)
HNO3 -1.3 OH 8.88 (13.7)
p-ClC6H4 3.99 Ph N (NH)
O H Me
HNO2 3.29 o-(CH3)3N+C6H4 1.37
OH Me N OH (+5.55)
p-(CH3)3N+C6H4 3.43 Ph N (18.5)
H2CrO4 -0.98, 6.50 Me
p-OMeC6H4 4.47 Me
CH3SO3H -2.6 (1.6) SULFINIC & SULFONIC ACIDS
O
PEROXIDES
CF3SO3H -14 (0.3)
R OH O O
NH4Cl 9.24 S -2.6
R= H 4.25 MeOOH 11.5 Me OH
B(OH)3 9.23 trans-CO2H 3.02, 4.38 O
CH3CO3H 8.2
S 2.1
HOOH 11.6 cis-CO2H 1.92, 6.23 Ph OH
*Values <0 for H2O and DMSO, and values >14 for water and >35 for DMSO were extrapolated using various methods.
For a comprehensive compilation of Bordwell pKa data see: http://www.chem.wisc.edu/areas/reich/pkatable/index.htm
pKa Table.1 11/4/05 1:43 PM
D.H. Ripin, D.A. Evans pKa's of Nitrogen Acids Chem 206
Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO)
PROTONATED NITROGEN AMINES IMIDES HYDROXAMIC ACID & AMIDINES
HN3 4.7 (7.9) O O O
N+H4 9.2 (10.5) 8.88 (13.7)
NH3 38 (41) OH (NH)
EtN+H3 10.6 NH 8.30 NH (14.7) Ph N
i-Pr NH
2 (36 THF)) H
i-Pr2N+H2 11.05
TMS2NH 26(THF) (30) NSO2Ph
O O R= Me (17.3)
Et3N +H 10.75 (9.00) PhNH2 (30.6) Ac2NH (17.9) R NH2 Ph (15.0)
PhN+H3 4.6 (3.6) Ph2NH (25.0) Me
Me SULFONAMIDE
PhN+(Me)2H 5.20 (2.50) NCNH2 (16.9) HETEROCYCLES
NH (37) RSO2NH2 R = Me (17.5)
Ph2N+H2 0.78 NH (44) Ph (16.1) H (20.95) H
Me CF3 N (16.4)
6.3 (9.7) N
2-napthal-N+H3 4.16 Me
MeSO2NHPh (12.9)
H2NN+H3 8.12 H2N N (26.5) H N
GUANIDINIUM, N
(11.9)
HON+H3 5.96 HYRDAZONES,- IDES, & -INES N NH (23.0)
AMIDES & CARBAMATES
Quinuclidine N+ H 11.0 (9.80) N+H2 (13.6) NNH2 (21.6) N
O R= H (23.5) Me2N NMe2 Ph Me X= O (24) N
CH3 15.1 (25.5) X= S (13.3) HN
Morpholine O N+H2 8.36 O
(18.9) N X (18.6)
R NH2
Ph (23.3) H
Ph NHNH2 X
N-Me morpholine 7.38 CF3 (17.2)
NO2 PhSO2NHNH2 (17.2) X= O (14.8)
(urea) NH (26.9) NH
2
PhNHNHPh X= S (11.8) N
+ OEt (24.8) (26.1) N (13.9)
O2N NH3 -9.3 N
O O
PROTONATED HETEROCYCLES H X
Ph 12 (20.5) X= O (24.4)
NO2 Et N N H
(21.6) O NH N X= S (27.0)
H (12) (estimate) N N
N+ H DBU (19.8)
2.97, 8.82 + H
DABCO N+ (2.97, 8.93) O Bn N
O H S S
H
n= 1 (24.1) (20.8) DMAP H (29.4) H (16.5)
H3N+ NH +
+NH 6.90, 9.95 n= 2 (26.4) O NH + NH N N+
3
( )n Me2N NH 9.2 6.95 Me Me
+NH +NH HN
3 3 i-Pr
-9.0, 12.0 O R Me
O R= H (PPTS) 5.21 (3.4) NMe N
Proton Sponge (--, 7.50) (15) (24)
O + t-Bu 4.95 (0.90) H H
O NH NH
N (12.1) N + (18.4) N+
H Me 6.75 (4.46) Me
Me
PhCN+H -10 R Cl, H 0.72 i-Pr
*Values <0 for H2O and DMSO, and values >14 for water and >35 for DMSO were extrapolated using various methods.
For a comprehensive compilation of Bordwell pKa data see: http://www.chem.wisc.edu/areas/reich/pkatable/index.htm
pKa Table.2 11/4/05 1:43 PM
 D.H. Ripin, D.A. Evans pKa's of CH bonds in Hydrocarbons and Carbonyl Compounds Chem 206
Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO)
O
HYDROCARBONS ESTERS KETONES
(Me)3CH O O Me
53 24.5 (30.3)
X
(Me)2CH2 51 t-BuO Me Me X
O (26.5)
X= H
CH2=CH2 Ph (23.6) Ph (19.8) X= H (24.7)
50
t-BuO (18.7) (25.7)
O SPh OMe
CH4 48 (56) NMe2 (27.5)
(20.0) COCH3 9 (13.3)
N+Me3 (23.8)
46 EtO SO2Ph (12.5) Br
O O O CN (22.0)
CH2=CHCH3 43 (44) 11 (14.2) 19-20 (27.1) O
EtO Me Et Et
O
PhH 43 O O (28.3) n
13 (15.7)
PhCH3 (43) i-Pr O i-Pr
41 MeO OMe
O (27.7)
Ph2CH2 33.5 (32.2) t-Bu O Me
n= 4 (25.1)
S (20.9) (25.8)
MeO (26.3) 5
Ph3CH 31.5 (30.6)
S Ph i-Pr 6 (26.4)
HCCH 24 O O 7 (27.7)
Ph
[30.2 (THF)] 8 (27.4)
PhCCH 23 (28.8) X
LiO Ph
XC6H4CH3 X= H (24.7)
AMIDES
CH3 (24.4) (28.1)
X= p-CN (30.8) O O
(26.6) Ph (17.7)
p-NO2 (20.4) Ph COCH3 (14.2)
Me2N
O COPh (13.3) (29.0)
p-COPh (26.9) (25.9) O
SPh CN (10.2)
Me Me Me2N
O F (21.6)
(26.1) (24.9) (22.85) O
N+Me3 OMe (25.5)
Me Me Et2N
O OPh (21.1)
SPh (16.9)
CN
20 (20.1) N (17.2) SePh (18.6)
NPh2 (20.3) O
O O (32.4)
15 (18.0) (18.2) N+Me3 (14.6)
Me2N Me NO2 (7.7) Me Me
S
H2 ~36 (25.7) SO2Ph (11.4)
Me2N Me
*Values <0 for H2O and DMSO, and values >14 for water and >35 for DMSO were extrapolated using various methods.
For a comprehensive compilation of Bordwell pKa data see: http://www.chem.wisc.edu/areas/reich/pkatable/index.htm
pKa Table.3 11/4/05 1:44 PM
D.H. Ripin, D.A. Evans pKa's of CH bonds at Nitrile, Heteroaromatic, and Sulfur Substituted Carbon Chem 206
Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO)
NITRILES SULFIDES SULFOXIDES SULFONES
O O O
NC X PhSCH2X
S X S X
X= Ph (30.8) Me Ph
X= H (31.3) CN (20.8) X= H (35.1) (29.0)
Ph (29.0) X= H
CH3 (32.5) COCH3 (18.7) SPh (29.0) CH3 (31.0)
Ph (21.9) COPh (16.9) O t-Bu (31.2)
NO2 (11.8) Ph (23.4)
COPh (10.2) S X
SPh (30.8) Ph CH=CH2 (22.5)
CONR2 (17.1) SO2Ph (20.5) X= H (33) CH=CHPh (20.2)
CO2Et (13.1) Ph (27.2) (22.1)
SO2CF3 (11.0) (18.2) CCH
(11.1) POPh2 (24.9) SOPh CCPh (17.8)
CN 11 O
(28.1) (24.5) COPh (11.4)
OPh MeSCH2SO2Ph (23.4) S (12.5)
Ph CHPh2 COMe
N+Me3 (20.6) PhSCHPh2 (26.7) OPh (27.9)
SPh (20.8)
(PhS)3CH (22.8) SULFONIUM N+Me3 (19.4)
CN (12.0)
SO2Ph (12.0)
(PrS)3CH (31.3) Me3S+=O (18.2) NO2 (7.1)
Me SMe (23.5)
Me (16.3) (20.5)
HETERO-AROMATICS S SPh
S+
(30.5) Ph CH2Ph SO2Ph (12.2)
S S PPh2 (20.2)
(28.2) H
Ph SULFIMIDES & SULFOXIMINES O O
N (PhS)2CHPh (23.0) S (22.3)
NTs Ph CHPh2
S
(30.1) X S O O
N Ph Ph R (31.1)
S
S R= Me (27.6) Me Me
N X= Ph (30.7) i-Pr (30.7) O O
(26.7) O NTs (18.8)
Ph CO2Me (20.8) S
S (24.5) CF3 Me
CN (19.1) Ph Me O O
RSCH2CN O NMe S (21.8)
Ph (24.3) (33) CF3 i-Pr
N+
(25.2) R= Me S
O O
Ph Me
Et (24.0) N+Me2 S (26.6)
O- O
(23.6) (14.4) CF3
i-Pr S
Ph (30.2) (22.9) Ph Me O O
O
t-Bu O NTs (32.8)
S
PhSCH=CHCH2SPh (26.3) S (20.7) Et Et
Ph (30.0) Ph CH2Cl
S BuSH 10-11 (17.0) (PhSO2)2CH2Me (14.3)
PhSH 7 (10.3)
*Values <0 for H2O and DMSO, and values >14 for water and >35 for DMSO were extrapolated using various methods.
pKa Table.4 11/4/05 1:44 PM
D. H. Ripin, D. A. Evans pKa's of CH bonds at Heteroatom Substituted Carbon & References Chem 206
Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO) Substrate pKa H2O (DMSO)
REFERENCES
ETHERS PHOSPHONIUM NITRO
DMSO:
P+H4 -14 RNO2
CH3OPh (49) JACS 97, 7007 (1975)
MeP+H3 2.7 R= CH3 10 (17.2) JACS 97, 7160 (1975)
MeOCH2SO2Ph (30.7)
Et3P+H 9.1 CH2Me (16.7) JACS 97, 442 (1975)
PhOCH2SO2Ph (27.9) JACS 105, 6188 (1983)
Ph3P+CH3 (22.4) CHMe2 (16.9) JOC 41, 1883 (1976)
PhOCH CN
2 (28.1) Ph3P+i-Pr (21.2) CH2Ph (12.2) JOC 41, 1885 (1976)
O JOC 41, 2786 (1976)
Ph3P+CH2COPh (6.2) CH2Bn (16.2)
MeO (22.85) JOC 41, 2508 (1976)
Ph Ph3P+CH2CN (7.0) CH2SPh (11.8) JOC 42, 1817 (1977)
CH2SO2Ph (7.1) JOC 42, 321 (1977)
CH2COPh (7.7) JOC 42, 326 (1977)
SELENIDES PHOSPONATES & JOC 43, 3113 (1978)
PHOSPHINE OXIDES O2N JOC 43, 3095 (1978)
O O JOC 43, 1764 (1978)
n JOC 45, 3325 (1980)
PhSe (18.6) (EtO)2P X
Ph JOC 45, 3305 (1980)
X= Ph (27.6) (26.9) JOC 45, 3884 (1980)
PhSeCHPh2 (27.5) n= 3 JOC 46, 4327 (1981)
CN (16.4)
(PhSe)2CH2 (31.3) 4 (17.8) JOC 46, 632 (1981)
CO2Et (18.6) JOC 47, 3224 (1982)
5 (16.0)
PhSeCH2Ph (31.0) Cl (26.2) JOC 47, 2504 (1982)
6 (17.9) Acc. Chem. Res. 21, 456 (1988)
PhSeCH=CHCH2SePh (27.2) SiMe3 (28.8) (15.8) Unpublished results of F. Bordwell
O 7
Ph2P X Water:
AMMONIUM IMINES
X= SPh (24.9) Advanced Org. Chem., 3rd Ed.
N Ph J. March (1985)
Me3N+CH2X CN (16.9)
(24.3) Unpublished results of W. P. Jencks
X= CN (20.6) Ph Ph
SO2Ph (19.4) PHOSPHINES Oxime ethers are ~ 10 pka units less THF:
(14.6) acidic than their ketone counterparts JACS 110, 5705 (1988)
COPh
Streitwieser, JOC 1991, 56, 1989
CO2Et (20.0) Ph2PCH2PPh2 (29.9) See cited website below for additional
data
CONEt2 (24.9) Ph2PCH2SO2Ph (20.2)
*Values <0 for H2O and DMSO, and values >14 for water and >35 for DMSO were extrapolated using various methods.
For a comprehensive compilation of Brodwell pKa data see: http://www.chem.wisc.edu/areas/reich/pkatable/index.htm
pKa Table.5 11/4/05 1:45 PM
 DMSO Acidities of Common Heterocycles
Bordwell, ACR, 1988, 21, 456
Bordwell http://www.chem.wisc.edu/areas/reich/pkatable/index.htm
N N N N
N N N
N N N N N N
H H H H H H
23.0 19.8 18.6 16.4 13.9 11.9 18.0
O O O
O
O O O
N N N N N O N O
H H H H H H
24.0 20.8 15.0 12.1 26.4 24.0
Me
O S Me Me
S Me
S N N
H
H H H
N+
N S N Me N+ N+
H N N Me Me
H H Me Me
Me
13.3 14.8 11.8 29.4 16.5 18.4 24
Pka Table.6.cdx 11/4/05 1:45 PM