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Biochemical Education 26 (1998) 205-210

The transformation of linear to cyclic monosaccharide structures

Ronald Bentley
Department of Biological Sciences, Universityof Pittsburgh, Pittsburgh, PA 15260, USA


The two-dimensional representation of the cyclic carbohydrate structures, furanose and pyranose, and the anomeric designations
are described. Methods are represented to convert Fischer projection formulae, and both vertical and horizontal zig-zag representations to cyclic forms. 1998 IUBMB. Published by Elsevier Science Ltd. All rights reserved.

I. Introduction

Students first encounter the monosaccharides as linear

polyhydroxy structures containing either an aldehyde or
ketone function and named, respectively, as aldoses or
ketoses. The stereochemistry at the multiple chiral
centres is indicated by Fischer projection formulae
[1]; only rarely is stereochemical nomenclature used,
with the prototype, D-glucose, being (2R,3S,4R,5R)(+)-2,3,4,5,6-pentahydroxyhexanal. They also learn that
internal cyclization involving the carbonyl group and a
hydroxyl group is possible, with the formation of a cyclic
hemiacetal. Depending on which hydroxyl is used, a
hexose such as D-glucose can form a five-membered
furanose ring (4C, 10), a six-membered pyranose ring
(5C, 10), or a seven-membered septanose ring (6C, 10).
Furanose and pyranose rings predominate for the usual
monosaccharides and septanoses will not be considered
here. A structure with vertical carbon atoms and showing
the hemiacetal ring will be described as a modified
Fischer projection; for examples, see Figs 1-4.
The previously achiral C1 (in an aldose, - C H O ) or C2
(in a k e t o s e , - C O - C H 2 O H ) becomes chiral in the cyclization to the hemiacetal forming the respective structures, - C ( H , O H ) - O - and -C(HOCH2, O H ) - O - .
Thus, for each cyclic form there are two possible structures, termed anomers; the new chiral carbon is the
anomeric carbon or anomeric centre. For some carbohydrates, this possibility is easily demonstrated.
Depending on the crystallization conditions, D-glucose
can be obtained as two different pyranose anomers, ~ or
ft. The anomers are diastereoisomers with different
melting points (~, 146C; fl, 148-150C), different values
for optical rotation (all values given as [~]g~, in water,
~, i n i t i a l = + l l 2 , falling to +52.7; fl,

initial = +18.7 rising to +52.7), and with different

reaction rates in some cases (e.g. in bromine water oxidation, the rate is more rapid with the fl form).
Nomenclature for anomeric forms depended initially
on optical rotations and has a complex history. They are
now defined by relating the configuration at the
anomeric centre to that of the chiral carbon ( > C H O H )
with the highest number when the structure is displayed
as a modified Fischer projection. Hence, the relationship

Hm,,,-~:,,~1 OH

HD,-- ,~,-,~OH

3 HOD--~-,qlH

6 CH20H

HO---C-.,H I

,OH I';II ~




HD" ~ .-,~mOH
0 HOmm,,-~.,,qUH


H D,-(~ .,~OH


~ 1

5 H ==,-C -,91" ~ J

HD" C" e O_H








H -- C -- OH

H--C--OIl OH






Fig. 1. Structural representations for D-galactopyranose and

D-galactofuranose. The structures are, respectively: Fischer, A, E;
Haworth, B, C and F, G; and Mills, D, H. Although Fischer projections
are usually written without wedges and dotted bonds (see Fig. 2), they
are included here (A, E) to emphasize the impossibility of forming the
hemiacetal ring in these structures. The 'imaginary' bond, CI-O-C5 in
A and Cj-O-C4 in E is drawn simply as a solid line. The two OH groups
used for the cc-D designation are underlined; in ~-D-galactopyranose,
A, the necessary C5 OH is part of the hemiacetal ring. Haworth structures are either 'complete' (B, F) or simplified by omitting hydrogen
atoms (C, G). Hydrogens are omitted from the Mills structures (D,


0307-4412/98/$19.00 + 0.00 1998 IUBMB. Published by Elsevier Science Ltd. All rights reserved.
PII: S 0 3 0 7 - 4 4 1 2 ( 9 8 ) 0 0 0 8 2 - X

R. Bentley~Biochemical Education 26 (1998) 205-210





H-~I - O H



HOCH 2 -

HO - C-- H


HOOC - C -- OH



H--C --OH
CH 2

0 H--C --OH





HO--C --H



I -






D ,',

Fig. 2. Relationships used in anomer designations. A,

~-D-glucopyranose; B, fl-L-fucopyranose; C, ~-D-fructopyranose;
(2-keto-3-deoxyD-octanoate, abbreviated as KDO). The relevant OH groups, or the
hemiacetal oxygen from OH, are underlined.The bond directions are
not shown, but can be inferred from Fig. 1.

HD,-- C ".~1 OH

is with the chiral carbon specifying membership in the D

or L configurational series. If these two configurations
are the same with respect to the hydroxyl groups the
structure is that of the c~ anomer; examples are
~-D-galactopyranose and ~-D-galactofuranose [Fig.
I(A) and (E)]. In other words, in the ~ anomer the
anomeric OH is on the same side of the carbon chain as
the OH determining membership in the D or L series. If
the configurations are different, the structure is that of
the/~ anomer, as in/~-L-fucopyranose [Fig. 2(B)].
In the modified Fischer projections [Fig. I(A) and (E),
Fig. 2 (A-D)] the bond lengths to the ring O atom are
impossible, since the bond directions are unfavourable.
Construction of the Fischer projection requires that for
an aldopyranose the bond from C, to O is directed
behind the plane of the paper. However, the C5 to O
bond is directed above the paper [Fig. I(A)] and in
Kipling's words, "never the twain shall meet". Similarly,
in a furanose, it is the Ca to O bond that is above the
paper plane [Fig. I(E)].

2. Hexagonal and pentagonal representations

To provide a more realistic representation for a ring of

five carbons and one oxygen, Drew and Haworth in 1926

H m=.,.-C -~IOH',


H==,..-C;...,~ OH

Hm,,.. C .-,~OH

3 HO m=,,- C - ~ I H

HO m=,..-C - ~ m H

H I=," C; - , ~ OH


H ~t~.,qmO

Hm=,-- ..~mOH ,:

HOCH2==" ' ~ H ,,' '


- - I





Fig. 3. The Fischer to Haworth transformation. To bring the C5 oxygen

atom of ~-D-glucopyranose, A, into linkage with C , (see B) a rotation
about the C4-C~ bond is used. Effectively, this places C~ through C5 and
the O atom in a plane, ABCD, at right angles to the plane of the paper.
This structure is turned into the plane of the paper giving C, and
rotation about an axis through the centre of the hexagon gives the usual
representation, D.


H2N-- C-- H

~N--C -- H



H--C--OH 9

H--C--OH r



6 CH20H


"Nl~ i/
OH /





~ H2




H2NX ~ / ~ O ' ~ o O H



Fig. 4. Further examples of Fischer to Haworth transformations. The

bond directions can be inferred from Fig. 1 and Fig. 3. In
~-L-arabinopyranose, A, the terminal C5 which contributes the hemiacetal oxygen is achiral and can be simply rewritten as B, thus giving the
Haworth structure, C. In ~-D-neuraminic acid (5-amino-3,5-dideoxyc~-D-glycero-D-galacto-nonulosonic acid) rotation to the left about the
C~-C6 bond in D yields E (the C7-C~-C9 moiety is abbreviated as X)
and hence Haworth structure, F. Note that F is a D carbohydrate with
a 'down' C5 substituent. Although the rings in B and E are written to the
right, they are actually in a plane at right angles to that of the paper (see
plane ABCD of Fig. 3); these rings could equally have been drawn to
the left. One problem with Haworth structures is that it is difficult to fit
a three carbon moiety into the drawing of the hexagon.

R. Bentley~BiochemicalEducation 26 (1998) 205-210

used a hexagonal drawing [2]. The ring was in the paper

plane, O was placed to the right, and the carbon atom
sequence around the ring was counterclockwise (lefthanded). Subsequently, Haworth reoriented the ring to
be at right angles to the paper plane and projecting
towards the viewer, and with substituents above or below
the ring plane [3]. Moreover, the carbon atom
numbering was clockwise. For a six-membered ring only
C5 and the O atom were actually in the plane of the paper
and for a five membered ring, only the O atom was in the
paper plane. It was Haworth who coined the name,
pyranose, for the six-membered rings (from the structure
of pyran) andfuranose for the five-membered rings (from
the structure of furan). The Haworth formulae have
been very widely adopted. The planar arrangement is a
fairly realistic representation for a furanose, but (as
Haworth realized) a planar arrangement for a pyranose
is structurally unrealistic. In a 'complete' Haworth structure, thickened bonds indicate the placement of the
pyranose or furanose plane and all substituents are
shown [for D-galactose, see Fig. I(B) and (F)]. More
commonly, the bond thickening is omitted as are the
hydrogen atoms [Fig. I(C) and (G)].


ties to students. The structure must be rearranged so that

the carbons and the oxygen of the ring are in the same
plane, keeping in mind the conventions employed in
~-D-glucopyranose [Fig. 3(A)], a rotation about the C4
to C5 bond is performed so that the bond to the C5
oxygen is pointing behind the plane of the paper, and in
the same plane as the bond to oxygen from C~. This
rotation does not change the configurational relationships but places the structure in a conformation different
from that required for a Fischer projection. The oxygen
atom is now in a plane (ABCD) at 90 to the paper plane
which also contains carbon atoms C~ to C5 [Fig. 3(B)]. If
this plane is turned into the plane of the paper, Fig. 3(C)
results and by further rotation of the structure through a
central axis the usual Haworth representation is obtained
[Fig. 3(D)]. More simply, after rearranging to Fig. 3(B),
a basic pyranose framework is drawn; all the groups to
the left of the carbon chain are placed (in proper order)
above the Haworth plane, those to the right below. As
noted earlier, H atoms are usually ignored. This process
can be generally applied as shown for ~-L-arabinopyranose [Fig. 4(A-C)] and c~-D-neuraminic acid [Fig.
The following points should be kept in mind:

3. Mills structures

In a representation proposed by Mills, the rings were

projected into the plane of the paper and the orientation
of groups (above or below) was indicated by darkened or
broken lines [4,5]. His intent was to regard pyranoses as
analogues of alicyclic compounds and to use a uniform
representation system. Thus, he wrote "To point the
analogy, we project these acetals in the manner
customary for terpenes and steroids." [4]. Stoddart [6] in
1971 was apparently the first to use the now preferred
standard stereochemical symbols of darkened 'wedges'
(to indicate above or front) and dashed lines (to indicate
below or back) [7]. Hydrogen atoms are generally
omitted [for D-galactose, see Fig. I(D) and (H)].
Although used exclusively in Stoddardt's text [6], the
Mills structures have found little favour even though
similar representations are widely used for other cyclic
natural products (e.g. alkaloids, steroids, terpenes).
Transposition between Haworth and Mills structures is
no problem. A Haworth 'up' OH (or other substituent)
or a 'down' OH become, respectively, "~OH and ---OH
in Mills representations. The Mills structures will be
useful in what follows and it is suggested that their
general use would have many advantages.

4. Rules for drawing structures

The construction of a Haworth structure from a given

modified Fischer projection sometimes presents difficul-

(1) Depending on the configuration of the OH being

used for ring construction, the hemiacetal ring will
be drawn either to the left or to the right of the
carbon chain in the modified Fischer projection. A
'right' (or 'left') hemiacetal ring indicates the D (or
L) configuration only if the OH defining membership in the D or L series is involved in ring construction. For example, there is a 'left' oxide ring in the
structure of D-neuraminic acid [Fig. 4(D)]. When
the structure has been rearranged so that the bonds
to the ring oxygen are both vertical [i.e. the ring is in
a plane at right angles to the paper plane as shown in
Fig. 3(B)] it is immaterial whether the ring is drawn
to the left or to the right.
(2) Because of the defined relationship between the
anomeric OH and the OH indicating membership in
the D or L series, the anomeric descriptor does not
change when an enantiomer is formed. For the
hypothetical carbohydrate, iupacose, the enantiomer
of ~-D-iupacopyranose is ~-L-iupacopyranose. A
further consequence is that the ~ fl descriptors
should only be used in conjunction with the configurational descriptor. Hence, methyl /~ glucoside is
not acceptable: it should be either methyl
/3-D-glucopyranoside or methyl fl-D-glucofuranoside.
(3) The anomeric configurations may be defined in
terms of the Haworth or Mills representations (Fig.
5). In a Haworth structure, drawn specifically with
the carbon atom numbering increasing in a clockwise


R. Bentley~BiochemicalEducation 26 (1998) 205-210





<-7 (05
, 8 - D or u - L
Fig. 5. Anomericdesignation in cyclicstructures.The numberingshown
refers to an aldose; for a ketose, numbering starts at 2 at the anomeric
position. The drawings show Haworth structures; to obtain Mills structures replace the 'down' OH in the top drawings with a dashed bond
and OH to the side and the 'up' OH in the bottom drawings with a
wedge bond and OH to the side.

(right handed) direction when viewed from above,

the ~ - D anomer has the C, O H (aldose) or C2 O H
(ketose) below the ring plane and t h e / 3 - D anomer
has this group above the ring plane. In the L configurational series this situation is reversed; the ~ - L
anomer has the anomeric O H above the plane, and
the/3-L has the anomeric O H below the plane. If the
D or L nature of the carbohydrate is known, the
position of the anomeric O H specifies ~ - D o r / 3 - L if
below a n d / 3 - D or c~-L if above. If configurational
series membership is unknown the position of the
anomeric O H cannot distinguish between ~ - D and
/3-L and between /%D and ~-L. With clockwise
numbering when viewed from above, the same
considerations apply to Mills structures. Thus, in Fig.
I(D) and (H), the 'down' C1 O H ( - - O H ) indicates
~-D-galactopyranose and ~-D-galactofuranose,
At first glance, it seems strange that a simple
hexagon or pentagon with a single indication of
chirality (at C1 for an aldose, C2 for a ketose) conveys
information about two chiral positions. While in
some cases, the O H determining D or L series
membership is actually a part of the ring structure
(e.g. D-glucopyranose, D-galactopyranose), in other
cases it is not (e.g. D-glucofuranose, D-galactofuranose, L-arabinose). Since the ~ /3 definition
involves a direct connection with the configuration at
the chiral carbon providing the D or L information,
an ~ anomer has the anomeric O H on the right side
of the carbon chain in modified Fischer projection
and effectively has the D configuration. The

anomeric O H group, therefore, becomes a 'down'

pointing group in the Haworth or Mills structure
(with the specified clockwise numbering).
(4) Students often assume the non-hydroxyl substituent
must be 'up' for a D carbohydrate; i.e. for a furanose
at C4 (aldose) or C5 (ketose) and for a pyranose at C5
(aldose) or C6 (ketose). This holds true only if the
hemiacetal ring is formed with the O H group that
defines membership in the configurational series.
Whether this substituent is 'up' or 'down' depends
~-D-galactofuranose [Fig. I(G)] the C5-C6 moiety
at C4 is 'down'. This is also the case for the ketopyranose, ~-D-neuraminic acid, where the CT--Cs--C 9
moiety at C6 is down [Fig. 4(F)].
(5) The nomenclature describes the actual configuration
at the anomeric position. The absolute configuration
at C1 in ~-D-glucopyranose is known to be S.
(6) The ~ fl definition is admittedly confusing and is
certainly not elegant. An attempt to use the R S
system states that if the highest numbered chiral
centre is R (or S), the ~ anomeric O H will be S (R);
if the two chiral centres are RR or SS, the structure is
the/3 anomer [8]. Unfortunately, this approach has
very limited validity because of the vagaries of the
sequence rule. Thus, for ~-D-glucopyranose, as
already noted, C1 = S, and Cs = R; however, in
~-D-glucopyranose 6-phosphate, C1 and C5 are
both S; in ~ - D - n e u r a m i n i c acid, C2 and C8 are both

5. More realistic representations

More realistic representations of linear monosaccharides are either vertical or horizontal zig zag
projections [1]. These projections can also be manipulated on paper to yield cyclic Mills and Haworth structures. As in the F i s c h e r ~ H a w o r t h transform, the
drawing must be rearranged so that the ring carbon
atoms and the oxygen atom are coplanar. It is convenient
to write an arbitrarily chosen configuration at the
anomeric centre and determine later whether it represents the ~ or /3 form. A rather detailed description
follows for the transformation of the vertical zig zag
projection of D-glucose to cyclic types. In actual
practice, some of the operations can be combined. In the
following description, A, B, C, etc, refer to the drawings
of Fig. 6.
(a) Redraw the original D-glucose structure, A, with
the O H group that will provide the ring oxygen atom
in the plane of the paper to give B.
(b) Construct the hemiacetal ring, C, writing an
arbitrarily chosen configuration at the anomeric

R. Bentley~Biochemical Education 26 (1998) 205-210




.o. _OH





14" ~
"" r , OH OH


C \








- OH










,o jc .,jo,



















Fig. 6. Transformation of a vertical zig zag projection to cyclic structures. Drawings refer to D-glucose, A, with specific operations
described in the text. Anomeric assignment could also be done more
simply on the basis of the Haworth structure, H, or Mills structures F or
G (but not E which has counterclockwise numbering). The 'down'
anomeric OH group for D-glucose, indicates the anomer (Fig. 5).

(c) The carbon and oxygen atoms in C are now in the

required plane, but still in a zig zag arrangement.
Make a further rearrangement to form a (roughly)
circular arrangement as in D; C3 must be swung to
the left by rotations about the C2 to C3 bond and the
C3 to C4 bond. This operation does not change the
configuration at C3; however, in the new conformation the O H which was above the plane in C is now
below the plane in D.
(d) Redraw as a Mills hexagon, E. This is a stereochemically correct diagram and could be used as it stands.
However, to transform to the conventional arrangement with O in the top right hand position, rotate
180 about the axis joining C3 and O to yield F and
then about the axis at right angles to the paper plane
and through the centre of the hexagon forming G. If
desired, redraw as Haworth structure, H.
(e) Determine the relationship between the configuration of the anomeric O H and the O H determining
membership in the configurational series (the chiral
centre of highest number). From structure C, dissect
out the sequence C2-C~-O (I) and from A the
sequence, C 6 - C 5 - C 4 (J). These partial structures are
both drawn in a vertical line with C1 at the top, C6 at
the bottom, exactly as in a Fischer projection; the C5
oxygen is drawn as it was prior to cyclization (i.e. as
OH). Since the two hydroxyls at C1 (I) and Cs (J) are
both on the same side (right), structures E - H all
represent c-D-glucopyranose. Alternatively, the
anomeric descriptor is obtained from the Haworth
structure, H, since it was posited that the carbohydrate was in the D series. Mills structures F or G
could also be used, but not E in view of the counterclockwise numbering.
While this procedure seems lengthy, with practice
several of the structures drawn for the detailed

Fig. 7. Transformation of a horizontal zig zag projection to cyclic

structures. The process is illustrated for D-galactose. Steps 1 and 2
described for Fig. 6 (see text) have been combined in the A ~ B change
and steps 3 and 4 for B--*C. The necessary rotations to give the conventional Mills structure, E, are C--*D (turning C about the O-C3 axis) and
D ~ E (rotation about the central axis of the hexagon). The stereochemical information in G is derived from inspection of B and in H
from inspection of A. Anomeric assignment could also be made from
Haworth structure, F, or Mills structures D or E. The 'down' anomeric
OH group for a D carbohydrate, indicates the ~ anomer (Fig. 5).

procedure can be left out. Fig. 7 shows some possible

abbreviated procedures for the horizontal zig zag projection for D-galactopyranose, and Fig. 8 for
D-glucofuranose and D-fructofuranose. It is often
convenient to make such transformations on paper, but

6 CIH20H


x = ~,- . 1OH

OH 5 H
, / 0. \I .l 0









6 CH20H
I "o OH


R= CH20H (lot 6)

Fig. 8. Further transformations of horizontal zig zag projections. Parts

of the structures have been abbreviated; in A, the grouping - C H O H CH2OH is denoted by X, and in E, the two CH2OH groups are denoted
by R. Steps 1-3 for Fig. 6 (see text), have been combined. For
D-glucofuranose, A, C2 has to be moved out of the zig zag arrangement to give B directly. By rotation about the C~-C4 axis, the Mills
structure, C, is obtained, and hence the Haworth structure, D. The
structures A - D all show the ~ anomer ('up' OH group) of D-glucofuranose. When the O atom of the hemiacetal ring is below the carbon
chain with left to right numbering, A, the required clockwise sequence
in the cyclic form, B, is obtained directly. Note also that when a
non-hydroxyl substituent has more than one carbon, the Mills style
shown for ct-D-galactofuranose [Fig. I(H)] can be used. For
D-fructofuranose, E, C3 has to be moved out of the zig zag arrangement to give F. Rotation around the central axis of the pentagon gives
Mills structure, G and hence Haworth structure, H, for


R. Bentley~Biochemical Education 26 (1998) 205-210

the use of models is strongly r e c o m m e n d e d w h e r e v e r

6. T h e future

We are long past the time when Fischer had to represent stereochemistry within the confines of 19th century
printing techniques and without knowledge of actual
(absolute) configurations. As we a p p r o a c h the 21st
century, should we not consider a b a n d o n m e n t of the
long revered Fischer projections and H a w o r t h structures? They have served their p u r p o s e nobly, but "times
they are a'changin'" [9]. With the aid of computers,
linear m o n o s a c c h a r i d e s can be easily and accurately
r e p r e s e n t e d by vertical or horizontal zig zag projections,
and cyclic forms by Mills structures; although not
discussed here, conformational representations can also
be used in m a n y cases. A text of organic chemistry has
taken a small step in this direction using horizontal zig
zag projections for a brief description of glycolysis (but
without specifying the stereochemistry) and for reactions
of the tricarboxylic acid cycle [10]. An opportunity exists
for a text of biochemistry/molecular biology in which
furanose and pyranose structures would be in the same
style as those used for other cyclic materials, and linear
materials (e.g. a m i n o acids, carbohydrates, fatty acids)
would be in zig zag projections in h a r m o n y with those
often used for terpenes. With no disrespect for Haworth,
it can also be argued plausibly that Mills representations

are m o r e elegant than the H a w o r t h structures. T o this

writer, this is the case when the two types are directly
c o m p a r e d , for example in the D - g a l a c t o s e [Fig. I ( D ) vs
(B) or (C) and (H) vs (F) or (G)] or D - g l u c o s e cases
[Fig. 6(G) vs (H)]. If such styles were a d o p t e d generally,
learning might be easier, if not m o r e interesting, for
coming generations of students.


[1] R. Bentley, Are Fischer projection formulas really necessary?

Biochemical Education 25 (1997) 216-220.
[2] H. D. K. Drew, W. N. Haworth, A critical study of ring structures
in the sugar group. Journal of the Chemical Society (1926)
[3] W. N. Haworth, The Constitution of Sugars, Longmans, Green
and Co, New York, NY, 1929.
[4] J. A. Mills, Conformations of cyclic acetals. Chemistry and
Industry (1954) 633-634.
[5] J. A. Mills, The stereochemistry of cyclic derivatives of carbohydrates. Advances in Carbohydrate Chemistry 10 (1955) 1-53.
[6] J. F. Stoddart, Stereochemistry of Carbohydrates, Wiley-Interscience, New York, NY, 1971.
[7] Anon. Basic terminology of stereochemistry (IUPAC Recommendations 1996), Pure and Applied Chemistry 68 (1996)
[8] H. S. E1 Khadem, Carbohydrate Chemistry, Academic Press, San
Diego, CA, 1988, p. 32.
[9] Bob Dylan, (Zimmerman, R.), Times they are a-changin'. Title of
a song, 1963.
[10] M.A. Fox, J. K. Whitesell, Organic Chemistry, Jones and Bartlett,
Sudbury, MA, 2nd edn, 1997.